Neuroscientifically Challenged

Neuroligin and Autism

2010-09-19T00:37:00.007-04:00

The rapid increase in autism spectrum disorder (ASD) diagnoses over the last 15 years is alarming. A number of reasons for the rise have been suggested, some of which have sparked debate that occasionally becomes laden with vitriol. Many people, surprised and frightened by what they see as the unprecedented appearance of a novel disorder, are looking for answers and pointing fingers at parties they feel may be culpable. The etiology of ASD is unknown, and perhaps we will find that some of the impassioned claims made by groups like Generation Rescue are valid. But the idea that the emergence of such a disorder occurred overnight is not completely accurate.

Perhaps the earliest documented case of autism was that of Hugh Blair in 1747 (he was 39 at the time). Over the years other cases were identified, while many were misdiagnosed (frequently as infantile schizophrenia). In the 1940s, Leo Kanner and Hans Asperger developed the foundation for the modern diagnosis of autism by laying out a clearer description of the disorder. Interestingly, Kanner was disturbed by how quickly the rate of diagnosis of new cases of autism rose after his paper was published. This was in the 1950s. Since then, of course, the diagnosis has been refined and subsequently broadened, resulting in the class of ASDs we are familiar with today. In many ways, the history of autism up to this point is not so different from the history of other debilitating disorders like schizophrenia in that it consists of slow acknowledgement of a unique set of symptoms, followed by attempts at classification and an increase in the number of diagnoses due to clearer diagnostic criteria.

How the story of autism plays out is yet to be seen. But as the debate over vaccines and other potential causes continues to smolder, science is plodding along attempting to develop animal models for the study of the disorder. Several genetic mutations have been associated with ASDs. Mutations in genes that encode for proteins involved in the healthy functioning of synapses, called neuroligins and neurexins, have been directly linked to ASD. The result has been that many now classify the disorder as a synaptopathy, or a disease that is primarily caused by synaptic dysfunction. This has also led to the development of neuroligin-3 knockout (KO) mice as a rodent model for ASD.

A study in this month’s issue of The Journal of Biological Chemistry goes a step further in determining exactly how mutations in neuroligin can result in synaptopathies. The group coerced cultured neurons to express neuroligin mutations, which caused the protein to be folded improperly after it was manufactured. Furthermore, the misfolded proteins were not sent from the cell body out to the limits of the neuron. Thus the dendrites had a dearth of the protein, a factor that could be at least partly responsible for the unhealthy synaptic function that occurs when the neuroligin gene is mutated.

Protein misfolding is a culprit in Alzheimer's and Parkinson's disease as well, among others. While this study is an important step toward understanding autism, there are many more questions to be answered about how dependent the disorder may be upon protein misfolding and what other factors may be contributing to its variety of symptoms. And unfortunately attempts at developing treatments for protein misfolding diseases have not yet met with much success. Regardless, this is a positive development in understanding ASDs, a task that remains important not just for their treatment but for quelling the anxiety of a public struggling to understand the troubling incidence of the disorder.

De Jaco, A., Lin, M., Dubi, N., Comoletti, D., Miller, M., Camp, S., Ellisman, M., Butko, M., Tsien, R., & Taylor, P. (2010). Neuroligin Trafficking Deficiencies Arising from Mutations in the / -Hydrolase Fold Protein Family Journal of Biological Chemistry, 285 (37), 28674-28682 DOI: 10.1074/jbc.M110.139519

The Many Sides of GABA

2010-09-09T16:28:00.004-04:00

If you have a superficial level of knowledge about neuroscience, you probably won’t associate psychostimulants with gamma-aminobutyric acid (more commonly known as GABA). Just as you learn in early biology that a mitochondrion is the “powerhouse of the cell”, you learn in early neuroscience that GABA is the “primary inhibitory neurotransmitter of the brain”. And while this is often true (exceptions are being found on a regular basis), it perhaps doesn’t do justice to the diversity of roles that GABA can play.

There are, for example, many instances of GABA having an inhibitory effect on another inhibitory neuron. This can in effect stop the inhibition, potentially allowing for excitation by another neurotransmitter. Exactly this happens every time you make a voluntary movement. Neurons in the striatum release GABA that inhibits the action of neurons in the globus pallidus. These neurons normally inhibit areas of the thalamus that are necessary for movement but when they are inhibited the thalamus is essentially freed up, allowing us to move.

So, GABA-ergic actions don't necessarily mean inhibition as an end result. This is also true when it comes to the addictive properties of drugs. Dopamine (DA) neurons in the nucleus accumbens (NAc) directly modulate GABAergic connections to the ventral pallidum (VP), which itself sends GABAergic projections back to the NAc. Thus, it is easy to imagine that influencing DA transmission in the NAc, an inevitable outcome of drug use, also has an effect on GABAergic activity throughout the reward system.

Because of this, researchers like Claire Dixon and colleagues have been interested in how GABAa receptors are affected by the administration of drugs like cocaine. In a study published earlier this year in PNAS, Dixon et al. used knockout (KO) mice that had the gene for the alpha2 subunit of the GABAa receptor deleted. GABAa receptors containing these subunits are highly expressed in the NAc.

While these KO mice still demonstrated a stimulant response to cocaine (based on locomotor assays), they failed to show sensitization to the drug, i.e. their activity remained the same on repeated administrations while the wild-type (WT) mice's activity progressively increased. Additionally, cocaine's ability to facilitate conditioned reinforcement (lever pressing) was vastly reduced in the KO mice.

This indicates that GABA may have a role in mediating an addictive response to drugs. The authors hypothesize that the ability of cocaine to increase behaviors associated with environmental cues connected to the drug (lever pressing), and with conditioned activity (sensitization), may depend upon GABAa receptors. Alpha-2 subunits may allow cocaine to strengthen the association between cues and a drug, an association that underlies some of the most compulsive aspects of addiction. Thus, perhaps GABA receptors represent a potential, if not unlikely, target for treating addiction.

Dixon et al. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAa receptors. PNAS, 107, 2289-2294.

Encephalon Celebrates its Emerald Anniversary

2008-09-29T01:50:00.007-04:00

Welcome to a landmark edition of Encephalon, the cream of the crop of brain science blog carnivals. This is the 55th edition of Encephalon, an anniversary achieved by less than 5% of married couples. Thus, this edition is a testament to the dedication of neuroscience bloggers: they don’t even take vows, yet they still stay committed to providing their readers with scintillating perspectives on developments in brain science. While more than 95% of married couples give up before their emerald anniversary, brain bloggers keep typing away, upholding their pledge to inform. (We will conveniently disregard the fact that Encephalon occurs biweekly, not annually, which, if considered, would make the analogy to marriage somewhat ridiculous.) Anyway, on to a selection of the best and brightest neuroscience blogs from the last couple of weeks.

Jeremy, a contributor to SharpBrains, provides a superbly written piece about assessing the affects of video games on adolescents. The rational perspective is greatly appreciated.

Greg from Neuroanthropology discusses neuroplasticity, and why the process has been oversimplified, the term overused, and the hype a little unjustified (hmmmm...this reminds me of mirror neurons).

The Neurocritic applies his caustic wit to the sensationalism that surrounds studies of the underlying personality traits of liberals and conservatives.

Cognitive Daily looks at a study of teenagers' sexual behavior. Listen up, abstinence-only advocates...

Dr. Shock MD reviews targets in the brain for deep brain stimulation, an intriguing treatment for highly resistant depression.

Mo at Neurophilosophy has an excellent and thorough discussion of a fascinating disorder: developmental topographagnosia.

Brain Blogger contributes its usual group of insightful posts. One discusses the potential antipsychotics may have in reducing the risk of suicide in depressed patients, something that current antidepressants fail at doing (they sometimes actually increase it). Another examines a little-known treatment for diabetes: the ketogenic diet.

Neuronism continues to impress with well-written contributions to Encephalon. This one is an overview of computational neuroscience, a little-understood but increasingly important field.

Dan at Sports are 80 Percent Mental is exceptional at getting us to consider the neuroscience of sports. This time he describes the success of different cognitive strategies in golf.

The Mouse Trap has two interesting postings about 8 common adaptive problems that drive evolution across species, they are here and here. Another post discusses a suggested expansion of the big five personality traits.

That's it for the emerald edition of Encephalon. Thanks for all your submissions! The next edition will be hosted by Combining Cognits on October 13th. Send your submissions to encephalon {dot} host {at} gmail {dot} com.

Encephalon #55 Call For Submissions

2008-09-22T21:59:00.002-04:00

Encephalon #55 will be hosted here next Monday--I may be too lazy to post original material, but I'm not too lazy to post links to other people's stuff! Please send potential postings to encephalon {dot} host {at} gmail {dot} com.

A Brief Hiatus

2008-09-05T23:20:00.003-04:00

Anyone who reads this blog regularly will have noticed that the frequency of posts has slowed quite a bit over the past few weeks. The truth is, between two jobs, an assistantship, classes, and my thesis I've occasionally had trouble finding time to eat and sleep, much less blog. So, I'm taking a brief hiatus to get my priorities under control. I'm definitely not closing up shop, and will still be hosting the 55th edition of Encephalon here on September 29th. Check back occasionally until then...thanks!

Have a Face Only a Mother Could Love? Without Serotonin She Thinks You're Just as Ugly as Everyone Else Does

2008-08-27T22:44:00.007-04:00

As the popularity of antidepressant medication has burgeoned over the past few decades, serotonin has become one of the more publicly recognized neurotransmitters. Along with that popularity has come a trend of attributing a wide variety of behaviors (especially depression) to “serotonin imbalances”. While this is a gross simplification in most cases, it does seem to be clear that there is a correlation between serotonin transmission and behavior.

A group of researchers at Case Western Reserve University has recently shown that the disruption of serotonergic function in mice is powerful enough to inhibit one of their strongest instincts: caring for their young. They used female mice with a mutation that causes a reduction in the expression of serotonergic genes and in the synthesis of the neurotransmitter, and monitored the survival of their young after they gave birth.

99% of the pups of the wild-type (normal) mice lived past the nurturing period of youth, but none of the pups of the serotonin-inhibited mothers survived. In fact, most of them were dead after 3-4 days. When the researchers took pups born to the serotonin-deficient mothers and gave them to the wild-type mothers to raise, the pups survived. The serotonin-deficient mothers failed to nurse their pups, didn't build nests for them, and didn't organize them near her in a huddle (which is necessary for their warmth and survival).

The serotonin-inhibited mothers did not seem to exhibit deficiencies in any other behavioral assay, such as maze-running or olfaction. They were not deemed to be overly anxious as measured by locomotor tasks, but instead of mothering they often simply paced the cage and engaged in repetitive digging. The authors suggest that anxiety behaviors may have been more prominent if not for the relaxing effect lactating has on rodents.

How applicable these findings are to humans is, of course, completely unclear. Postpartum depression is often treated with selective serotonin reuptake inhibitors, but even if untreated doesn’t generally lead to abandonment of one’s children. Regardless, finding a neurochemical substrate for an instinct like caring for one's young is notable, as it is a behavior essential to what is widely considered the goal of existence: high reproductive fitness.

Reference:

Lerch-Haner, J.K., Frierson, D., Crawford, L.K., Beck, S.G., Deneris, E.S. (2008). Serotonergic transcriptional programming determines maternal behavior and offspring survival. Nature Neuroscience, 11(9), 1001-1003. DOI: 10.1038/nn.2176

Cocaine and Glutamate, Part Two

2008-08-18T22:33:00.004-04:00

Ten years ago, if you had asked a neuroscientist what neurotransmitter is most important to the development of an addiction, nine out of ten times they would have said “dopamine”. Ask the same question today, however, and you’ll probably be told that it is impossible to pin such a complex process on one neurotransmitter, as clearly (at least) both dopamine and glutamate are integral to the addiction process.

In hindsight, it is not surprising that glutamate be involved in addiction. Glutamate is the most abundant excitatory neurotransmitter in the brain. It is utilized in a number of cognitive processes, but essential to synaptic plasticity, and thus to learning and memory. And addiction is really just a type of learning—perhaps learning gone haywire, but learning nonetheless. It involves the association of a positive experience with the drug that was taken to induce it, resulting in a seeking of the drug to reproduce the experience. In addiction, however, unlike other learning processes, this seeking becomes obsessive and compulsive.

It is now thought that cocaine use causes glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA), a midbrain region of the reward system, to become stronger—even after just a single use. This makes the dopamine neurons there more sensitive to glutamate, causing a hyper-sensitivity to cocaine that results in addiction. It is believed the strengthening of these glutamatergic synapses involves changes in the composition of subunits of glutamate receptors.

In order to shed more light on the specifics of this subunit restructuring, a study published last week in the journal Neuron investigates the behavioral results of changes in glutamate receptor structure. The authors created genetically engineered mice that lacked one of three types of glutamate receptor subunits: GluR1, GluR2, or NR1.

As expected, they found that cocaine-induced strengthening of synapses on dopamine neurons was dependent on the functionality of glutamate receptor subunits, specifically the GluR1 and Nr1 subunits. They also, however, made two major discoveries. First, deletion of the GluR1 subunit caused the extinction of cocaine-seeking behavior to be slowed. Thus, these mice continued to seek cocaine long after cocaine had been withheld from them, when normal mice had already “forgotten” about the drug. By extension, this might mean that pharmacological stimulation of this receptor could have potential as a treatment for addiction.

Additionally, they found that the NR1 receptor subunit was necessary for the reinstatement of drug-seeking behavior after extinction. This is analogous to relapse behavior in humans. Once again, this could have pharmacological potential in addiction treatment.

Of course, these pharmacological applications, if viable, will take some time to work out. As you can imagine, it will not be easy to create a treatment that can selectively inhibit specific subunits on glutamate receptors in a particular brain region (although this can and has been done with other receptor subunits). And, with how important glutamate is to learning in general, there is potential that a treatment aimed at glutamate receptors could disrupt other cognitive processes. So, if you’re waiting for a pill to solve your cocaine problem, you may have to wait a while longer. A cocaine vaccine (see here) may be available first.

Reference:

ENGBLOM, D., BILBAO, A., SANCHISSEGURA, C., DAHAN, L., PERREAULENZ, S., BALLAND, B., PARKITNA, J., LUJAN, R., HALBOUT, B., MAMELI, M. (2008). Glutamate Receptors on Dopamine Neurons Control the Persistence of Cocaine Seeking. Neuron, 59(3), 497-508. DOI: 10.1016/j.neuron.2008.07.010

Encephalon #52 at Ouroboros

2008-08-18T16:53:00.003-04:00

Encephalon #52 is up at Ouroboros, a science blog that focuses on the biology of aging--which is also my current area of research! Check it out...

Why You Can't Remember Where Your Keys Are

2008-08-14T22:45:00.004-04:00

Why do we remember? To some this might seem like a ridiculous question. Memory is so intricately intertwined with our conception of existence that it is difficult to objectively ask questions about why we developed the capacity for it, or to imagine the possibility of a life without it. If one is to assume, however, that like every other facet of the human condition, memory evolved from rudimentary beginnings, then “why do we remember?” becomes not only a reasonable question, but an important scientific inquiry.

Looking at memory from an evolutionary standpoint, one must assume that it developed to serve an adaptive purpose. Of course, when one begins to cogitate on what that purpose might be, it is easy to stumble into purely speculative territory. Evolutionary psychologists have received much criticism for this. Examples of hypotheses about evolutionary origins gone wrong shouldn’t serve to negate the efforts of the entire field, however, it should just encourage a more cautious approach.

Two psychologists from Purdue University, James Nairne and Josefa Pandeirada, published an article in this month’s Current Directions in Psychological Science that describes their lab’s approach to the evolution of memory. It attempts to avoid blatant speculation by beginning with simple hypotheses about the purposes of memory, and testing their validity before moving on to more complex explanations.

They start with three basic assumptions that an evolutionarily adaptive perspective on memory would require. The first is that memory probably didn’t evolve just to recall the past. In other words, memory must serve a purpose, allowing us to predict the probability of future events given certain circumstances. Second, memory should be governed by priorities. We shouldn’t remember all environmental stimuli with equal clarity. This would lead to a maladaptive inability to remember the most salient stimuli, and would clutter our memories with unimportant details about our environment. Third, memory should assign the highest salience to environmental stimuli that improve reproductive fitness and evolutionary adaptiveness. So, those things in our environment that have historically proven to be the most important for survival should garner the most mnemonic attention.

Based on these assumptions, Nairne and Pandeirada conducted behavioral experiments to determine if survival-related processing enhances retention. After an initial study indicated that participants were able to remember survival-related words better than other words that required a similar level of processing, the researchers designed a large study that compared survival processing to some of the most renowned mnemonic techniques, like imagery and the use of autobiographical cues. They found that survival processing resulted in higher average recall rates than any of the other techniques tested.

So perhaps we remember because it allows us to predict where danger might lie, who we can trust, successful ways to court a mate, how to obtain food, etc. Maybe this seems obvious, but it only becomes so with a little thought. Our inherent predisposition toward an anthropocentric view of the world often causes us to unconsciously regard our mnemonic abilities as above the laws of science and the progression of evolution. We don’t usually think of our memory as evolving in the same way that our bodies have, but the idea that we have developed context-specific cognitive modules through evolution is becoming hard to ignore. Then again, perhaps there is a reason we have a tendency to ignore such explanations for our cognitive abilities. Anthropocentrism may be adaptive in its own right.

Reference:

Nairne, J.S., Pandeirada, J.N. (2008). Adaptive Memory: Remembering With a Stone-Age Brain. Current Directions in Psychological Science, 17(4), 239-243. DOI: 10.1111/j.1467-8721.2008.00582.x

Cocaine's Addictive Influence Begins Even Before Euphoria

2008-08-11T22:12:00.008-04:00

It has long been known in the addiction field that exposure to drug-associated stimuli, commonly referred to as relapse triggers, is one of the primary causes of relapse in abstinent addicts. Neuroscience studies have added evidential support for this perspective by providing a molecular explanation for it. It is thought to principally involve two neurotransmitters: dopamine and glutamate, and a region of the reward system called the ventral tegmental area (VTA).

The VTA is part of the midbrain, and two major dopamine pathways—the mesolimbic and mesocortical—run through it. It is chock full of dopamine, glutamate, and GABA neurons. When a subject who has acquired the self-administration of a drug like cocaine is exposed to environmental stimuli they have associated with the drug, glutamate and dopamine are released from the VTA. This rush of neurotransmitters activates another area of the reward system, the nucleus accumbens, and usually leads to an attempt to reinstate drug-using behavior.

As might be expected, cocaine use itself also results in increased dopamine and glutamate transmission in the VTA. Interestingly, however, this increased neurotransmitter activity begins before the pharmacological effects of cocaine can occur. While it takes about 10 seconds for cocaine to cross the blood-brain barrier and exert its psychotropic influence, dopamine levels rise almost immediately. Thus, it would seem that the reinforcing qualities of the drug may not be solely attributable to the euphoria it produces.

Roy Wise, Bin Wang, and Zhi-Bing You published an article last week in PloS One that investigates this phenomenon. They injected cocaine methiodide (MI)—an analogue to cocaine that does not cross the blood-brain barrier to have a psychotropic effect—into rats and measured the resultant changes in neurotransmitter levels.

In rats that had never been exposed to cocaine, the MI had no effect. But in those that had previously acquired cocaine self-administration, the MI caused VTA glutamate release. It was also enough to cause these rats to reacquire cocaine-seeking behavior that had been rendered extinct.

This study speaks to the complexity and potency of the inclination toward relapse. While it has been known that external cues can cause changes in brain chemistry that predispose one toward relapse, this is the first evidence that internal cues (besides the actual rewarding mental influences of the drug) may also play a role in reinstating drug use. Fortunately, these added influences can be avoided by continued abstinence from the drug. But once a drug is used, how pleasurable the resultant experience is may have little to do with the re-emergence of drug cravings.

Reference:

Roy A. Wise, Bin Wang, Zhi-Bing You, Antonio Verdejo García (2008). Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release. PLoS ONE, 3 (8) DOI: 10.1371/journal.pone.0002846

The Evolution of Schizophrenia

2008-08-07T22:50:00.008-04:00

Schizophrenia is one of the more frightening and debilitating mental disorders. It can cause hallucinations, delusions, and social withdrawal, as well as a variety of other cognitive afflictions. While scientists have yet to decipher the etiology of the disease, its high inheritability rate (60-85%) has led many to look for answers in genetics. Since schizophrenia affects cognitive functions that are distinctly human (like language-related abilities), some have begun to consider ways in which the human brain has evolved, and how this could shed light on the causes of schizophrenia.

A group of researchers published a study this week in Genome Biology that examines the relationship between schizophrenia and the evolution of higher order processes in humans. They first investigated the evolution of molecular mechanisms involved in human cognition. Then they examined the changes that occur in schizophrenic patients, and looked for an overlap between the two data sets.

They found that, of 22 biological processes that show a strong indication of recent positive selection, 6 involve disproportionate numbers of genes that are implicated in schizophrenia. All of those 6 are implicated in energy metabolism, or the regulation of energy flow through the body/brain.

The group then performed comparative analyses between schizophrenic patients, healthy controls, chimpanzees, and rhesus macaques. The reason other primates are used in such a study is to further delineate the evolutionary picture. If an evolutionary change in the brain can be found between a human and a chimpanzee, for example, then one can assume it was a human development that took place after the divergence of chimps and humans.

The researchers saw distinct differences between the four groups, indicating recent evolutionary changes. They again found that metabolites that play key roles in energy metabolism (e.g. lactate, glycine, choline) were affected.

These results caused the scientists to suggest that recent evolutionary changes in our brain’s energy metabolism may have been integral in the development of the higher order processes we associate with the human brain. These changes would have been necessary to meet increased energy demands as the brain went through increases in size, number of synaptic connections, extent of neurotransmitter turnover, etc.

It seems that brain energy metabolism is negatively affected in disorders like schizophrenia. For example, decreases in blood flow to the prefrontal cortex have been reported when schizophrenics attempt cognitive tasks. The researchers in this study suggest that, after the last 2 million years of rapid evolution, the human brain is basically pushing the limits of its metabolic abilities. Thus, any aberrations in the brain’s energy metabolism capabilities could have drastic results, schizophrenia being one example.

According to this perspective, schizophrenia is a by-product of our rapidly evolving brains. Because we are operating at near-capacity levels, any reduction in our ability to produce and process brain energy can be debilitating. In order to verify this hypothesis, however, much more work examining the correlation between evolution, energy metabolism, and brain disorders will need to be done.

Reference:

Khaitovich, P., Lockstone, H.E., Wayland, M.T., Tsang, T.M., Jayatilaka, S.D., Guo, A.J., Zhou, J., Somel, M., Harris, L.W., Holmes, E., Paabo, S., Bahn, S. (2008). Metabolic changes in schizophrenia and human brain evolution. Genome Biology, 9(8), R124. DOI: 10.1186/gb-2008-9-8-r124

Good News for Fruit Fly Truckers

2008-08-04T20:15:00.006-04:00

Science has arrived at credible hypotheses to explain a number of complex waking behaviors. Yet an overtly simpler behavior—one that doesn’t vary much from situation to situation or person to person, and involves a minimal amount of physical and mental activity—baffles us, leaving us with a surfeit of hypotheses that seem to explain some aspect of it, but none that is sufficient to explain it as a whole.

That perplexing behavior is sleep. It comprises 1/3 of our lives, yet we don’t really know why. It seems to play a number of roles. It acts as a restorative influence on the body, bolstering the immune system and our overall feeling of restedness. It also seems to be very important during development, occupying most of an infant’s time as its brain is rapidly maturing. And indications are that it's an important part of memory consolidation.

But none of these purported reasons for sleep can explain on its own why it may have evolved. For example, it seems that the restorative functions of sleep could be achieved without putting ourselves in a state where we are oblivious to our external environment—something that is very dangerous evolutionarily. The necessity of sleep during development doesn’t explain why adults need to continue doing it, and, while it may be less efficient, memory storage is still possible after sleep deprivation.

The unsatisfying nature of each of these hypotheses on their own has caused some to support an explanation of sleep that stresses its adaptive importance in helping our ancestors remain safe from predators. Sleep incapacitates us at a time (in the dark) when we are most vulnerable, keeping ancient humans out of the paths of nocturnal carnivores. While this might be evolutionarily adaptive, however, it doesn’t explain why we experience minimal conscious ability to monitor our environment during sleep (why not just a restful but conscious state?), or why animals that are predators and not generally hunted sometimes sleep a great deal (e.g. lions).

In addition to lacking a clear purpose for sleep, we have yet to understand the physiological mechanisms behind it. This has caused some scientists to turn to the model organism Drosophila for answers. The sleeping state of Drosophila has much in common with that of mammals. It involves homeostatic and circadian regulation, consists of long periods of immobility, becomes more fragmented with age, etc.

While scientists still haven’t come to a consensus on the reason for sleep, Drosophila research has led to several findings that have aided in the elucidation of its physiology. For example, it has helped to explain the role of neurotransmitters, like serotonin, that play a key role in sleep regulation. Recently, it has led to an amazing discovery: a way to reverse the effects of mental fatigue due to sleep deprivation by manipulating gene expression.

The cognitive deficits that Drosophila develop as a result of sleep deprivation are similar to those exhibited by humans. The extent of the impairment is correlated with the amount of time spent awake. Learning in Drosophila has been found to be dependent on a structure known as the mushroom bodies (MBs)—thought to be somewhat homologous to our hippocampus—and a dopamine receptor called the dopamine D1-like receptor (dDA1).

Scientists at the Washington University School of Medicine recently investigated whether sleep-loss induced learning impairments could be reversed in Drosophila. They used a learning task that takes advantage of the flies’ predisposition to fly towards a light. The flies were placed in a T-maze with a lighted tunnel and a dark tunnel. The lighted tunnel also contained a piece of filter paper soaked in quinine, which has a bitter taste and repels flies. On repeated trials, the flies had to learn to resist their urge to fly down the lighted tunnel by associating it with the bitter smell of quinine.

Sleep deprivation led to a decreased ability to perform on the learning assay. Additionally, the researchers found that learning the task at all was heavily dependent on the functionality of the dDA1. When they studied mutant flies with a deficiency in this receptor, learning was significantly reduced. Thus, they manipulated dDA1 in the MBs to be over-expressed and surprisingly found that this caused learning deficits after sleep deprivation to return to baseline levels.

The authors of the study use these findings to make a couple of postulations about sleep and sleep deprivation. First, they suggest that, although sleep deprivation probably affects several pathways, it may target specific brain areas that are essential for functioning (in this case, the MBs). Also, they hypothesize that one of the functions of sleep may be to restore levels of neurotransmitters essential to proper functioning, like dopamine.

While this finding has already led to speculation on popular science sites about a pharmacological method of negating sleep-deprived cognitive impairments, it’s important to remember that this was a study done in fruit flies, and much work would have to be done to find if it is potentially applicable to humans. Regardless, while the overall purpose of sleep continues to be a mystery, this study does add one more piece to the puzzle in understanding its physiological mechanisms.

Reference:

SEUGNET, L., SUZUKI, Y., VINE, L., GOTTSCHALK, L., SHAW, P. (2008). D1 Receptor Activation in the Mushroom Bodies Rescues Sleep-Loss-Induced Learning Impairments in Drosophila. Current Biology DOI: 10.1016/j.cub.2008.07.028

Dopamine and the Bruce Effect

2008-07-30T23:59:00.006-04:00

If you take a recently impregnated female mouse and place her in a cage with an unfamiliar male, something curious often happens. The female, upon smelling the new male's urine, spontaneously aborts the fetus as her body drastically reduces its production of prolactin (PRL), a hormone responsible for progesterone secretion and thus essential to maintaining a pregnancy. The embryo fails to implant and the female begins ovulating again, making her receptive to copulation attempts by the new male. This strange phenomenon was first noticed by biologist Hilda Margaret Bruce in 1959, and is referred to as the Bruce effect.

The Bruce effect has been a curiosity to biologists since its discovery, as many have sought to explain why the female mouse’s body would seemingly be programmed to destroy her own offspring. After all, isn’t reproduction supposed to be the “goal” of evolution, and thus of life?

Several explanations have been offered to make sense of the Bruce effect. One is that it is an adaptive mechanism to protect the female’s potential maternal investment from being lost to infanticide. Infanticide is a fairly common practice among many species, and is usually committed by the male.

A male often cannot visibly determine if a female is pregnant when he encounters her (if her fertilization has been recent). Thus, upon copulating with her, he takes a risk that she may already be pregnant. If she were to produce offspring from another male, he might mistake them for his own and invest his resources in raising them (whatever “raising” may mean in the particular species). The risk being, if they are not his offspring he makes the investment but does not gain the benefit of his genes being passed on to a new generation. This is evolutionary suicide, and some biologists believe the males of many species instinctually go to great lengths to avoid it.

One way to make sure none of one’s resources go to raising another’s offspring is to simply get rid of the offspring. Male mice will frequently be infanticidal for the first three weeks after copulating with a female. Then they act paternally for about two months, after which they regress to their infanticidal tendencies. Coincidentally (not really), the mouse gestation period is three weeks and the weaning period is about two months. So the male times his infanticidal behavior perfectly to ensure that any offspring he helps to wean are his (note again that this is instinctual, not conscious behavior).

So, many biologists have suggested the Bruce effect may be a way for the female to avoid going through a pregnancy and investing all of her resources in it, just to have her progeny killed by a new male. Instead, she can abort the fetus and be receptive to him, in the process ensuring that she will have the opportunity to raise offspring into adulthood.

An alternative explanation for the Bruce effect involves mate selection. In this hypothesis, blocking the pregnancy is beneficial to the female by providing her with a novel mating partner. In highly territorial animals like rodents, a female may be more inclined to mate with the mouse whose urine she can currently smell, as he is most likely dominant in that territory.

Whatever the reason for the effect, a female also seems to reach a point when she has too much invested in the pregnancy already for it to be beneficial to abort. In mice, this occurs after the first few days of pregnancy, when the embryo becomes implanted. After this point, the Bruce effect no longer occurs. This is thought to involve a type of evolutionary weighing of the pros and cons. After three days of pregnancy, the female “decides” she has put enough time into her fetus that it would be counter-productive to start over. She must take the risk.

While the evolutionary cause of the Bruce effect may not be known for some time, a study published in July's Nature Neuroscience brings us closer to understanding the neural mechanism behind it. It seems to be dependent upon the versatile neurotransmitter dopamine.

When the female mouse smells another male’s urine, two sense organs in the nasal cavity are involved in processing the scent. One, called the vomeronasal organ (VNO), has pheremone-sensing capabilities. The other, the main olfactory epithelium (MOE), detects odorants. Both organs project fibers to the main olfactory bulb (MOB) and accessory olfactory bulb (AOB). The MOB contains a large population of dopaminergic interneurons, known as the juxtaglomerular dopaminergic interneurons (JGD).

As these dopamine interneurons are highly involved with olfaction, the scientists involved in the study wondered if they might also play a role in blocking pregnancy through urine odor detection. When they measured dopamine levels in the female mouse brain, they found a surge in dopamine occurred after the third day of the pregnancy—the time at which male odor no longer has an abortive effect on the fetus.

When they administered a dopamine antagonist, which blocks dopamine transmission, spontaneous abortion again occurred, even after implantation on the third day. Therefore, dopamine appears to interfere with the perception of the male urine odors, and is responsible for the suppression of the Bruce effect after the third day of a mouse pregnancy.

These findings represent a new understanding of the roles of the olfactory bulb, implicating it in the control of reproduction and social behavior in rodents. While not really applicable to humans, making sense of the Bruce effect is important in comprehending social behavior that, without knowledge of evolutionary theory, seems otherwise inexplicable.

Reference:

Che Serguera, Viviana Triaca, Jakki Kelly-Barrett, Mumna Al Banchaabouchi, Liliana Minichiello (2008). Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy Nature Neuroscience, 11 (8), 949-956 DOI: 10.1038/nn.2154

Gene Therapy for Prion Diseases

2008-07-26T13:44:00.007-04:00

Prion diseases are relatively rare in humans. The most common, Creutzfeldt-Jakob disease (CJD), afflicts only about one in every million people. Despite their low prevalence, however, these diseases (also known as transmissible spongiform encephalopathies, or TSEs) receive a fair amount of attention from the media and the scientific community. This interest is probably due to their enigmatic mechanism, potential for epidemic spreading, frightening neurodegenerative features, and (as of yet) incurability.

TSEs are neurodegenerative diseases thought to be the result of a prion infection. This distinguishes them from most other sicknesses, which are caused by microbial infections. Prions are infectious agents made up entirely of proteins (the word itself comes from a combination of proteinaceous and infectious).

A prion protein called PrPC (the C stands for cellular, and actually should be in superscript but I can't get Blogger to do this) is commonly present on the membranes of our cells, although its function has not yet been fully resolved. PrPSc (the Sc is for Scrapie, the first identified prion disease—in sheep) is an isoform of PrPC and the toxic form of PrP. When it enters the brain it can cause conformational changes in PrPC, turning it into PrPSc.

PrPSc is extremely resistant to being broken down. Thus, it accumulates in the brain, forming protein aggregates known as amyloid fibers. These are toxic to brain cells, and eventually kill them. Astrocytes, which perform a number of supporting functions in the cell (one of which is cleaning up), find the dead neurons and digest them.

This creates actual holes in the brain, giving it a sponge-like appearance (and the reason for these disorders being referred to as spongiform). This continued neurodegeneration leads to a number of clinical symptoms, like changes in personality, depression, involuntary movements, lack of coordination, dementia, and eventually the complete loss of the ability to move or speak. TSEs are currently incurable, and an effective method of therapeutic treatment has not been found. The aggregation of PrPScs occurs over a long period of time, giving the diseases incubation periods that range from 10-60 years depending on the disease type.

TSEs can be the result of genetic or sporadic (non-genetic) causes. A mutation in the prion protein (PRNP) gene can cause the production of PrPSc instead of PrPC, leading to a prion disease. TSEs are also contagious—not through the air or normal contact, but through exposure to infected tissue, body fluids, or contaminated medical instruments (due to the durability of prions, they can survive normal sterilization procedures).

Unfortunately, we have learned about how TSEs are spread by witnessing several deadly epidemics. Around the middle of the twentieth century, a TSE arose in a New Guinean tribal people called the Fore. It is thought to have spread through cannibalistic ritual practices, and killed over 1,000 of their people. In the 1980s 60 deaths were linked to the transmission of CJD through contaminated medical instruments. Around the same time, 85 people died after receiving prion-infected growth hormone injections. In the 1990s, a type of CJD called variant CJD (vCJD) was linked to eating beef infected with the bovine form of TSE, bovine spongiform encephalitis (BSE), or mad cow’s disease. vCJD has a shorter incubation period than CJD, with the median age at death being 28, versus 68 for CJD. The illness also has a longer duration, with a median of 15 months for vCJD and only 4-5 months for CJD. Up to 200 people worldwide have died from vCJD.

BSE is thought to be caused by feeding cattle the remains of other infected cattle. This practice was stopped in 1989. Due to the long incubation period of the disease, however, some fear that the real mad cow disease epidemic has yet to manifest itself.

An article in PloS One this month addresses a possible way to control such an outbreak, with the successful application of a gene therapy treatment for TSEs. A natural resistance to prion diseases has been discovered in both animals and humans, and specific mutant forms of the mouse Prnp gene have been found to reduce the replication of prions in infected cells.

The researchers involved in the study injected this mutant gene into the brains of mice infected with prions. In order to make the study more relevant to human TSEs, they did this during late stages of the disease, at 80 and 95 days post infection. This increases relevance because, due to the long incubation period of TSEs, most people are unaware they have contracted them until serious symptoms develop.

They found that, after two injections, treated mice survived 20% longer than non-treated mice. They exhibited substantial improvements in behavioral symptoms, as well as a significant reduction of spongiosis and astrocytic activity in the brain.

The authors suggest this effect occurred because the mutated Prpn gene produces a protein that cannot be converted into PrPSc. Additionally, the protein it makes competes with PrPC for PrPSc, slowing the conversion of existing PrPC to the toxic form. Basically, this means that the PrPSc doesn’t realize the new proteins can’t be transformed, and still attaches itself to them. This delays the overall disease progression, as many of these PrPScs are busy trying to make conformational changes to no avail.

These results are promising not only because they slow down the aggregation of toxic prions, but because the effect was demonstrated at such a late stage of disease. Unfortunately, the disease was slowed but not cured. Regardless, the hint of a successful method of treatment for prion diseases might be comforting to nervous meat eaters who are fearing a future vCJD outbreak. I’m a vegetarian (and have been for a long time), so as long as the soybeans in my tofu weren’t grown with meat and bone meal fertilizer, I feel reasonably safe.

Reference:

Karine Toupet, Valérie Compan, Carole Crozet, Chantal Mourton-Gilles, Nadine Mestre-Francés, Françoise Ibos, Pierre Corbeau, Jean-Michel Verdier, Véronique Perrier, Alfred Lewin (2008). Effective Gene Therapy in a Mouse Model of Prion Diseases PLoS ONE, 3 (7), 0- DOI: 10.1371/journal.pone.0002773

The Singing Bass: Kitschy or Insightful?

2008-07-22T23:18:00.000-04:00

If you were listening in on a discussion about the evolutionary origins of language, you might expect to hear theories bandied about concerning evidence for language-like processes in apes. You probably wouldn’t be too shocked to hear someone bring up an example of language in parrots. You might, however, be a little surprised if the conversation turned to the origins of human vocalization in toadfish.

Perhaps this isn’t that surprising, though, when one considers how much of our evolutionary beginnings are shared with fishes. While (of course) fish don’t have language in a human sense, some species do have the ability to make vocalizations in certain situations, like courtship or defense of territory. Although they lack an air tube leading to the mouth, and a larynx to create the vibrational variations more common to land animal utterances, some are able to make noises with an air sac used primarily for buoyancy control and secondary respiration, known as the gas bladder. Fish of the batrachoidid family in particular (i.e. the midshipman and toadfish) have a diverse group of vocalizations. They vary depending on the context, with specific calls for aggression, surprise, or mating (among others).

This leads to a couple of different hypotheses. One is that the ability to vocalize evolved independently a number of times throughout history: in fish, amphibians, reptiles, mammals, and birds. Another is that there is a common origin for the ability to vocalize that can be traced back millions of years to a piscine ancestor. A study published in this week’s Science explores the latter hypothesis by investigating the development of the neural circuitry for vocalization in larval fish.

Studying embryos or larvae is a method used in evolutionary developmental biology. Similarities in the embryonic development of two organisms are considered evidence of a common ancestor. This conclusion is based on the fact that evolution works by the alteration of existing structures. Thus, two related organisms will theoretically have similar embryonic development to a certain point, where it will then diverge in order to form the structures that make the two creatures taxonomically different. A commonly given example of this is the vestigial pharyngeal pouches (gill slits) that human embryos possess early in development.

The authors of the study in Science found that the vocal motor neurons in batrachoidid fish develop in a segmental region that spans the caudal hindbrain and rostral spinal cord. This is similar to the pattern of development found in other vertebrates like frogs and birds. Adult phenotypes seem to indicate a comparable developmental process in reptiles and mammals as well, although embryological studies here are lacking.

The authors conclude that these analogies in the distribution of vocal neurons indicate a conserved developmental pathway that involves Hox gene expression. They suggest this pathway predates the radiation of fish, originating over 400 million years ago. Thus, perhaps the Big Mouth Billy Bass is a more astutely-developed toy than it first appears to be…no, it’s still stupid.

Reference:

Bass, A.H., Gilland, E.H., Baker, R. (2008). Evolutionary Origins for Social Vocalization in a Vertebrate Hindbrain-Spinal Compartment. Science, 321(5887), 417-421. DOI: 10.1126/science.1157632

Mirror Neurons May Be Responsible For Global Warming & U.S. Economic Woes

2008-07-18T00:59:00.009-04:00

Since their discovery in the 1990s, mirror neurons have experienced a degree of fanfare uncommon to findings in the field of neuroscience. Mirror neurons are so named because they are activated both when a primate participates in a task, and while watching another complete the same task, thus “mirroring” the behavior of the other animal. This unique activation pattern has led some to suggest that mirror neurons are integral not only to imitation, but also to understanding that others have their own mental states (theory of mind). By extension, it has been hypothesized that mirror neurons are necessary for language acquisition and social interaction. Dysfunctions in mirror neurons have even been offered as a possible cause of autism.

Thus, they have come to be viewed as a very special kind of neuron, with a versatility and importance to brain function that is unrivaled by other types of brain cells. But, do mirror neurons deserve the exalted status that some have ascribed to them? In short: probably not.

Mirror neurons do seem the play an interesting role in cognition. Primate studies have found mirror neurons to be activated in correlation with focusing on a particular goal or intention of movement. They are also activated in a selective fashion, with specific groups corresponding to different goals of an action, e.g. grasping to move vs. grasping to eat. Of additional interest, they have been found to respond to sounds associated with an observed action.

fMRI studies in humans have revealed specific activity in areas where mirror neurons are thought to be located, such as the ventral premotor (vPM) and anterior intraparietal sulcus (alPS), during observation and imitation of movement.

But, while these findings in humans and non-human primates are intriguing, they don’t support the rampant speculation that has followed about the role of mirror neurons in overall cognitive function. Experiments with monkeys to date haven’t assessed the ability to imitate, experience empathy, display theory of mind, or use language. Of course, it is debatable to what extent some of these attributes even exist in non-human primates, or if they can be studied if they do.

As for humans, neuroimaging experiments have allowed scientists to determine which regions of the brain are active during imitation or observation of an action. The specific neurons that are utilized, however, and any physiological characteristics that make them unique, cannot be assessed with current imaging technology.

Thus, the roles attributed to mirror neurons in the last decade since their discovery may have been an overly ambitious attempt to describe their function. By extension, implying that their malfunction is critical in autism could really be jumping the gun.

In an essay in last week’s Nature, Antonio Damasio and Kaspar Meyer discuss the exaggerated claims about mirror neurons, and suggest a rational hypothesis for how they may work. Twenty years ago Damasio proposed a theory known as “time-locked multimodal activation” to explain the development of complex memories. The theory is based on the proposed existence of groups of neurons that, during the encoding of memories, receive input from a number of different sites. Damasio termed these neuronal groups convergence-divergence zones (CDZ). He suggested there are two types of CDZs: local CDZs, which collect information from areas close to a sensory cortex (e.g. the visual cortex), and non-local CDZs, which are higher-order structures of the brain where the information from local CDZs converges.

According to this theory, when a memory is formed—Damasio and Meyer use the example of a monkey opening a peanut shell—all the information about the event converges on a non-local CDZ. Then, if the monkey hears a peanut shell opened in the future, this would activate a local auditory CDZ, as well as the non-local CDZ where memories associated with the noise are stored. Signals are sent out from the non-local CDZ to all local CDZs that were involved in the original experience of the event, activating these sites and resulting in a sort of recreation of the original peanut-cracking.

Mirror neurons are represented by the non-local CDZs. In this scenario, however, mirror neurons are not physiologically unique. They are normal neurons involved in a network that has less to do with “mirroring” than with integrating and syncing the various aspects of elaborate memories. This does not take away from the role and function of this network, but should detract a little from the aggrandized status attributed to individual mirror neurons, in favor of an appreciation of the holistic complexity of the brain.

The CDZ hypothesis, however, has not been tested, although research does indicate that networks involved in observing and imitating behavior spread beyond purported mirror neuron sites. Regardless of whether the specifics of the CDZ hypothesis come to be supported by future studies, I feel it represents a more sensible approach to mirror neurons. To credit mirror neurons alone with a function that carries such importance, like the ability to infer the mental states of others, seems to oppose much of what has been learned thus far about neuroscience. We have never found language neurons, love neurons, or fear neurons. Instead we have found networks that spread throughout brain regions that correlate with the ability to experience these aspects of cognition. I suspect we will soon say the same about mirror neuron networks and their involvement in social interaction.

References:

Damasio, A., Meyer, K. (2008). Behind the looking-glass. Nature, 454(7201), 167-168. DOI: 10.1038/454167a

Dinstein, I., Thomas, C., Behrmann, M., & Heeger, D.J. (2008). A mirror up to nature. Current Biology, 18 (1), 13-17.

If I Beat Up a Robot, Will I Feel Remorse?

2008-07-14T22:49:00.009-04:00

At times, when my computer's performance has transformed it from an essential tool into a source of frustration, I will find myself getting increasingly angry at it. Eventually I may begin cursing it, roughly shoving the keyboard around, violently pressing the reset button, etc. And I can’t help noticing that, during these moments of anger, I have actually begun to blame my computer for the way it is working—as if there were a homunculus inside the machine who had decided that it was a good time to frustrate me and then started fiddling with the wires and circuitry.

I’m sure I’m not alone. Human beings have a general tendency to attribute mental states, or intentionality, to inanimate objects. There could be several reasons for this attribution, known as mentalizing, being a general human strategy that we overuse and mistakenly apply to nonliving things. One is that our knowledge of human behavior is more richly developed than other types of knowledge, due to the early age at which we acquire it and the large role it plays in our lives. Thus, perhaps we are predisposed to turn to this knowledge to interpret actions of any kind, sometimes causing us to anthropomorphize when examining non-human actions.

Another reason may be that assigning intentionality to an action in our environment is the safest and quickest way to interpret it. For example, if one is walking in tall grass and the grass a few feet ahead of them begins rustling, it would be more adaptive to think there is a predator behind that movement than to assume it is just the wind. Someone who decides it is the wind may end up being wrong, and getting killed or injured. Someone who assigns intention to it may also be wrong, but in either scenario has a better chance of being safe because their erroneous conclusion probably resulted in them using a defensive or evasive, instead of a nonchalant, strategy.

One more possible reason for our overuse of Theory of Mind (the understanding that others have their own mental states) may be based on our need for social interaction. Studies have indicated that people who feel socially isolated tend to anthropomorphize to a greater extent. Thus, perhaps part of the reason we assign intentionality so readily is that we have a desire for other intentional agents to be present in our environment, so we can interact with them.

A study published this month in PloS ONE further explores our behavioral and neural responses when we interact with humans and machines that vary in their resemblance to humans. Twenty subjects participated in the study and engaged in a game called prisoner’s dilemma (PD), a contest that has been extensively used in studying social interaction, competition, and cooperation.

PD is so called because it is based on a hypothetical scenario where two men are arrested for involvement in the same crime. The police approach each individual separately and offer him a deal in which he would have to betray the other. The prisoners are faced with the decision to remain silent or to betray their partner. If both stay silent, they face a very minor sentence because the police don’t have enough evidence to make the greater charge stick. If both betray, however, they each face a 10-year sentence. If one betrays and the other remains silent, the betrayer goes free and the silent accomplice receives the full sentence. The game is usually modified to involve repeated situations of cooperate or betray, in which the players can base their decision on the actions of their opponent in the previous round.

In the PloS ONE study, participants played PD against a computer partner (CP) (just a commercial laptop set up across the room from them), a functional robot (FR) consisting of two button-pressing mechanisms with no human form, an anthropomorphic robot (AR) with a human-like shape, hands, and face, and a human partner (HP). Unbeknownst to the participants, the form of their opponent did not have any relationship to the responses given. All were random. The participants’ impression of their partners was gauged after the experiment with a questionnaire. The survey measured how much fun the participants’ reported when playing against each partner, as well as how intelligent and competitive they felt each player to be. Participants indicated that they enjoyed the interactions more the more human-like their partner was. They also rated the partners progressively more intelligent from the least human (CP) up to the most human (HP). They judged that the AR was more competitive than its less-human counterparts, despite the fact that its responses were randomly generated, just as the others were.

The brain activity of the participants during their interactions was also measured using fMRI. Previous research has indicated that mentalizing involves at least two brain regions: the right posterior superior temporal sulcus (pSTS) at the temporo-parietal junction (TPJ), and the medial prefrontal cortex (mPFC). In the present study, these regions were activated during every interaction, but activity increased linearly as the partners became more human-like.

These results indicate that the more a machine resembles a human, the more we may treat it as if it has its own mental state. This doesn’t seem to be surprising, but I guess what intrigued me more about the study was that there was activity in the mentalizing areas of the brain even during the interaction with the CP, as compared to controls. The activity also increased significantly with each new partner, even when the increase in human likeness was minimal (see picture of the partners above). These examples are evidence of our proclivity to mentalize, as even a slight indication of responsiveness by an object in our environment makes us more inclined to treat it as a conscious entity.

The authors of the study point out that these results may be even more significant when robots become a larger part of our lives. If the frustration I experience with my computer is any indication, I foresee human on robot violence being an epidemic by the year 2050.

Reference:

Krach, S., Hegel, F., Wrede, B., Sagerer, G., Binkofski, F., Kircher, T., Robertson, E. (2008). Can Machines Think? Interaction and Perspective Taking with Robots Investigated via fMRI. PLoS ONE, 3(7), e2597. DOI: 10.1371/journal.pone.0002597

Computational Neuroscience and Systems Biology

2008-07-11T23:26:00.004-04:00

In 1952, Alan Hodgkin and Andrew Huxley published a paper that was the result of several years of experimentation on the axon of the giant squid. They had been measuring action potentials, a task made easier in the giant squid due to the large diameter of its axons (up to 1mm, compared to 1 micrometer, or millionth of a meter, in humans). Using a device (known as a voltage clamp) that allowed them to manipulate the voltage of the axon membrane and measure the resultant current that flowed through its ion channels, they developed a mathematical model that could be used to calculate current flow across excitable membranes. They won the Nobel Prize in 1963 for their work, and amazingly their equations are still used today in their original form.

This mathematical modeling of neuronal function might be considered the first historical step in the creation of a field that is known today as computational neuroscience. Computational neuroscience involves the translation of brain function into quantifiable models. This usually necessitates drawing from a number of different fields, such as neuroscience, cognitive psychology, electrophysiology, mathematics, and computer programming.

A recent article in PloS Computational Biology summarizes the history of computational neuroscience and examines the interaction of the field with another: systems biology. Systems biology is an approach to studying biology that emphasizes looking at a biological system as a whole. This is in contrast to a reductionist methodology, which involves breaking something down into its constituent parts in order to understand how it functions.

Biology has had to rely on reductionism for much of its history, simply because there has not been enough information to understand whole systems. Now, however, sub-fields like genomics and proteomics have led to drastic gains in the extensiveness of our knowledge of biological processes, allowing complex computational modeling of biological systems to occur for the first time.

As pointed out in the PloS article, however, these two fields that use computational methods to explore neuroscience and biology, respectively, are distinctly separate from one another, and have little interaction or overlap. Why is this?

One reason is that the information available to systems biology is much more comprehensive. Data like an entire genome is accessible to use in computational modeling. Neuroscience, on the other hand, usually has to take a more theoretical approach. For example, computational neuroscientists do a lot of work with neural network models. These models, however, are usually general examples and don’t attempt to mimic specific networks in the brain. At this point, accurate modeling of distinct networks is a little too ambitious of an endeavor. The disparity in the information available to the two fields has led to differences in methods and tools (e.g. the software used for modeling), which make integration of the areas even more difficult.

It seems, however, that this chasm between computational neuroscience and systems biology will eventually be abolished. At this point it may be unavoidable, as knowledge of neuroscience lags behind that of other biological areas for various reasons that range from the complexity of the brain to the history of our philosophical approach to studying it. But the understanding of biological processes like gene expression and protein synthesis that makes systems biology capable of large-scale modeling attempts will eventually lead to an improved elucidation of how the brain works. This will inevitably allow for the integration of computational neuroscience and systems biology. After all, the brain is a pretty important part of the overall system.

Reference:

De Schutter, E., Friston, K.J. (2008). Why Are Computational Neuroscience and Systems Biology So Separate?. PLoS Computational Biology, 4(5), e1000078. DOI: 10.1371/journal.pcbi.1000078

Foreign Accent Syndrome

2008-07-10T22:23:00.004-04:00

Watching someone you know recover from a stroke or other serious brain insult can be extremely difficult. Cognitive deficits (including dementia), apraxia, and speech problems are among the disabilities that these patients may have to endure. At times, these impairments can make it hard to find the individual you knew before the incident in the post-accident patient. This is perhaps the most trying aspect of the experience.

Well imagine if, when you attempt to speak to a stroke survivor you knew before the stroke, you find not that they have difficulty producing speech, but that they have strangely adopted a new British (or German, Dutch, etc.) accent. While it may seem to be the lesser of two evils, you can certainly envision that it might be also be a disconcerting experience (for all parties involved).

This rare (but real) disorder is known as foreign accent syndrome. It occurs after a severe brain injury or stroke. The patient develops an abnormality of speech that seems, to most listeners, to resemble a foreign accent. A recent case, one of the first in Canada, involved a woman who had a stroke, then adopted an accent that sounded like Maritime Canadian English—a dialect the woman was previously unfamiliar with.

What exactly is going on here? At first an enigma, recent investigations into foreign accent syndrome have begun to shed some light on the mechanisms underlying the problem. According to a review article in the Journal of Neurolinguistics, “foreign accent syndrome” is actually something of a misnomer, as patients do not demonstrate a speech pattern that consistently corresponds to a particular foreign accent. Instead, they display general changes in linguistic prosody that listeners mistakenly attribute to a different dialect.

Prosody is the rhythm, stress, and intonation of speech, and disruption has an effect on overall speaking ability, but is particularly problematic to vowel production, pitch, and syllable stressing. According to the review, phoneticians who have listened to foreign accent syndrome patients have asserted that their speech doesn’t consistently resemble a foreign dialect. Instead, it fluctuates in its similarity to various languages, and even to different families of languages. Thus, the foreign accent syndrome tag may be a simplification.

It is not a surprise to learn that most cases of foreign accent syndrome appear to be associated with lesions to the left hemisphere of the brain, which is typically correlated with language. Patients usually have damage to Broca’s area, the motor strip adjacent and inferior to this region, and/or the middle frontal gyrus. Details beyond these general areas are scarce, however, leaving the specific neural basis of the syndrome largely unknown.

Probably the important take-home message at this point is that the syndrome doesn’t involve the mysterious acquisition of a foreign accent. Instead, it is a general affliction of speech that causes distortions in prosody, which are interpreted as foreign dialects by listeners. All in all, it is perhaps one of the less debilitating effects of brain injury/stroke. Regardless, one can imagine the upset it must cause at an already difficult time. Perhaps some of that distress will be assuaged in new patients by an improved understanding of the syndrome.

Reference:

BLUMSTEIN, S., KUROWSKI, K. (2006). The foreign accent syndrome: A perspective. Journal of Neurolinguistics, 19(5), 346-355. DOI: 10.1016/j.jneuroling.2006.03.003

Encephalon #49 Celebrates Independence! (from Lamarckism)

2008-07-07T00:45:00.009-04:00

The first week in July is a time of great significance—one that reminds us of change, revolution, and how an age-old view of the world can be drastically altered by the persistent belief in one's own novel ideas. This, of course, is because July 1st marks the anniversary of the presentation of Charles Darwin and Alfred Russel Wallace's independently-developed theories of evolution and natural selection to the Linnean Society of London. The reading represented the first public explanation of the theory, which would eventually come to be the foundation upon which the world of science rests. Last week's anniversary is a special one, marking the 150th year since the publication. So, as you peruse Encephalon's round-up of the latest and greatest neuroscience blogging, remember that all roads in science today lead back to July 1st, 1858, at the Linnean Society.

Darwin developed his theory without the luxury of knowing anything about genes. Brain Stimulant skeptically discusses the use of gene therapy in psychiatry. Just the ability to have the conversation, however, is representative of how far our understanding of genetics has come in 150 years.

Mind Hacks questions whether our rapidly improved methods of imaging the brain are resulting in sensationalized reporting on experimental results.

Cognitive Daily describes what makes voices more or less attractive.

Neurophilosophy provides an intriguing look at the brain's ability to reorganize itself after a cerebrovascular accident. It appears that cells in the brain are much more versatile than once thought.

Neuroanthropology looks at the relationship between music and movement, and how it is manifested in the drumming that accompanies Sundanese martial arts demonstrations, as well as gives us a rational perspective on the debate over the biological origins of homosexuality, and a good reason to relax.

Sharp Brains discusses how physical exercise and mental exercise compare in improving the health of your brain. An interview with Dr. Art Kramer from the University of Illinois provides a way to engage in both forms of exercise at the same time: walking book clubs! And, tests to determine "brain age" are called into question.

The Winding Path provides an in-depth description of the co-evolution of the brain and culture, and then focuses specifically on the evolution of complex social interaction.

Brain Blogger asks if religion has neural or supernatural roots, and looks at the ramifications of implanting microchips containing medical information in patients.

Finally, The Neurocritic takes Science to task for not practicing what it preaches about fMRI translation. He also summarizes a unique review article that uses Dilbert cartoons to help explain the neural correlates of prediction error signals.

Be sure to check out the next edition of Encephalon at Sharp Brains on July 21st. Send your submissions to encephalon{dot}host{at}gmail{dot}com.

Bisexuality in Drosophila

2008-07-03T01:18:00.005-04:00

The fruit fly, like many organisms, has a stereotypical courtship ritual that precedes mating. After noticing a female, a male fly will follow her with a persistence that is strangely reminiscent to me of behavior that can be observed in any local pub on a busy night. The male will then tap the female with his foreleg, which allows him to sense her pheromones through chemoreceptors on his leg, and verify whether she is sexually receptive. If so, he will extend one wing and vibrate it, producing a species-specific courtship song. He also licks her genitalia to further test her pheromones. Of course these last few steps aren’t as noticeable at the local bar, and if they are you may be in the wrong place (perhaps a strange fetish pub). If she doesn’t reject him, he mounts her and attempts to copulate.

See the ritual here:

A fruit fly’s ability to discriminate between males and females is based on visual, auditory, and chemical cues, such as the pheromones 7-tricosene and cis-vaccenyl acetate (cVA). Flies that don’t produce these pheromones are deemed female and courted by other males. Mutant flies that cannot sense the pheromones attempt to copulate indiscriminately with males and females. Normally, however, homosexual behavior in drosophila is relatively rare.

Earlier this year, a joint research team from France and America set out to determine what the biological difference between bisexual and heterosexual flies is. Is it that bisexual flies have difficulty sensing pheromones like 7-tricosone and cVA, or that they are sense the pheromones and are attracted to the opposite sex? What is the mechanism that causes that difference in attraction?

The group identified a mutation in drosophila that drastically increased homosexual encounters. They named it genderblind (gb) due to the resulting phenotype, which exhibited bisexual behavior. They determined, using an immunoblot, that the gb mutation causes a reduction in gb protein quantity. An immunoblot is also known as a western blot, and involves separating proteins with gel electrophoresis and then probing for specific proteins with antibodies that have been raised against them (presence of the protein will invoke an antibody response).

In order to determine if homosexual behavior in flies was simply a result of the misinterpretation of sensory cues, the group manipulated visual and chemosensory cues and measured fly response. They found that, although reducing the availability of visual cues affects the ability of the fly to discriminate between sexes, it was not enough of an effect to explain gb behavior. When they exposed the gb flies to mutant males that did not produce 7-tricosene and cVA, homosexual behavior was reduced to wild-type levels. When they applied these pheromones topically to the mutants, however, homosexual behavior from the gb flies was restored. This suggested that gb flies sense the pheromones, but interpret them differently than wild-type flies.

The group was able to identify the genderblind protein as a glial amino-acid transporter subunit and a regulator of glutamate in the central nervous system (CNS) of the fly. One function of glutamate is to reduce the strength of glutamatergic synapses through desensitization. The gb mutants had reduced genderblind protein levels and lower levels of extracellular glutamate. This resulted in increased glutamatergic synapse strength in the CNS. A glutamate antagonist administered to gb flies caused them to revert back to wild-type sexual behavior, indicating that the stimulation of glutamatergic circuits is responsible for the homosexual behavior. Additionally, inducing the overexpression of glutamate in the CNS of the fly caused an increase in homosexual behavior in both gb and wild-type flies.

Amazingly, the homosexual behavior could basically be turned on or off by manipulating glutamate transmission. The researchers suggest that this implies there is a physiological model for drosophila sexuality in which flies are pre-wired for both heterosexual and homosexual behavior. The homosexual behavior, however, is normally suppressed by genderblind proteins. A similar model has been proposed for mice.

So, the natural question is: what, if anything, does this say about homosexuality or bisexuality in humans? Well, the authors of the study state that genderblind has a high homology to a mammalian protein, the xCT protein. This is a cystine/glutamate transporter and may be an important regulator of glutamate in the CNS, similar to genderblind in the fly.

Despite this similarity, however, in my opinion it is improbable that a relationship between xCT protein levels and bisexuality/homosexuality that is similar to the one in drosophila and genderblind protein exists in humans. This isn’t to say there couldn’t be a correlation, just that the direct connection seen in fruit flies would appear too simple to be a basis for human sexual orientation, which is probably governed by a number of gene-protein relationships. So, while glutamate levels could play a part in suppressing homosexual behavior, they probably couldn’t act like a “bisexuality-switch” they way they do in the fruit fly.

Reference:

Grosjean, Y., Grillet, M., Augustin, H., Ferveur, J., Featherstone, D.E. (2008). A glial amino-acid transporter controls synapse strength and courtship in Drosophila. Nature Neuroscience, 11(1), 54-61. DOI: 10.1038/nn2019

Send in Submissions for Encephalon #49!

2008-07-02T19:02:00.004-04:00

Encephalon #49 will be at Neuroscientifically Challenged on Monday, July 7th. Please send your posts in by 6pm on Sunday the 6th to encephalon {dot} host {at} gmail {dot} com.

The Commonalities of Buffalo Wings, Szechuan Peppers, and Ritalin Snorting

2008-06-30T00:11:00.008-04:00

Spicy food—you either love it or hate it. Whichever group you fall into, though, there’s a good chance you’ve never thought about how intriguing a natural deception it really is. When we eat spicy food we may experience a variety of sensations (depending on the specific cuisine) ranging from tingling to numbness to painful burning. Yet, a short time later the feeling disappears, leaving no redness, scarring, or irritation behind, indicating that the previous unpleasantness we experienced was—literally—all in our heads.

The substance responsible for the burning sensation one may experience when eating chili or buffalo wings is known as capsaicin. It was identified in the 1800s, and a whole family of similar molecules, called capsaicinoids, were discovered in chili peppers in the 1960s. While capsaicin is an irritant to mammals, it has analgesic properties in birds when they consume it. Chili pepper seeds are broken down in the digestive tracts of mammals. Birds, however, pass the seeds intact. Thus, the capsaicin deters mammalian feeders and makes the peppers more palatable to birds, allowing the seeds to be dispersed efficiently through bird migrations. Hence, the burning feeling caused by capsaicin is probably a mechanism that evolved to promote seed dispersal.

It wasn’t until the late 1990s, however, that scientists began to unravel the mystery behind the phantom sensation caused by capsaicin. To understand it necessitates a little knowledge about neurophysiology. So, I’ll try to summarize half a semester of neurophys in a few short paragraphs.

Neurons (and some other types of cells) communicate with one another through pulses of voltage called action potentials. A neuron maintains a certain regular voltage, known as its resting potential. The membrane of a neuron is broken up by apertures called ion channels. When they are open, certain charged particles can pass in or out of them (which particles and to what extent depends on the type of channel and a number of other factors).

Neurons are influenced primarily by four types of ions: K+ and organic anions (A-) that are concentrated inside the cell, and Na+ and Cl-, which are for the most part outside of the cell. The resting potential across a neuron’s membrane is usually about –70mV. This potential is maintained by a sensitive pump that constantly pulls K+ in, while sending Na+ out.

When a neuron is excited, voltage-dependent ion channels quickly open that allow floods of Na+ into the cell. This causes a change in the voltage of the neuron, referred to as depolarization. The rapid depolarization is the trigger that sends a wave of voltage, the action potential, down the axon of the neuron. If it is strong enough, it will reach the end of the neuron, causing the release of neurotransmitter, which binds to surrounding neurons to open their ion channels, resulting in depolarization, and so on.

So, back to buffalo wings, chili, and capsaicin. Capsaicin is a ligand that binds to a specific receptor, the TRP vanilloid receptor subtype 1 (TRPV1). This receptor can also be stimulated with actual heat and physical injury. When it is activated, it opens ion channels that depolarize nerve cells by allowing an influx of Na+. This produces action potentials that travel to the brain and produce what is, in this case, a false sense of pain.

If you’ve ever eaten Szechuan peppers, you’ll know that the feeling they evoke is different than that of chili peppers. Szechuan peppers cause a tingling, sometimes numbing, feeling. Instead of capsaicin, their active ingredient is hydroxy-alhpa-sanshool (sanshool). How sanshool acts to produce its numbing effect was somewhat of an enigma until a study published last week in Nature Neuroscience offered an explanation.

According to the authors of the study, sanshool acts on a different group of neurons than capsaicin. Capsaicin affects small-diameter sensory neurons that express proinflammatory peptides (which are responsible for the pain), but sanshool acts on large diameter neurons usually associated with proprioception and detection of touch or vibration.

Sanshool was thought to have an effect by opening Na+ channels, in a manner similar to capsaicin. The Nature study, however, found that sanshool actually inhibits K+ channels. The result is still an action potential, but through a different mechanism.

You may be thinking this is a lot of research money being wasted to figure out why food is spicy. But understanding these subtleties of the sensory system is important in that it brings us closer to an overall comprehension of how our senses work. Also, both capsaicin and sanshool have applications as analgesics (ironically capsaicin can reduce pain when applied topically, possibly because it floods the sensory neurons to the point where they go numb).

A side note: A couple of years ago a Harvard researcher, Clifford Woolf, made a novel suggestion. Since the most highly abused prescription drugs like OxyContin and Ritalin generally lead to addiction when users begin snorting them, why not mix capsaicin in with them? This, Dr. Woolf asserted, would not affect the oral digestion of the pills but would make snorting them like “snorting an extract of 50 jalapeno peppers”.

One thing that has always amazed me about pills like these is how amenable they are to being crushed up and snorted. Elizabeth Wurtzel, in her book about Ritalin addiction More, Now Again: A Memoir of Addiction implies that pharmaceutical companies purposely make their drugs like this in order to increase demand and black market consumption. I don’t know if I agree with her or not yet, but when there seem to be options to change the consistency of the pill, or when deterrents like adding capsaicin are available, and they are ignored, it does become suspicious.

Reference:

Bautista, D.M., Sigal, Y.M., Milstein, A.D., Garrison, J.L., Zorn, J.A., Tsuruda, P.R., Nicoll, R.A., Julius, D. (2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neuroscience, 11(7), 772-779. DOI: 10.1038/nn.2143

Encephalon #49 Will Be Right Here--Send in Your Submissions

2008-06-27T00:02:00.004-04:00

Neuroscientifically Challenged will host its first Encephalon Blog Carnival on July 7th and needs submissions! Please send your post on brain science or related topics to encephalon {dot} host {at} gmail {dot}com by 6pm on July 6th.

It's All About Timing: Circadian Rhythms and Behavior

2008-06-26T23:30:00.008-04:00

Anyone who has ever tried to drastically alter his or her sleep schedule (e.g. going from working days to working nights) knows that it is one of the more difficult biological tasks we can take on. Even altering one’s sleep patterns by a couple of hours (such as the shift experienced by cross-country travelers) can be disruptive, and enough to make us feel tired, mentally unclear, and grumpy. But why are we so inflexible when it comes to our daily routine? Why are our otherwise diverse bodies so sensitive to an adjustment of our biological clocks by just a few hours? Perhaps it is because millions of years of evolution have led to a daily body clock so fine-tuned that this sensitivity is adaptive.

Circadian (from the Latin for “around” and “day”) rhythms are endogenous biological patterns that revolve around a daily cycle. They are found in all organisms that have a lifespan that lasts more than a day. They are adaptive in the sense that they allow an organism to anticipate changes in their environment based on the time of day, instead of just being a passive victim to them. Thus, to foster that readiness, they usually involve the coordination of a number of physiological activities, such as eating/drinking behavior, hormonal secretion, locomotor activity, and temperature regulation.

A major nucleus of the mammalian brain, located in the hypothalamus and called the suprachiasmatic nucleus (SCN), is responsible for acting as the master time-keeper in mammals. When the SCN is lesioned (i.e. in rodents), it results in a complete disruption of circadian rhythms. The animals will demonstrate no adherence to a daily schedule, sleeping and waking randomly (although still sleeping the same total amount of time each day).

The SCN receives information from ganglion cells in the retina, which keep it appraised of whether it is light or dark out, and maintain its synchrony with a diurnal schedule. It is not, however, completely dependent on visual input for keeping time. A number of other environmental cues, such as food availability, social interaction, and information about the physical environment (other than light) are thought to play an important role in the SCN’s ability to maintain regular daily rhythms.

Although the SCN is the center for circadian rhythms, it seems that many individual cells are not directly controlled by the SCN. Instead, they are thought to maintain their own time-keeping mechanisms. Known as peripheral oscillators, these cells are present in a number of organs throughout the body, and can be sensitive to environmental cues as well as the signals of the SCN.

So, how do the neurons of the SCN actually “keep time”? They appear to be controlled by a cycle of gene expression, which consists of a natural negative feedback mechanism. Throughout the day, a gene known as CLOCK (circadian locomotor output cycles kaput) is activated based on daytime environmental cues. This gene acts with another, BMAL1, as a transcription factor, driving the transcription of proteins period (PER) and cryptochrome (CRY). When large amounts of PER and CRY have been created, they form a complex, and act on the CLOCK and BMAL1 genes to inhibit their own expression. This occurs during the night, and the result is that PER and CRY proteins become diminished, allowing CLOCK and BMAL1 to begin transcribing them again. This happens around the morning of the next day. Thus, the feedback loop is synchronized with a 24-hour cycle, allowing the clock in the SCN to oscillate at a regular rate.

Disorders of the SCN can result in disruptive sleep problems, such as advanced sleep phase syndrome (early sleep and wake times) or delayed sleep phase syndrome (preference for evenings and delayed falling asleep). More attention is now being focused on the role a dysfunctional circadian system may play in already identified behavioral problems. A recent review in PloS Genetics examines the potential influence circadian rhythm disturbances may have in disorders like depression, schizophrenia, and even autism.

Circadian disruptions are present in all major affective disorders, including depression, bipolar disorder, and schizophrenia. Although the exact role circadian rhythms play in these disorders is not yet known, it may be substantial. This is supported by the influence changes in sleep patterns can have on the alleviation of primary symptoms of these disorders. For example, sleep deprivation has been demonstrated to have an antidepressant effect (albeit short-lived) in patients. And some affective disorders, such as seasonal affective disorder, seem to have a basis in the length of the day, and shape emotional states.

Autism spectrum disorders (ASD) are correlated with low melatonin levels, and a gene responsible for the synthesis of melatonin is considered a susceptibility gene for autism. Mice with a mutant form of this gene demonstrate deficits in social interaction, anxiety, and increased occurrence of seizures. It is postulated that behavioral problems in ASD may be influenced by the failure of an individual’s circadian clock to effectively take note of social and environmental cues.

Variants of a number of time-keeping genes, such as PER1, CLOCK, and CRY have been found to be associated with behavioral disorders. It has yet to be determined if these variations are causative, contributive, or unrelated to the disorders. Keeping in mind how influential a disturbance of circadian rhythms can be in our daily lives, however, it seems logical to investigate the possibility of their contribution to pathologies.

Reference:

Barnard, A.R., Nolan, P.M., Fisher, E.M. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing. PLoS Genetics, 4(5), e1000040. DOI: 10.1371/journal.pgen.1000040

Changes in Gene Expression and Addiction

2008-06-25T23:39:00.003-04:00

As I discussed in a post last week, addiction seems to correspond to abnormalities in dopamine (DA) transmission throughout the reward areas of the brain. Specifically, initial uses of a drug tend to correlate with low levels of dopamine receptor availability in the nucleus accumbens (NAc), while long-term use affects DA transmission throughout the entire striatum (the NAc is located in the ventral portion of the striatum, or the part nearer the front of the brain).

The striatum is a subcortical region of the brain, and part of the mesocorticolimbic DA pathway, which is integral to the evaluation and appreciation of rewards (like drugs). Striatum is from Latin, and means striped. It is so named because the entire region has a striped appearance, due to the alternating bands of gray and white matter that make it up.

The changes that occur in the striatum are postulated to be responsible for the long-lasting behavioral changes that drug addicts can experience, such as cravings for drug use, an inability to enjoy previously rewarding experiences, and proneness to relapse. It has been suggested that these changes must be preceded by some sort of synaptic remodeling in order to have such a long-lasting effect, and those synaptic changes could be a result of fluctuations in DA transmission. How exactly they occur, however, has yet to be elucidated.

A study to be published in an upcoming issue of Nature may shed some light on the mechanism behind these changes. It involves gene expression, and a phosphoprotein known as DARPP32 (dopamine-and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa).

A phosphoprotein is a protein that has had a phosphate group attached to it, through a process known as phosphorylation. Phosphorylation is an important event in cells, as it often is the catalytic process that activates enzymes and receptors. Dephosphorylation can “turn off” these enzymes, and involves proteins called phosphatases.

When dopamine 1 receptors (D1R) are stimulated, they in turn activate DARPP32, which inhibits a phosphatase known as protein phosphatase 1 (PP1). This signaling cascade affects the phosphorylation of numerous proteins in the cytoplasm and nucleus of a cell.

In the Nature study, the researchers found that the administration of amphetamine, cocaine, or morphine to mice caused DARPP32 to accumulate in the nuclei of striatal neurons. Further studies of neural cultures indicated that dopamine prevents a specific DARPP32 phosphorylation site, Ser97, from being phosphorylated. Ser97 appears to be responsible for exporting DARPP32 from the nucleus of the cell, thus DARPP32 builds up inside the nucleus.

When DARPP32 accumulates in the nucleus, it causes the phosphorylation of a histone, H3. Histones are proteins that DNA winds around to make chromatin, the protein and DNA complex that makes up chromosomes. Phosphorylation of histones often affects chromatin structure, and gene expression as a result.

Mice with mutations in the Ser97 site demonstrated long-lasting aberrations in their behavioral responses to drugs and other rewards. They showed decreased acute locomotor responses to morphine administration, along with a reduced locomotor sensitization to cocaine. Their motivation to obtain a food reward was also diminished.

Thus, this signaling pathway may be responsible for one of the most potent behavioral changes in addiction, when euphoria achieved from the drug diminishes along with the pleasure once obtained from other rewards. This change can contribute to compulsive drug seeking, as an addict obsessively continues to seek the pleasure once associated with their drug of choice. If altered gene expression is responsible for these changes, it would help to explain why they can persist for such a long period of time after the cessation of drug use—sometimes continuing to affect the behavior of an addict for years, and often making their efforts to stay sober much more difficult.

My Evolutionarily Adaptive Response to Dog Poop

2008-06-25T01:56:00.005-04:00

Any dog owners out there who (like me) don’t have their own yard in which to let their dog run wild, will probably agree that picking up after your dog is the most unpleasant daily aspect of having one. Every time I lean down to scoop up a pile of my dog Zooey’s regular gift to me, my nose wrinkles up, my eyes squint—and occasionally I may gag a little bit.

This expression of disgust is a common one. Charles Darwin, in The Expression of the Emotions in Man and Animals, noticed that some expressions like this occur throughout the world in many different cultures, and even in some animals. Thus, he hypothesized, they may have a biological rather than environmental origin. If so, Darwin suggested, they probably also have an adaptive purpose.

Recently a group of researchers from the University of Toronto investigated this 130-year-old hypothesis. They took two expressions that are widely considered to be universal: the wrinkled nose, raised lip, and narrowed eyes of disgust, and the wide eyes and flared nostrils of fear. They developed computer-generated images of faces displaying a typical rendition of each of these visages, then asked volunteers to recreate them while they underwent breathing and vision tests.

They found that each expression had specific effects on breathing and vision that could be considered adaptive. The look of disgust limited air flow and vision, a reaction which could be beneficial in keeping potentially noxious substances out of the eyes and mouth. The fearful expression improved peripheral vision, made eye movement quicker, and increased air flow—all responses that could theoretically make someone more prepared to face danger.

While these results may seem obvious in hindsight, I must admit it’s not something I ever thought about before when I picked up after Zooey.

The Darwinian Paradox of Homosexuality

2008-06-18T21:30:00.011-04:00

Homosexuality has been an acknowledged aspect of human society since our earliest recorded history. In some civilizations, such as ancient Greece, homosexuality was relatively common and accepted. It is also a behavior that is not specific to humans. It has been documented in over 500 non-human animals, including penguins, bonobos, and grizzly bears.

Over the past few decades, evidence has begun to accumulate that homosexuality is a behavior that appears primarily due to biological or genetic influences. While environmental factors may play a part in the expression of a homosexual phenotype, most scientists would suggest their influence is not powerful enough to cause an otherwise heterosexual organism to become homosexual (although there are environmental conditions that may encourage transient homosexual behavior, e.g. captivity).

This dependence on biological factors, however, creates a paradox for evolutionary theorists. The assumed goal of all organisms, and thus of evolution, is reproduction—the passing on of one’s genes to a new generation. Since homosexuals reproduce at a much lower rate than the heterosexual population, one might think a genetic basis for homosexuality—even one that involved several different genes—would by now have disappeared from the gene pool.

A number of hypotheses have been proposed to explain this paradox, although none of them has gained the full support of the scientific community. One early explanation, which has for the most part fallen out of favor, is kin selection. Kin selection occurs when an organism acts in a way that fosters the reproductive success of its relatives, even at a cost to its own reproductive success. In this scenario, childless homosexuals might put more effort into helping raise nieces or nephews. These relatives might carry some of the same genes as the homosexual, and thus if they eventually reproduce they may pass on genes essential for homosexuality. Evidence in support of this theory is limited, however, and most feel it doesn’t tell the complete story.

More accepted explanations today include: 1) overdominance, 2) maternal effects, and 3) sexually antagonistic selection. Overdominance occurs when a heterozygous version of a gene provides an organism with some type of reproductive advantage. For example, a straight man might have a heterozygous gene that, if it were homozygous, would increase his chances of being gay. In a heterozygous state, however, it could result in increased sperm motility. Thus, when it is passed on through reproduction, its recessive allele (which predisposes for homosexuality) is as well.

The maternal effects hypothesis suggests a fetus is influenced by the environment of the mother’s womb, resulting in changes that predispose one toward homosexuality. This hypothesis was proposed after evidence began to appear that homosexuality in males is predicted by high numbers of older brothers. In trying to make sense of this statistic, scientists postulated that a mother might build immunity to male-specific antigens with each birth of a male child. The progressive immunization to these male antigens may eventually affect the brain of a male fetus. This could happen, for example, if antibodies crossed the placenta and attacked male-specific regions of the brain necessary for sexual differentiation.

Sexually antagonistic selection, which appears to have the most evidential support at this point, is a mechanism whereby genes are spread throughout a population by giving a reproductive advantage to one sex while disadvantaging another. In the case of homosexuality, the mother may have increased fertility at the expense of her child’s ability to procreate. This concept can be expanded upon to include female homosexuality as well, whereas any trait with a gender-specific benefit may have evolved by increasing female fertility.

Although the evolutionary explanation of homosexuality is still elusive, evidence for a biological basis for homosexuality continues to accrue. An article published this week in the Proceedings of the National Academy of Sciences reports that the brains of homosexuals have similarities to the brains of heterosexuals of the opposite sex. Using magnetic resonance imaging (MRI), researchers compared heterosexual and homosexual brains. They found that the brains of heterosexual men and homosexual women have a slightly larger right hemisphere than the brains of gay men and straight women. It has been found in the past that there are differences in activity between the right and left hemispheres in different sexes.

The researchers in this study also found, using positron emission tomography (PET), that the connectivity of the amygdala, an area of the brain important in emotion, was more similar in lesbians and straight men, and gay men and straight women, respectively.

These findings provide further evidence for homosexuality having a biological origin. Of course they don’t preclude the possibility that there are environmental influences on the expression of homosexuality. Instead, however, they make much less plausible the often bandied about argument that homosexuality is a “choice”. As the correlation between brain structure and a particular behavior becomes stronger, the involvement of choice usually decreases proportionally.

Hox Genes and Neurodevelopment

2008-06-17T22:37:00.004-04:00

In the 1980s, scientists knew surprisingly little about the role genes play in the development of an embryo. The discovery of a particular group of genes, however, known as Hox genes, drastically improved our understanding of embryology. At the same time it revolutionized genetics and developmental biology.

In the 1890s, an English biologist named William Bateson was repeatedly amazed when he came across “freaks” of nature in his studies. These included examples like a moth born with wings where its legs should be, or an insect born with legs for antennae. In 1915, another biologist, Calvin Bridges, gave a name to these aberrations, calling them homeosis (meaning the transformation of one body part into another). Bridges had noticed homeosis in fruit flies that were born with an extra pair of wings. Intrigued, he kept this strain alive through selective mating.

In the 1980s, scientists were finally able to isolate the gene that was causing the extra wing mutation in the fruit fly. They traced it back to a small group of genes, which they called Hox genes. They found that, by manipulating these genes, they could create virtual monsters, such as flies with legs that came bursting out of the middle of their heads.

The creation of these monsters, however, helped to elucidate the function of Hox genes. Hox is short for homeobox, which is the name for the DNA sequence that these genes have in common. Hox genes become active in early embryonic development. Their job is to designate which parts of the embryo will turn into which body parts (legs, wings, head, etc.). Hox genes are so specific that, if one that controls limb development is transplanted to the head of the embryo, a limb will grow out of the head.

Scientists began to find these types of master control genes in every embryo, regardless of the organism. Even more surprisingly, the genes are considerably similar across species. Scientists found they could replace a defective Hox gene in a fly with one from a mouse without any ill effects. Hox genes and other master control genes are present in humans as well, and play the same role in embryonic development. This congruity across species indicates that Hox and master control genes are probably an ancient evolutionary mechanism, developed before much speciation took place, but still present and active.

While understanding Hox and master control genes has led to great advancements in the comprehension of embryonic development, the development of the brain has still remained a little unclear. Specifically, scientists have had trouble figuring out how specialized neurons in our brain are formed in one region, then migrate to the areas they eventually have to settle in in order to function properly.

A study published online this week in PloS Biology may shed some light on the issue, however, and Hox genes are an important part of the explanation. The authors of the study investigated pontine (from the pons) neurons in mice. Pontine neurons are formed in the rear of the brain and then must migrate in the brainstem to eventually become part of the precerebellar system. This is an area that is necessary for coordinated motor movement, and provides the cerebellum with its principal input. So the question is, once these pontine neurons are formed, how do they “know” they have to travel to the precerebellar region?

The researchers who conducted this study found Hox genes to be the guide that leads the neurons to their appropriate resting place. A specific Hox gene, Hoxa2, was found to influence neuronal migration, preventing them from going astray through the influence of a pathway of molecular signaling. The Hoxa2 gene regulates the expression of a particular receptor, known as Robo. The receptor binds to a chemical called Slit, which prevents the neurons from being drawn toward other chemoattracants. This allows the neurons to ignore outside influences and to travel directly to the precerebellar region, where they belong. When the scientists knocked out the Hoxa2 gene, the pontine neurons were unable to resist being drawn to chemoattractants and often didn’t reach their final destination.

This adds some insight into the process of neuronal migration, something that has been problematic to neuroscientists for years. It is just the beginning of the story, however. Not all of the neurons reacted to Hoxa2, suggesting there may be other Hox genes involved in brain development. Thus, scientists will continue to search for other Hox genes that are part of the process. The success of this study, however, at least provides an indication that Hox genes, some of the most highly conserved in our bodies, may also be responsible for some of the most important aspects of brain development.

Reference:

Geisen, M.J., Meglio, T.D., Pasqualetti, M., Ducret, S., Brunet, J., Chedotal, A., Rijli, F.M., Zoghbi, H.Y. (2008). Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling. PLoS Biology, 6(6), e142. DOI: 10.1371/journal.pbio.0060142

Why Pretzels and Gunshot Wounds Make Us Thirsty

2008-06-14T15:57:00.003-04:00

I re-watched one of my all-time favorite movies the other night: Unforgiven. After William Munney (Clint Eastwood) shoots his first victim, the camera zooms in on the fallen cowboy as he begins complaining about how thirsty he is, begging his companions for water. In a moment of compassion, Munney agrees to put down his gun to allow the cowboy’s friends to bring him a canteen.

You’ve probably all seen a similar scene before in another movie, if not this one (hopefully you’ve never seen it in person). Victims of gunshot wounds, or other wounds that involve a drastic loss of blood, are often portrayed as being very thirsty. I’m not sure if the reason why this occurs is common knowledge, but in case it’s not, I thought I would write a quick explanation.

First, a little about water in the body. The cells in our body not only contain water, but also are surrounded by what is called interstitial fluid. This fluid bathes the cells in a “seawater” type solution that contains water, sodium (Na), amino acids, sugars, neurotransmitters, hormones, etc. The cell is normally in an isotonic, or balanced, state in relation to its extracellular environment, meaning water doesn’t generally leave or enter the cell at large rates.

Water is also an important constituent of blood. It is essential for keeping blood volume at a level that allows for proper functioning of the heart. If volume gets too low, the atria of the heart don’t fill completely, and the heart cannot pump properly.

The need to keep the fluid balance in the body at a regular level results in the occurrence of two types of thirst that affect us when that equilibrium is disturbed: osmometric thirst and volumetric thirst. Osmometric thirst occurs when the osmotic balance between the amount of water in the cells and the water outside the cells becomes disturbed. This is what happens when we eat salty pretzels. The Na is absorbed into the blood plasma, which disrupts the osmotic balance between the blood plasma and the interstitial fluid. This draws water out of the interstitial fluid and into the plasma, now upsetting the balance between the cells and the interstitial fluid. The result is water leaving the cells to restore the balance.

The disruption in the interstitial solution is recognized by neurons called osmoreceptors, located in the region of the anterior hypothalamus. They send signals that cause us to drink more water, in order to restore the osmotic balance between the cells and the surrounding fluid. In the case of pretzel eating, if we don’t drink more water, eventually the excess Na is simply excreted by the kidneys.

Now, to the graver situation of a gunshot wound, and the other type of thirst: volumetric. Volumetric refers to the volume of the blood plasma, which is highly dependent upon water content of the body. As mentioned above, maintaining an adequate blood plasma volume is essential to proper functioning of the heart. If it gets too low, the heart can’t pump effectively.

When someone is injured and loses a lot of blood volume (known as hypovolaemia), less blood reaches the kidneys. This causes the kidneys to secrete an enzyme called renin, which enters the blood and catalyzes a hormone called angiotensinogen to convert it into a hormone called angiotensin. One form of angiotensin (angiotensin II) causes the pituitary gland and adrenal cortex to secrete hormones that prompt the kidneys to conserve water as a protective measure. Angiotensin II also affects the subfornical organ (SFO), an organ that lies just outside the blood-brain barrier. Through the SFO angiotensin II stimulates thirst.

There are also receptors in the heart that recognize decreases in blood plasma. Known as atrial baroreceptors, they detect reductions in blood plasma volume and subsequently stimulate thirst by signaling neurons in the medulla. So, when someone is shot and losing a lot of blood, it is because of the decrease in blood plasma volume that brain regions are stimulated through both of the above pathways to stimulate thirst.

Processes that stimulate thirst are really much more complicated than this brief explanation. But, I thought this was enough to give a general idea of why salty foods and gunshot wounds have similar effects on our desire to drink water.

Impulsivity and a Predisposition to Addiction

2008-06-13T19:04:00.012-04:00

The improved understanding of addiction that has emerged over the past few decades has transformed the question of whether or not addiction is a choice into a search for predisposing factors that make the risk of addiction much higher for some people than for others. This is a drastic improvement from the times when it was even considered that addiction was a voluntary process—a decision made by degenerates who had no motivation to live a successful life. It has also led to a great deal of research in an attempt to isolate specific genotypes and phenotypes that result in a susceptibility to drug abuse.

Much of that research has focused on two such phenotypes: the sensation or novelty-seeker, and the impulsive personality. Novelty-seeking has been considered a predisposing factor to drug abuse for some time. This was reinforced by studies in the 1980s that found it to be correlated with the acquisition of cocaine self-administration (SA) in rats. Last year, however, a group of researchers at Cambridge found that an impulsive phenotype in rats was more of a predisposing factor to the compulsive use of cocaine that is traditionally associated with addiction.

Novelty-seeking and impulsivity may sound very similar, but there is a distinction between the two types of behavior. In rats, novelty-seekers have a greater tendency to explore a new environment than to stay in one place. Impulsive rats perform poorly on trained responses that will reward them with food, acting too quickly and making premature responses. When it comes to cocaine use, novelty-seeking rats (known as high responders, or HR) have shown a tendency to acquire the SA of cocaine more rapidly. Highly impulsive (HI) rats, on the other hand, don’t acquire SA more quickly, but they are more prone to allow their cocaine use to progress from occasional to compulsive. Thus, HR are more likely to try cocaine, but HI rats are more liable to develop an addiction to it.

Another group of Cambridge researchers (including a few who were also involved in the study mentioned above) published a study in this week’s Science that further explores the difference between HR and HI rats. In order to gain greater relevance to human addiction, they focused on the observation in rats of actual Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for addiction, specifically 1) an increase in motivation to obtain the drug, 2) an inability to refrain from drug taking, and 3) maintained drug use despite aversive consequences (punishment in this case). Each of the rats was given an overall addiction score based on these criteria (0-3), which corresponded to a score on the Addiction Severity Index (ASI)—a valid, reliable, and widely used addiction assessment tool.

The HI rats were found to have the highest addiction scores, being represented largely in the 2 to 3 point range, whereas low-responder (LR), HR, and low-impulsivity (LI) rats usually had a score of 0 or 1. These results reinforce previous findings that the propensity to use cocaine and the tendency to progress to addiction are influenced by separate (although perhaps overlapping) behavioral traits.

These two patterns of drug use are very distinct in humans as well. The percentage of people who try or experiment with drugs/alcohol is much higher than the percentage who actually become addicted, mirroring the separation in rats between SA and compulsivity. It also makes sense that impulsivity could be more of a negative influence when attempting to stave off the urges of an addiction than novelty-seeking, whereas novelty-seeking could be a primary factor in spurring an initial interest in drug experimentation.

As might be expected, it also seems that different brain regions in the rat control these different types of drug use. Previous studies have found that addiction (in rats and primates) is correlated with lower levels of the availability of a specific dopamine (DA) receptor—the D2/D3 receptor. Cambridge researchers last year found that limited D2/D3 receptor availability in the ventral striatum/nucleus accumbens (NAc) of rats exists before drug use. As other studies have found limited D2 availability throughout the striatum during and after drug addiction, this group suggested that, while NAc D2 deficiencies may predate drug use, the abuse itself (and the excessive DA transmission associated with it) causes downregulation of DA receptors throughout the striatum. Therefore, the reduction in D2 availability in the dorsal striatum may represent more closely the switch to compulsive drug use seen in HI rats. A deficiency in NAc D2 receptors, however, could be a risk factor for the initial use of the drug.

These developments in our understanding of addiction serve several important purposes. They solidify the association that can be made between a predisposition to drug abuse, and addiction itself. As more data indicates that specific phenotypes and genotypes predispose organisms to drug use/abuse, the question of the involvement of choice in addiction will slowly fade into the background as attempts to treat its neurobiological underpinnings become of primary importance. And, as scientists come to more explicitly understand neurobiological influences on drug abuse, social attitudes toward addiction may necessitate revision. Many questions, both philosophical and legal in nature, will have to be examined. For example, should a drug addict be imprisoned for repeated drug possession arrests, when no other crime is involved? How much are they to be held responsible for neurophysiological dissimilarities that made the decision for them to abstain from drugs much more difficult than it is for someone without such deficits?

While the social reverberations may not be felt for some time, however, research will continue into both the genotypes and phenotypes that correlate with addiction, in the hopes of finding improved treatments for the affliction in the near future. Identifying the genes associated with pre-drug decreased D2 receptor density, for example, could lead to the development of a treatment to correct the deficiency (for information on a promising vaccination treatment for addiction, see this post). Already a staggering 1,500 genes that are associated with addiction have been identified, along with eighteen molecular pathways for the disorder, five of which are shared by common drugs of abuse. So, although there is much work to be done, a solid foundation has been laid. And, with each new finding, we come a bit closer to comprehending what was previously one of the most misunderstood brain disorders.

Reference:

Belin, D., Mar, A.C., Dalley, J.W., Robbins, T.W., Everitt, B.J. (2008). High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking. Science, 320(5881), 1352-1355. DOI: 10.1126/science.1158136

Still Experiencing Technical Difficulties...

2008-06-10T15:49:00.002-04:00

AT&T has found a way to turn a simple transfer of high speed internet service to a new address into a very complex, convoluted process. I will be back by Friday with some new postings, and a new internet provider. Thanks to anyone who is still hanging in there with me!

Be Back Soon...

2008-06-06T13:24:00.001-04:00

To anyone who has checked in with this blog over the past week, I apologize for the lack of postings. I am in the process of moving to a new apartment and currently without internet access. I hope to be back up and running by the end of this weekend.

Robots Controlled by Monkeys May One Day Enslave Humans

2008-05-29T14:42:00.003-04:00

Or they might just eat all of our marshmallows and fruit. Either way, I’m basing my prediction on research published online this week in the journal Nature. Scientists at the University of Pittsburgh School of Medicine developed a robotic arm that they attached to monkeys, whose actual arms were restrained. Using signals from their brains alone, the monkeys were able to control the robot arms to feed themselves marshmallows and fruit.

In order to accomplish this, probes are inserted into the monkeys’ brains, specifically into the motor cortex, where voluntary movement is initiated. The probes can detect the stimulation of motor neurons when a monkey desires to move its own arm to reach for a piece of food. The electrical activity is fed into a computer program, which translates it into an analogous movement of the robotic arm.

This isn’t the first time brain activity has been indirectly converted into some form of external action. Past successes have primarily been with simpler tasks, however, such as the movement of a cursor on a computer screen.

In the case of the robotic arm, the monkeys must learn to visualize reaching for the food. The movement of the arm is reasonably fluid and the researchers suggest the monkey eventually comes to think of it as a natural extension of its own body.

This type of device could have amazing potential for sufferers of spinal cord injuries or “locked-in” conditions like Lou Gehrig’s disease (amyotrophic lateral sclerosis).

Have a look at the robot arm in action below. Emotions may range from kinda cute to kinda creepy.

Improving Electroconvulsive Therapy

2008-05-28T15:41:00.007-04:00

Electroconvulsive therapy (ECT) is thought by many in the general public to be a brutal and inhumane form of treatment. This perception likely has a number of causes, including improper use and administration in its earlier days, its depiction as a method of torture in fictional accounts like that found in One Flew Over the Cuckoo’s Nest, and perhaps even as a backlash against invasive psychological procedures, which may have grown out of the disastrous frontal lobotomy experiments.

The truth, however, is that when ECT is applied properly, it can be an effective form of treatment for those who suffer from severe depression. At times it may be the only form of treatment (besides talk therapy) for a subsection of this group who don’t respond to antidepressant drugs. The exact mechanism by which it works is poorly understand, although there are indications it may prompt production of brain derived neurotrophic factor (BDNF) in patients who don’t gain this beneficial effect from drugs. (See my post here for more info on the importance of BDNF levels in depression.)

ECT is not without its side effects, however. Even when administered appropriately, it can result in retrograde and/or anterograde amnesia. Other cognitive problems (e.g. disorientation) have also been noted. In most cases, these side effects clear up fairly quickly after treatment. Occasionally they are found to linger for weeks or even months, though—enough to make one hesitant to use, or agree to undergo, an ECT treatment.

A group of scientists from Columbia University, however, have just released a report detailing a form of ECT that not only has higher rates of effectiveness than standard ECT, but also results in less cognitive side effects. The group used a different form of electrical pulse called an “ultrabrief pulse”, and compared the outcome to the use of traditional ECT in a group of 90 depressed patients. The ultrabrief pulse lasts about 0.3 milliseconds compared to the traditional 1.5 milliseconds.

Of the 90 patients, 73% responded to the ultrabrief pulse, compared to 65% who responded to the standard form of ECT. More importantly, the group who received the ultrabrief pulse reported less severe cognitive side effects than the traditional group. They were monitored for a full year after treatment.

This may be promising news for severely depressed patients. If ECT can be administered with lower rates of concomitant cognitive dysfunction, it may become a more viable alternative for those who don’t respond to today's antidepressants. Another important step in the use of ECT, however, is to be able to fully understand why it works—something that has yet to be elucidated.

The Neuroscience of Distributive Justice

2008-05-24T15:24:00.003-04:00

Since the emergence of philosophical thought, an unresolved debate has persisted about a general definition of justice and equity. An aspect of that debate involves distributive justice, or how goods and benefits should be dispersed throughout a society in a fair and just manner. As an extreme example of this dilemma, imagine you are commissioned to deliver 100 lbs. of food to a famine-stricken region that consists of two villages a hundred miles apart. If you deliver half of the food to the first village, then travel to the second, 30 lbs. of the food will spoil during the trip. Would you deliver all of the food to the first village, or provide each village with only 35 lbs. of food in the pursuit of equity? What if you knew that 35 lbs. of food was not enough to fully alleviate the suffering of either village until the next shipment of food arrived?

Philosophers have offered several solutions to debates of this nature. Utilitarianism, a concept with ancient roots but most frequently associated with Jeremy Bentham and John Stuart Mill, asserts that one’s primary goal should be the achievement of a maximal amount of good or happiness. In the situation described above, a utilitarian might opt to deliver all of the food to the first village. This would maximize the sum of individual fulfillment, while the halving of the food would maintain a static level of suffering. Thus, delivering all of the food to the first village is the greater good.

Another approach to such a quandary is known as deontological ethics, which emphasizes not the consequences of one’s actions, but whether the actions are right or wrong, just or unjust. From a deontological perspective, it would be unjust to distribute the food unequally. A desire for some degree of fairness in all dealings seems to be a universal human trait, something deontologists point to in support of their doctrine.

Another question about distributive justice involves the extent to which emotion plays a role in the decisions it calls for. Many philosophers, both ancient and contemporary, assert that rational thinking is what allows us to make choices in difficult situations like the one above. Others argue that the processes behind those decisions cannot be devoid of an emotional influence, specifically one of an empathetic or sympathetic nature.

A study in this week’s Science examines distributive justice from a neural perspective, asking: what areas of the brain are active when we make such decisions? To find out, researchers used fMRI to scan the brains of 26 adults while they made decisions about allocating money to groups of children living in an orphanage in Uganda. During the allocations, the participants were forced to make a number of decisions that involved trade-offs between efficiency (analogous to Utilitarianism) and equity (deontology).

The investigators found that distinct neural regions are activated in the consideration of equity and efficiency. The putamen, a mid-brain structure that forms part of the dorsal striatum, seemed to be correlated specifically with efficiency. On the other hand, activity in the bilateral insular cortex was correlated with inequity. Regions of the caudate were activated by both. They also found that individual differences in aversion to inequity corresponded with higher neural activity in the insula.

Overall, the participants showed the greatest neural reaction to an inequitable distribution of food, leading the authors of the study to speculate that distributive decisions are made to avoid inequality more so than to engender efficiency. Thus, the results of this experiment seem to support the deontological argument. As the insular cortex is thought to play an important role in emotional processing, the experiment also indicates that our decisions are not devoid of an emotional element (contrary to the beliefs of Kant and Plato).

Thus, the imaging evidence from this study may help to explain why the debate over distributive justice has never been resolved. The concepts of equity and efficiency, and their respective values, are deeply rooted in our brains. Perhaps evolution never resulted in the disappearance of one or the other because they both are valuable in the decision-making process, depending on the situation. When all is said and done, though, it may be that the evolutionary value of fairness overrides that of efficiency.

Reference:

Hsu, M., Anen, C., Quartz, S.R. (2008). The Right and the Good: Distributive Justice and Neural Encoding of Equity and Efficiency. Science, 320(5879), 1092-1095. DOI: 10.1126/science.1153651

Does Money Affect the Way You Think?

2008-05-21T17:08:00.003-04:00

Money, perhaps more so than any other modern symbol, can elicit a vast array of emotions (depending to a large degree on its abundance in one’s life), including yearning, anxiety, pride, greed, envy, depression, and happiness. Of course there is not simply a direct correlation with money and any one of these emotional states, such as more money equaling more happiness or vice versa. In fact, past research has found that the effects money has on one’s well-being can be very disparate. On one hand, having more money may be good for your health and emotional state. On the other, people who place a high value on money have been found to have poorer social relationships than those who are more moderate in their view toward the attainment of wealth.

A group of researchers recently conducted a series of experiments to explore this paradoxical aspect of affluence. They formulated two hypotheses about the dual nature of money in the modern world. First, since money is the basis of most exchange in today’s society, they suggested that the thought of money should make people more focused on cost-benefit analyses and a market-pricing view of their environment. They thought that this perspective might encourage more emphasis on individual performance, since money is often correlated with the completion of personal tasks in our business-based economy. They predicted people with money on their mind would think of life in terms of inputs and outputs, with an awareness that greater input should result in a greater output.

They also hypothesized that the market mentality, while beneficial for personal performance, might hinder one’s ability to interact socially. Because it fosters a focus on individual performance, it might cause a decrease in sensitivity towards the needs of others.

To test their hypotheses, they used several different methods of exposing participants to money-related cues, while attempting to make the cues subtle enough that the subjects wouldn’t be aware of their presence. In one experiment, some participants sat at a desk with a screensaver that depicted money, while others saw screensavers of fish or flowers. In another, participants had to organize phrases that were or were not related to money, such as “I cashed a check” or “I wrote the letter”. Several other methods of exposure to money cues were used.

After being exposed to the cues, the participants were put in various social situations that tested their desire to be helpful, generous, sociable, or industrious. For example, to test willingness to help, a confederate would walk by and drop a handful of pencils (27 to be exact). Or, in another situation, a confused colleague would ask for assistance in understanding a task they were attempting to complete. Those who were exposed to money cues picked up fewer pencils, and those who weren’t spent 120% more time helping the confused colleague.

When given an opportunity to donate a portion of $2 the participants were given at the start of the study, those who had been reminded of money donated 39% of their payment, while those who hadn’t been donated 67%. They also, when allowed to situate the chairs in a room while waiting for another person to arrive, put more distance between their chair and the other person’s than the money-naïve group. When given a list of solo vs. group activities to take part in, the money-exposed group chose more individual activities than the control group (even when some activities included family members and friends).

With the choice of working on a task alone or getting help from a peer, the money-reminded participants chose to work alone, even though it meant doing more work. When faced with a challenging task, they spent 48% more time working at it before seeking help from the experimenter.

The researchers suggest these results may appear because a money-oriented person is focused on the inputs and outputs of the market, a view that tends to lead to an emphasis on individualization and self-sufficiency. They found no changes in emotion between the two groups, and thus assert that the differences in behavior are probably not due to a distrusting of others. Additionally, the fact that those who were reminded of money chose to persist on a task before asking for help indicates the results are not based purely on selfishness, as a selfish person would not have been so eager to do more work than necessary.

Regardless, the results do suggest that money can inspire an aversion to social interaction and a focus on the self. In modicum, however, this may be a necessary part of a capitalistic society, where one is forced to place an emphasis on ensuring they are treated equitably and compensated fairly for their work—and where they are forced to compete for their livelihood. An interesting follow-up to this experiment would be to use neuroimaging to see what is going on in the brains of participants when they make decisions after exposure to money cues, and how it is different from controls.

Reference:

Vohs, K.D., Mead, N.L., Goode, M.R. (2008). Merely Activating the Concept of Money Changes Personal and Interpersonal Behavior . Current Directions in Psychological Science, 17(3), (in press).

microRNAs and Schizophrenia

2008-05-19T17:37:00.011-04:00

Over the past twenty years, our understanding of gene expression has grown tremendously. As is often the case, however, with that increased level of comprehension has come a realization that the process is even more complex than originally thought. Thus, the relatively simple model of mRNA being transcribed from DNA, then traveling to ribosomes where it is translated into proteins (with the help of tRNA and rRNA), is now thought to be just a rough summary of the process. A number of other molecules, such as transcription factors (TFs) and microRNAs (miRNAs), are also involved in the expression of genes.

TFs are proteins that bind to sections of DNA and control the transfer of genetic information from DNA to RNA. They are integral to development, management of the cell cycle, responding to environmental changes, and intercellular communication. miRNAs are small, single-stranded RNA molecules that are transcribed by DNA but not translated into proteins. They are complementary to a particular section of mRNA, and by binding to mRNA can suppress gene expression. TFs and miRNAs can control anywhere from dozens to hundreds of genes in the human genome, with some estimates being much higher.

Fully understanding the role of TFs and miRNAs is essential for uncovering the etiology of genetically based disorders. Recently researchers at Columbia University Medical Center (CUMC) found that changes in miRNA levels can result in cognitive and behavioral deficits. They believe miRNAs could be involved in the development of schizophrenia in humans.

In the past, a higher incidence of schizophrenia has been correlated with a deletion of a small part of chromosome 22, at a location designated as q11.2. One of the genes in that chromosomal section is called Dgcr8. It plays an integral role in miRNA production. Thus, the researchers at CUMC hypothesized that the absence of Dgcr8 and the resultant reduction in miRNAs might be part of the etiology of schizophrenia.

They engineered a strain of mice that lacked the Dgcr8 gene. As they predicted, the mice were found to exhibit the same behavioral and neuroanatomical deficits seen in people with schizophrenia.

While this is an important step in understanding one of the most perplexing disorders medicine has ever had to confront, it is not exactly heartening. miRNAs have widespread effects on gene expression throughout the brain. This may help to explain why schizophrenia has been so difficult to decipher, as it is probably the result of a number of genetic aberrations. Unfortunately, though, it is further indication that schizophrenia is very complex, and much more investigation will be needed to fully comprehend its origin.

Would You Vaccinate Your Kids Against Drugs?

2008-05-14T18:48:00.008-04:00

This is not just a question intended to incite thought or debate, it’s an issue that any future parents, or parents with children under the age of 10 may actually be faced with before your child reaches 18. Clinical trials are currently underway for vaccines intended to treat cocaine and nicotine addiction, respectively. Both have been shown to be effective without any adverse effects in phase I trials, and have moved on to phase II. So, if the treatments continue to demonstrate efficacy without harm, it is conceivable they could be available for use in humans within a decade.

Cocaine has proven to be one of the most frustrating drugs of abuse for the pharmacology field because, unlike heroin (methadone), alcohol (naltrexone), and nicotine (buproprion, nicotine gums, etc.), no accepted pharmaceutical treatment for cocaine dependence has been developed. Yet cocaine is one the most addictive drugs of abuse, as well as one the most widely used, with over 14 million users across the globe. According to Scientific American, reducing the rate of cocaine use in the United States alone could result in a savings of $745 million in medical, legal, and other related expenses.

A failure to find acceptable methods of treatment for cocaine addiction has led researchers to investigate the plausibility of using immunotherapy. Immunotherapy involves administering a vaccine to raise an immune response against the drug. In order to do this, the drug must be delivered along with an immunogen, or antigen. An immunogen is a substance, often a protein, which can cause an immune response. Since the drug obviously cannot raise an immune response itself (or drugs wouldn’t be so popular), the drug is linked to an antigen and then administered to the patient. When the immune system senses the presence of the antigen, antibodies bind to it. This antibody-immunogen complex is too large to pass the blood-brain barrier, causing most of the drug to be unable to enter the central nervous system (CNS). This drastically reduces the influence of the drug, for the most part eliminating the rewarding quality of its use.

Since initial vaccines were developed, research has uncovered even more effective methods of vaccination against cocaine use. A few years ago a group at The Scripps Research Institute found a monoclonal antibody that has an extremely high affinity for cocaine. When displayed on the coat of a bacteriophage, they found the antibody could be carried past the blood-brain barrier and into the CNS, where it could be even more efficient at diminishing the effects of cocaine.

A bacteriophage is a virus that infects bacteria. They usually are made up of genetic material enclosed by a protein coat. Despite the nocuous connotation to their name, they are not dangerous to eukaryotic cells. They are useful as vectors because they tend to be very durable and able to withstand great variations in external conditions. Their ability to pass through the blood-brain barrier made them a great candidate for an immunogen. Their use in this study resulted in significant reductions in the psychostimulant effects of cocaine on rats.

A form of this vaccine developed by The Scripps Research Institute is now working its way through the clinical trial process. A vaccine against cocaine or nicotine would still necessitate some aspect of compliance, however. From most indications, a vaccine would require several injections over a period of up to 3 months to take effect. After that, regular vaccinations every 2 to 6 months would probably be necessary.

So, for adults, the desire to get treatment (or a court-ordered treatment in certain situations) would be a necessary first step. For minors, however, it’s conceivable a parent could be given the option of mandating a vaccination schedule, whether it be therapeutic or preventative. So, for all you parents with children who won’t be 18 within the next decade, what will you do?

Important associations between a drug and its rewarding quality are made within the first several uses of the drug. Would you take the steps to vaccinate your child against nicotine, so that when she tries cigarettes the first few times she will spit them away with disgust and wonder what the big fuss is all about? Or against cocaine, so if he is at a party and happens to try it, he will not experience a rewarding effect? Would you tell her that you are vaccinating her? If you did, it might still allow her to harbor some curiosity about drug use, as she would know that, while vaccinated, she’s not experiencing its “real” effects. This could make him more inclined to try a drug after age 18, when you can no longer have such a peremptory influence. Think about it, it may be a decision you will one day have to make…

Reference:

Carrera, M.R. (2004). From the Cover: Treating cocaine addiction with viruses. Proceedings of the National Academy of Sciences, 101(28), 10416-10421. DOI: 10.1073/pnas.0403795101

Encephalon #45

2008-05-12T17:07:00.003-04:00

It is up at PodBlack Blog, in tribute to Erik Erikson on the anniversary of his death. Enjoy and mourn, in whatever proportion you deem appropriate.

Ketamine and Depression

2008-05-10T19:31:00.002-04:00

Ketamine is a drug with a very wide range of uses. Developed in 1962 to be an alternative anesthetic to phencyclidine (PCP), it was first used as a battlefield anesthetic. It eventually became a popular veterinary medicine, used for anesthetic purposes with small animals (e.g. cats) and as an analgesic for larger animals like horses. It also became an established recreational drug, known for its psychedelic side effects and commonly referred to as “special K”.

Several years ago doctors noticed an unexpected behavioral effect while using ketamine to treat complex regional pain syndrome (CRPS) in human patients. It appeared to alleviate symptoms of depression associated with the CRPS. Further studies verified this therapeutic effect, while noting one advantage over other contemporary antidepressant medications: it began working within 24 hours of the dose.

This aroused great interest in understanding the mechanism of ketamine. Due to its side effects, most were unwilling to advocate the use of the drug itself. But if its method of action could be elucidated, then perhaps similar quick-acting antidepressant drugs (without psychedelic side effects) could be developed.

Research has indicated that the neuropharmacology of ketamine is complex. It is thought that it affects the glutamate system of the brain, a system that only recently has been implicated in depression. Ketamine is an antagonist (i.e. inhibits action) at a glutamate receptor called the NMDA receptor. The inhibition of this receptor seems to cause an increase in glutamatergic activity at another receptor, known as the AMPA receptor. It is thought this secondary activity may be integral to ketamine’s quick action.

Recently a neuroimaging experiment shed some more light on how ketamine exerts its effects regionally. Researchers at the University of Manchester found that almost immediately after injection of ketamine, high levels of activity in the orbitofrontal cortex (OFC) stopped.

The OFC is thought to be involved in the regulation of affective states, and abnormal activity has been found there in depressed patients. The researchers in this study suggest it is the quick action of ketamine to quiet overactivity in the OFC that may be responsible for its rapid antidepressant effects.

Watch for more research to focus on the glutamatergic system in relation to depression. The greatest downside of antidepressant drugs today is the long time a patient must wait for them to have an effect (up to 4 weeks in many cases). Manufacturing a quick-acting antidepressant would be a boon for any pharmaceutical company, so expect them to heavily investigate the potential of glutamate-influencing drugs.

Ghrelin and the Omnipresence of Food

2008-05-06T23:35:00.011-04:00

It really is difficult to travel a mile in this country without being exposed to something trying to entice you to eat. Billboards, mini-marts, and restaurants have saturated our environment with visual cues that remind us of the importance of feeding. When at home the television, radio, or internet can be helpful if one has a tendency to forget the necessity of food—especially that of the fried, dripping, or cheesy variety. The advertisers behind all of these reminders are hoping that when you encounter them, your stomach will be coincidentally flooding your hypothalamus with ghrelin.

Ghrelin is a hormone produced by the gut. You may have heard of ghrelin’s counterpart: leptin, a hormone that is integral in letting the brain know you have had enough to eat. This is important, as can be seen by looking at mice with a genetic mutation that results in an inability to produce leptin:

Ghrelin seems to play the role opposite to leptin’s, it lets you know that the stomach is getting empty and it is time to eat. Ghrelin levels are highest before a meal and lowest afterwards. When ghrelin levels are raised experimentally, people are found to eat more than those administered a placebo.

Ghrelin receptors (and leptin receptors) are especially prevalent in the hypothalamus, but a recent neuroimaging experiment shows that ghrelin may have a much more widespread effect on the brain.

A study published this week in Cell Metabolism describes the use of functional magnetic resonance imaging (fMRI) to investigate ghrelin-related brain activation. Participants were scanned while looking at food and nonfood images. Some of the subjects received an infusion of ghrelin before the fMRI.

The ghrelin injection resulted in an increase in brain activation in areas associated with evaluating the hedonic value of a stimulus—the “reward centers” of the brain, along with a large network that includes visual and memory areas. These are some of the same regions thought to be responsible for drug-seeking and other types of addictive behavior.

Thus, high levels of ghrelin may make our advertisement-laden and food-available environment a dangerous one in which to live. But the hormone may also represent a plausible method for treating obesity. Vaccines that raise an immune response against ghrelin have been shown to be effective in reducing weight gain in rats. Their use with humans is currently being investigated.

Until (and if) they are found to be effective it is best just to try to ignore the constant urgings all around us to “eat, eat, eat”.

Gene Therapy: Struggling to Leave the Past Behind

2008-05-01T00:12:00.011-04:00

Gene therapy is a relatively new method of treatment that involves replacing the defective allele of a gene with a functional one. The technique, originally thought to hold great potential for the treatment of genetic diseases, was at first greeted with excitement and enthusiasm. This enthusiasm continued to grow after the first successful administration of gene therapy in 1990, to improve the health of four-year old Ashanthi Desilva (born with severe combined immunodeficiency).

Since then, however, gene therapy has had its ups and downs, hitting rock bottom with the death of 19-year old Jesse Gelsinger in 1990. Gelsinger wasn’t in a life or death situation. He volunteered for the study because of a brush with death he had early in life due to a genetically inherited liver disease. He volunteered with the hopes that a cure would relieve others from suffering through some of the trials he had as a young boy. Gelsinger, however, wasn’t informed of some of the possible dangers of the treatment he was about to undergo—dangers that the scientists involved in the study were cognizant of. They neglected to tell him, and he died several days after treatment.

Since then, gene therapy has struggled to creep out from under the shadow of that dark incident. Continued successes, however, indicate that gene therapy may still have the opportunity to live up to its once heralded potential. One example is a study reported this week in the New England Journal of Medicine that describes successfully using gene therapy to restore vision in three young adults born with severe blindness.

The subjects suffer from a disease known as Leber congenital amaurosis (LCA), which usually leads to complete blindness by middle age and is thought to be caused by a mutation in a gene called retinal pigment epithelium 65 (RPE65). The gene encodes for a protein that converts vitamin A into a form that can be used by the rods and cones of the eye to make rhodopsin (a pigment that absorbs light).

The researchers injected one eye of each patient with a harmless virus carrying the healthy form of the RPE65 gene. After only two weeks, all of the participants reported improved vision in dimly lit environments. Within six weeks, some of the patients were able to read several lines of an eye chart or navigate an obstacle course—dramatic improvements over their previous levels of legal blindness. The researchers involved suggest that, due to the efficacy of this treatment, it could eventually be applied to other eye disorders, such as macular degeneration.

Every advance made in the use of gene therapy is a major one, as after the death of Jesse Gelsinger, many were quick to condemn the use of the procedure as unsafe and irresponsible. While the scientists involved in the Gelsinger debacle deserve those criticisms, the procedure itself holds great promise for understanding and ameliorating some of the worst afflictions humans face. Hopefully one day the number of lives improved and saved through the use of gene therapy will soften the sting of the egregious mistakes made in its early history.

Encephalon #44 at Cognitive Daily

2008-04-28T15:45:00.003-04:00

The 44th edition of Encephalon, a first-rate brain-blogging carnival, is up at your favorite cognitive psychology website, Cognitive Daily. There are plenty of posts in this edition, a boon for the neuroscientifically-inclined reader.

Neuroimaging and the Social Ladder

2008-04-24T01:37:00.009-04:00

Social hierarchies, and the corresponding struggles to move up within them, are ubiquitous throughout the animal kingdom. It is common to observe the attainment of dominant, as well as the relegation to submissive, roles in animal groups. As is so often the case, when we turn our attention to our own species, however, we rarely describe ourselves in such ethological terms as dominant and submissive. To do so causes one to draw an uncomfortably amorphous line between the human and nonhuman kingdom, one that many of us avoid as it has a tendency to tarnish the uniqueness of the human condition, allowing for the propagation of the more comfortable idea that we are separate from “lower” forms of animal life.

But social rank exists, and is as evident in human societies as it is in any other. It affects every aspect of our lives, including our health. A famous study of British civil servants found an inverse correlation between social status and cardiovascular and mental health. This corresponds with numerous animal studies that have demonstrated the detrimental health effects lower social status can result in.

The concept of social hierarchy seems so universal as to suggest it may be an innate behavior, caused by neural architecture evolved specifically to regulate it. A group of researchers at the National Institute of Mental Health (NIMH) investigated this recently using neuroimaging techniques. They were hoping to find areas of the human brain that are activated specifically when assessing social rank, either of oneself or others.

To do so they used an interactive computer game that participants played for a monetary prize while their brains were scanned with functional MRI(fMRI). Throughout the game, a participant would intermittently see the pictures and scores of other players, who they thought were playing simultaneously in other rooms. In reality, the subject being scanned was the only player.

The researchers found a number of brain areas that were activated according to whether the participant felt she was succeeding or failing compared to her imaginary competitors. The reward area of the brain, specifically the ventral striatum, was activated just as highly in response to a rise in comparative ranking among other players as it was to a monetary reward itself, underscoring the importance the participants’ placed on social position. When the participants did worse than a player with an inferior ranking, areas of the brain correlated with emotional frustration were activated more strongly than when they were beat out by an equal, or superior, player. Specific areas of the brain were also activated just in the assessment of other players as they appeared on the screen, before negative or positive results of the game had been achieved. This may involve something of a “sizing-up” process, used to assess potential competition. Additionally, more competitive players experienced increased reward stimulation when they won, but also more emotional pain when they lost to an inferior player.

This supports the concept that our brains are designed to struggle for social dominance, even in a society where pure dominance is relatively rare. It certainly makes sense, however, considering the competitive drives that lie in many of us, and the desperation one can experience when one feels humiliated or reduced in stature. While our competition may be much more subtle than the violent dominance battles of bears, primates, or elephant seals, it still exists, and in a much more palpable way than many care to realize.

The Serotonin Hypothesis and Neurogenesis

2008-04-21T22:21:00.008-04:00

Although it has become a commonly accepted explanation for the neurobiology of depression among the general public (mostly due to misleading advertisements by pharmaceutical companies), the idea that depression is caused primarily by a serotonin “imbalance” is a description of the processes underlying the disorder so simplified it renders itself inaccurate. The serotonin hypothesis, proposed decades ago, gained increased support of late due to the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating depression. SSRIs increase extracellular levels of serotonin by blocking its reabsorption from the synaptic cleft back into the cell. The effectiveness of SSRIs led many to draw a one to one correlation between depression and low serotonin levels.

The truth is, however, that the reason why SSRIs work is not very well understood. Experimental attempts at isolating serotonin as the primary factor in depression have been unsuccessful. Regardless, many drug companies latched on to the serotonin hypothesis in promoting their antidepressants because it was simple for the consumer to understand.

The broader picture of the neurobiology of depression is much more complex. It begins with the proper mixture of genetic predisposition and environmental stressors. When that mixture is unfortunately encountered, higher than normal levels of the stress hormone cortisol may be released. These high cortisol levels are thought to cause neuronal damage, especially in the hippocampus. Glucocorticoid receptors (GR), which are receptors for cortisol (a type of glucocorticoid), may become desensitized, resulting in a persistent stress response, causing further neuroendocrine disruption.

This overactivity of the neuroendocrine system, specifically the hypothalamic-pituitary-adrenal (HPA) axis, can cause the release of cytokines. Cytokines are part of an immune response, but in this case they may end up causing further instability in the neuroendocrine system along with concomitant fatigue, loss of appetite, hypersensitivity to pain, and reduced libido.

Levels of a neurotrophin, called brain-derived neurotrophic factor (BDNF), also appear to be affected by all this upset in the HPA and hippocampus. Neurotrophins are proteins that are dedicated to neural support, and BDNF is integral to neurogenesis, plasticity, cell maintenance, and growth. Reduced levels of BDNF have been found to be strongly correlated with depression in human patients. These diminished BDNF levels may be responsible for the hippocampal damage mentioned above, as BDNF is the primary neurotrophin of the hippocampus.

Now enter serotonin. Serotonin is a type of neurotransmitter known as a monoamine, as are dopamine and norepinephrine. After they are released into the synaptic cleft, monoamines are quickly broken down by an enzyme called monoamine oxidase A (MAO-A). Then their constituents are taken back up into the neuron and recycled for future use.

MAO-A activity appears to be increased during depression. Thus, monoamines are metabolized more quickly, allowing less of them to reach their receptors on the other side of the synaptic cleft. Lower monoamine levels can negatively affect mood, cognition, motivation, and sensation of pain. It is thought that higher levels of cortisol may increase MAO-A levels, intensifying the symptoms of depression, and providing the explanation for why SSRIs can alleviate them.

Even this is a simplified illustration of the processes of depression, making the “chemical imbalance” described in drug commercials more similar to a children’s book than a thorough explanation. And a full understanding of the process has not yet been reached. An article in this week’s Science leads us closer to that understanding, however, by examining the effects of fluoxetine on neuronal plasticity in the visual cortex of the rat.

The neurogenesis and increases in BDNF caused by antidepressants appear to be as closely, if not more so, correlated with their effectiveness as changes in the neurotransmission of monoamines like serotonin. In order to further elucidate exactly how these processes work, and specifically if they cause beneficial modifications of neuronal circuitry in the brain, the authors of the report in Science investigated whether fluoxetine (Prozac) could cause plastic changes in the visual cortex that would improve vision in an impaired rat's eye.

They found that the neurogenesis promoted by fluoxetine was significant enough to restore vision in the rat's eye if the other eye was covered (covering the strong eye causes the cortex to focus on making improvements to the visual system through modifying the connections for the weaker eye). They had set out to investigate antidepressant-induced brain plasticity and neurogenesis, and in the process found that antidepressants may also be effective in the treatment of amblyopia (often referred to as lazy eye). Additionally, they provided further support for the idea that neurogenesis and the regulation of BDNF is just as important in treating depression as monoamine levels—and probably the more essential factor. The serotonin hypothesis is a useful way for drug companies to easily explain depression, but it seems to be far from the whole truth.

Reference:

Vetencourt, J.F., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., F. O'Leary, O., Castren, E., Maffei, L. (2008). The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex. Science, 320(5874), 385-388. DOI: 10.1126/science.1150516

Using Gene Therapy to Treat Addiction

2008-04-19T00:31:00.005-04:00

When you take into consideration the number of ways in which it can manifest itself, addiction is probably the most prevalent mental disorder that we don’t yet have a pharmaceutical treatment for. By identifying common neurobiological substrates that underlie all types of addiction, however, scientists hope to find drug targets that may one day allow it to be treated at least as methodically as other widespread disorders like depression. One of these commonalities found in the brains of addicted subjects involves a reduction of the number of available dopamine receptors in reward areas of the brain. Specifically, the density of a receptor called the D2 receptor is found to be decreased.

This diminished D2 receptor density can lead to addiction in two ways. A normal level of D2 receptors in an area of the brain called the nucleus accumbens is thought to play an important role in regulating impulsivity, and thus in avoiding an initial exposure to large amounts of drugs (or any addictive substance). Low levels may predispose drug users not only to trying drugs, but also to using them in amounts large enough to lead to addiction.

When a drug is used, it increases dopamine transmission. Over a period of time, this increase in dopamine activity in the brain can cause D2 receptors throughout the reward system to become depleted. This occurs due to a process called downregulation, which is a natural response of the body to decrease the number of receptors for a substance if the substance seems to be available in excessive amounts. Downregulation can lead to a disruption of the reward system that causes an addict to have difficulty finding pleasure in “normal” activities. The drug is the only substance that can facilitate a sense of pleasure, and compulsive use becomes difficult to avoid.

This understanding of the role of D2 receptors in addiction led researchers at the U.S. Department of Energy’s Brookhaven National Laboratory to search for a way to increase the number of D2 receptors in an addicted brain, in the hopes that doing so could reverse the process of addiction. They found gene therapy to be a successful way to do it.

First, the scientists trained a group of rats to self-administer cocaine (not a difficult thing to do, as most organisms tend to like cocaine). They then injected an innocuous virus that carried the gene for D2 receptor production into the rats’ brains. It was hoped the virus would insert the D2 receptor gene into the cells of the rats’ reward system, leading to an increase in D2 production, and a consequent reduction in addictive behavior.

After the gene therapy treatment, the rats showed a 75 percent decrease in cocaine self-administration. The change lasted for about six days before the rats returned to their previous usage. The group at Brookhaven has conducted a comparable experiment in the past with alcohol-addicted rats, and found similar results.

D2 receptor density has been shown to play a role in predisposition to addiction, as well as in the propagation of addictive behavior after its onset. With experimental results like those seen at Brookhaven, it appears manipulating D2 receptor density may have potentially beneficial effects in treating addiction. Unfortunately, given gene therapy’s checkered past (see here), it will be quite some time before such methods become available for use with humans. Primate studies, however, will most likely be the next step, and if all goes well perhaps gene therapy may one day end up being able to treat what could arguably be called the greatest behavioral scourge of our species: the repetitive pursuit of rewards long after they’ve lost their rewarding value, a.k.a. addiction.

Who's the Decider?

2008-04-15T22:30:00.003-04:00

It’s too bad Benjamin Libet didn’t live another year. If he did he would have been able to see the first neuroimaging evidence to support what he found with an electroencephalogram (EEG) almost thirty years ago: what we consider our conscious decisions are preceded by unconscious neural activity, which seems to be the actual—as President Bush would say—decider.

Libet conducted his most influential experiment involving neural activity and conscious decision-making at the University of California, San Francisco, in 1979. While he measured their brain activity with EEG, he asked participants to carry out a simple motor task (like pressing a button) at their own volition during a period of time. How many times and when they completed the task was up to the participant, but Libet asked them to note exactly when they felt they had made the conscious decision to make the movement. He found there was significant stereotypical neural activity that preceded the conscious decision-making, indicating there may be unconscious processes at work in choosing to execute a motor task.

Libet’s study sparked a great deal of controversy, as some saw it as a denunciation of free will. And rightly so, as Libet himself suggested the only evidence in support of free will is our own assertion that it exists. His experiments appeared to show unconscious brain activity that preceded conscious choice, making the entire concept of “conscious choice” questionable.

A study published in Nature Neuroscience this week adds more ammo to the materialist’s belt. A group of researchers in Germany conducted a study very similar to Libet’s, but used functional MRI (fMRI) to measure brain activity instead of EEG. They analyzed the images with computer software developed to recognize specific patterns of neural activity, in this case those that anticipated the participants’ decisions to press the button.

Not only did the group find neural activity that preceded conscious choice, but using the computer programs they were able to predict what choice the participant would make—up to 7 seconds before they “decided” they had made it. The predictions were not perfect, but much better than chance.

The researchers assert that this study doesn’t exclude the existence of free will. Even Libet maintained that there was a role for consciousness in decision-making, not in initiating an act, but in the ability to suppress it. The authors of this study agree, indicating that the capacity to reverse a decision made by the unconscious brain—something they plan to investigate in the future—would support a type of free will.

Libet died in July of last year, unfortunately less than a year before current brain scanning technology caught up with his theories of the late 1970s.

Epigenetics and Alcoholism

2008-04-09T00:42:00.008-04:00

Many of us, even those without alcohol problems, may feel more inclined to have a drink after a bad day, when stress is building up, or when we are trying to take our minds off of something that’s bothering us. This is one of the reasons alcohol is so popular: it has the ability to relieve anxiety and stress, at least while it’s being served (the next morning is another story). It’s also, however, one of the reasons alcoholism is so insidious. For an alcoholic, periods of alcohol withdrawal involve severe anxiety. When in the throes of this angst, it is extremely difficult for an alcoholic to avoid returning to what their brain has identified as the most efficient stress-reducer within their reach. A recent report in The Journal of Neuroscience indicates that this withdrawal anxiety may be due to changes in gene expression.

Previous research has pointed to the importance of a neuropeptide transmitter called neuropeptide Y (NPY) in managing anxiety, and in modulating alcohol consumption. Low levels of NPY, specifically in the amygdala, have been found in animals that have a preference for alcohol. Additionally, knockout mice who are engineered to lack NPY receptors exhibit an increased proclivity for alcohol.

The researchers involved in the current study wanted to determine how fluctuations in NPY occur. They found that NPY transmission in rats is influenced by transient changes in gene expression. These changes, known in biology as epigenetic processes (epi- meaning “in addition to”), involve chemical modifications of DNA that can alter gene expression, but don’t affect the actual DNA sequence of the organism. Thus, the gene expression is somewhat temporary (in that the DNA is not permanently altered), although how long it actually lasts depends on the specifics of the process.

DNA is wound around proteins called histones, and how tightly they are knitted together can affect gene expression epigenetically. There are enzymes that can loosen how tightly they are wrapped up, called histone acetyltransferases (HATs), and those that can tighten the packing, known as histone deacetylases (HDACs). HATs generally promote gene expression, while HDACs inhibit it.

The research team in this study found that exposure to alcohol decreased the activity of the gene inhibitors (HDACs) in rats’ amygdalas, leading to increased gene expression. This expression resulted in higher levels of NPY, and the corresponding low anxiety levels that alcohol is known for. Withdrawal, however, increased HDAC activity, reducing NPY levels, and causing a significant increase in anxiety behavior. When the group administered a drug that blocks HDAC activity, they were able to prevent observable anxiety from occurring during withdrawal.

This suggests that a possible future treatment for alcohol withdrawal could involve pharmaceuticals that inhibit HDACs. Removing the consuming anxiety caused by withdrawal would be a potent tool in the treatment of the disorder. And, studying epigenetic processes may be a fruitful method of finding treatments for addiction in general, as transient changes in brain function (which could be due to gene expression) seem to be involved in many cases.

Trying to Make Evolutionary Sense of Menopause

2008-04-07T22:34:00.007-04:00

This is a bit of a deviation from neuroscience (although neuroscience and evolution are fundamentally related), but I stumbled upon an article in PNAS about menopause that I found interesting, and I wanted to comment on it. I never really thought much about the evolution of menopause, and now that I have, it is a very unusual biological process (as well as a very unpleasant one for women). I don’t know if Darwin ever considered menopause in reference to his theories. If any readers know of any instances where he did, I’d be grateful if you could give me some page numbers or quotes.

According to evolutionary theory, the goal of any organism is to procreate—to pass on its genes. Thus, it has always been an enigma to evolutionary theorists why human females live so long after they have lost the ability to reproduce. They are the only ones in the primate family that have a long postreproductive life. It is confusing in and of itself that they lose the ability to reproduce during their lifetime, as it is quite rare in the rest of the animal kingdom.

This anomaly has caused some to suggest that menopause is not an adaptive trait, but a byproduct of the medical advancements we’ve made that have resulted in an extended human lifespan. Proponents of this argument assert that women now simply outlive their supply of egg follicles. This hypothesis is contradicted, however, by the fact that even in contemporary hunter-gatherer societies that have no access to modern medicine, women still experience menopause and live into their sixties.

Thus, evolutionary biologists have continued to try to develop an evolutionary explanation for menopause and a long postreproductive lifespan. In order to do so, it is necessary to figure out why these things may have conferred an adaptive advantage to our ancestors. This has given evolutionary theorists fits.

The first reasonable explanation was espoused by Dr. George C. Williams in 1957. He hypothesized that menopause is adaptive because it keeps older women from being exposed to the risks associated with childbirth (which were much higher for our ancestors). This allows them to remain alive long enough to ensure their children are raised to maturity to have their grandchildren (thus continuing the original mother’s gene line). This became known as the grandmother hypothesis.

Dr. Kristin Hawkes and colleagues elaborated on this hypothesis in 1997, when they studied a contemporary hunter-gatherer society in Tanzania called the Hadza. Hadza grandmothers are among the most assiduous workers in the society. They spend up to eight hours a day gathering food, which they bring home to feed their grandchildren. When Dr. Hawkes’ group saw how important the role of the grandmother was in Hadza society, they suggested that a long postreproductive life allowed those women to focus on the health of their grandchildren. This ability to provide for grandchildren and encourage the continuation of their genetic heritage, Hawke asserted, could have led to natural selection for menopause and living long afterwards.

Evolutionary biologists, however, were still not satisfied with this hypothesis. In order for menopause to outweigh the advantage of a continued ability to reproduce, a postmenopausal woman’s children would have to have twice as many children themselves. Infant mortality among those grandchildren would also have to be virtually nonexistent. Thus, when one crunches the numbers, the grandmother hypothesis doesn’t seem to quite add up. Certainly grandmotherly assistance in raising a daughter’s children is adaptive, but a quantitative analysis can’t justify the loss of childbearing ability to begin with.

Researchers at the Universities of Cambridge and Exeter published a paper last week in PNAS that they hope may help to resolve the debate over the evolutionary origins of menopause. They suggest that previous models have focused on personal-fitness and kin-selected fitness, or in other words, the health risks of reproduction for an older woman and the assistance she provides to the survival of her kin (like seen in the Hadza). What is ignored, they assert, is competition—namely reproductive competition between new females introduced into a group and older females who already have offspring in the group.

Their model is based on what is called “female-biased dispersal”, which simply means that in the hunter-gathering times of our species, females were more prone to move between social groups than men. A female newcomer in a group would have no genetic ties to anyone else in the group, and would have to compete with other women in the group for chances to reproduce. Older women who already had children could still continue their genetic heritage through grandchildren, instead of having more children themselves. Thus, the newcomer female would win the competition because procreating with a male in the group was her only reproductive option, while the older female had the option of gaining a grandchild and helping it to survive—an option that results in a greater chance of promoting her genetic heritage than procreating herself.

As evidence for this model, the authors present data that shows the reproductive overlap in humans is extremely low when compared to other primates. On average, women have their first baby at age 19, and their last at age 38—exactly when their first-born has reached normal breeding age. They also state that the rate of attrition of the initial oocyte stock in human females should allow for reproduction up to an age of about 70. At around age 38, however, there is an increased rate of ovarian follicular hazard. By age 50 (the average start of menopause), follicle stocks have dropped below reproductive levels. Thus, according to the researchers, at the age when they can begin to expect reproductive competition from the next generation of females, reproductive senescence is accelerated.

The authors suggest this hypothesis as a complement to, not a replacement for, the grandmother hypothesis. While the assistance a grandmother provides in caring for her grandchildren has an adaptive quality, they argue it cannot explain a female’s loss of reproductive ability. A combination of both theories, they state, best explains menopause and a long postreproductive lifespan.

While this is certainly a feasible hypothesis, it is far from the last word on the topic. In order for this theory to develop a stronger foundation, more studies must be conducted on other species that have cooperative breeding societies. It will be important to find if the reproductive overlap in these groups is similar to that seen in humans. And, although the reproductive overlap data is intriguing, menopause still seems to me to be an awfully complex mechanism to have evolved to reduce reproductive competition. Of course, evolution has resulted in many other inexplicably complex mechanisms.

If I were a woman I would be a little disgusted with evolution for forcing me to go through all of these uncomfortable processes like monthly cycles, pregnancy, and menopause. If evolution were fair, men would have to deal with at least one of these burdens. On the other hand, as a man I’m glad evolution isn’t fair—sorry!

Reference:

Cant, M.A., Johnstone, R.A. (2008). Reproductive conflict and the separation of reproductive generations in humans. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0711911105

A Triumph for Stem Cell Research

2008-04-02T23:44:00.015-04:00

Although the potential applications of stem cell therapy are numerous, right now some of its most promising conceivable uses are in the treatment of degenerative brain disorders, such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). In both of these afflictions, essential brain regions deteriorate, leading to notoriously debilitating symptoms. In AD, cholinergic neurons are depleted, while a loss of dopaminergic neurons is responsible for the effects of PD. Some scientists see disorders like these as ideal cases for stem cell treatment. For, in theory, if cholinergic or dopaminergic neurons are deteriorating, one could implant stem cells into the brain of the patient that could then be prodded to form new neurons. This could offset the atrophy caused by the disease.

Thus far, attempts to do this in laboratory animals have had mixed results. Sometimes a slight improvement can be seen, lending credence to the potential validity of the procedure. But failure for a diseased animal to get better after stem cell injection is more common, indicating there are problems with the technique. It is thought that those problems may have to do with the genetic compatibility of the stem cells being implanted into the subject’s brain and the subject's immune system. Perhaps the immune system is recognizing the stem cells as foreign and initiating a response to destroy them. This could be responsible for the animal’s lack of improvement.

Any scientists in training might want to pause for a moment before reading on and try to think about a logical solution to this problem. If a mouse’s immune system is rejecting stem cells from another mouse, what is a way to get around this?

The answer is: use stem cells genetically identical to the subject mouse’s cells. A group of researchers at Memorial Sloan-Kettering Cancer Center induced PD in mice by injecting them with a toxin. They then took skin cells from the tails of the mice and did a little DNA switcheroo. They took the DNA out of the skin cells and transferred it into mouse egg cells that had already had their own DNA extracted from them. The group then prodded the egg cells to divide, eventually producing stem cells as a part of normal embryonic development. The researchers added the appropriate growth factors to the stem cells to cause them to differentiate into brain cells.

They then injected the newly formed brain cells into the PD mice. The immune systems of the mice recognized the brain cells as “self”, since they were genetically identical. Thus, no immune response was mounted, and the mice showed significant neurological improvement. Out of about 100,000 genetically similar brain cells injected into each PD mouse, approximately 20,000 cells survived to function in each brain. Of course the study also had a group for comparison that received genetically dissimilar cells, and these mice did not get healthier. Only a few hundred of the genetically different cells survived in the brains of the mice in this group (of the same number injected).

This is what stem cell researchers have been waiting for: the use of somatic cell nuclear transfer (cloning) technology to make replacement cells for the body, resulting in clear evidence that it can lead to significant recovery from degenerative disorders. It is vindication for those who have been proclaiming the limitless possibilities of stem cells.

It, however, does not get around the fundamental problem stem cell advocates face. It requires the use of embryonic cells to create the stem cells. Thus, despite the potential it has, it will continue to face harsh political opposition. One has to hope, however, that as these procedures become perfected in organisms like mice, opponents will have to adopt a more utilitarian perspective. Perhaps using some of the half a million frozen embryos that are collecting dust in the in vitro fertilization clinics across the country would be considered a little more in depth if their ability to alleviate the suffering of living PD sufferers, which number over a million in the U.S. alone, had been demonstrated repeatedly in animal studies.

For other posts from me on stem cells, go here or here.

Encephalon #42 is Up at Of Two Minds—“It’s hot,” says Paris

2008-03-31T23:41:00.009-04:00

Your favorite brain blogging carnival is up at Of Two Minds. Paris Hilton makes a guest appearance.

Imaging Gene Expression in the Brain

2008-03-31T22:08:00.016-04:00

An integral aspect of finding better treatment for some of our most intimidating neurological afflictions, like multiple sclerosis (MS) and Alzheimer’s disease (AD), is improving our ability to detect them early. Our capacity to do so has improved drastically with the advent of neuroimaging techniques. But even with neuroimaging, early stages of these diseases may not be discerned if they have not yet caused considerable damage to the brain. What if we could find a way, however, to image the expression of genes that were activated to repair damage done to the brain, however slight it may be? That might be a way to start aggressive treatment of a disease without having to wait for the damage it wreaks to be evident on a brain scan, or without having to do an invasive biopsy.

And it is just what Researchers at Harvard have done recently. Their goal was to be able to detect gliosis in a living brain after damage to the blood-brain barrier (BBB). Gliosis is the accumulation of supporting neural cells called glial cells in areas of the brain where there has been an injury. A particular type of glial cell, called an astrocyte, is involved in gliosis. So, when an area of the brain is injured (in this case, the BBB), one can observe a proliferation of astrocytes in that area. Astrocytes contain a protein, glial fibrillary acidic protein (GFAP), which is integral to their supportive role (more on that in a second).

Since the researchers at Harvard were investigating the brain’s reaction to trauma, they induced BBB damage in mice through a number of different methods. The expectation was that the areas of damage would become engulfed with astrocytes intended to repair the injury. But astrocytes aren’t detectable with standard neuroimaging techniques.

So, the group developed a magnetic resonance (MR) probe that was connected to a short DNA sequence complementary to the mRNA of GFAP. Their reasoning was, if the DNA sequence runs into mRNA that encodes for GFAP, the two will anneal. Remember, GFAP is a protein found in astrocytes. Thus, the probe will accumulate in areas of astrocytic activity. This will be detectable by an MRI and indicate spots where neurological damage has occurred.

That’s exactly what happened. The scientists administered the probe—get this—through an eye drop. That’s about as noninvasive as it gets. The probe accumulated at the places where the BBB damage had been induced. Therefore, the probe seemed to indicate areas of acute neurological damage, before it could be measured otherwise without extremely invasive techniques.

The applications of this could be profound. They could include an improved ability to detect brain damage associated with AD, MS, stroke, and glioma (tumor), among other neurological problems. This could mean earlier detection, and better treatment, which in some of these disorders could mean a world of difference in quality of life after their onset.

Beta-Blockers May Act on the Brain

2008-03-27T22:34:00.016-04:00

When beta-blockers were discovered, they held such promise that the National Heart, Lung, and Blood Institute (NHLBI) halted trials of one such drug nine months early. They felt it was unethical to continue administering placebos to the control group in the study, based on the significantly improved survival rates they were seeing among those who were taking the beta-blockers. By the late 1990s beta-blockers had become a standard facet of therapy for patients suffering from congestive heart failure. They can be a very effective form of treatment, correlating with significantly reduced mortality rates in congestive heart failure patients.

Beta-blockers are so called because they block the action of epinephrine and norepinephrine on beta-adrenergic (BA) receptors. Epinephrine and norepinephrine are better known to some as adrenaline and noradrenaline. They are hormones responsible for modulating the “fight or flight” response of an organism. This response occurs when an organism is faced with a stressful situation, and results in an increase in both heart rate and force of myocardial contraction, along with the constriction of blood vessels in many parts of the body. Understandably, this puts a strain on the heart, a strain which beta-blockers seem to mitigate by blocking adrenaline from binding to BA receptors and reducing the intensity of the fight or flight response.

BA receptors are located throughout the body, however, and it has never been completely understood exactly where beta-blockers work to improve heart health. It was assumed (although not proven) that most of their action was on receptors in the heart. It was thought that the antagonistic effects of beta-blockers on these receptors inhibited the action of epinephrine, lowering heart rate, dilating blood vessels, and thus having an antihypertensive effect.

But a group of researchers at University College London recently demonstrated that beta-blockers may also have an influence on areas of the brain that regulate heart function. They studied the brains of rats that underwent infarction-induced heart failure and found the beta-blocker metoprolol acted directly on the brain to slow that heart failure. The location of the action was in an area the group had previously found to be associated with blood pressure and heart rate.

This doesn’t mean beta-blockers don’t work on the heart as well. It does, however, provide an impetus for further research into their mechanism. For, if they do have an effect on the central nervous system, understanding that influence could open the door for more comprehensive, and perhaps more specific, therapies to treat congestive heart failure, and heart disease in general.

Every Sweet Hath its Sour

2008-03-26T22:03:00.011-04:00

People, along with many other animals, have a preference for sweet foods. This is putting it mildly, as our love of sugary sustenance has immensely influenced our culture, economy, and health. Even our vocabulary has been affected by an affinity for sugar, as the word “sweet” itself has a positive connotation, in English and other languages (e.g. la dolce vita).

But, our predilection for sweetness has come with a cost, as evidenced by a worldwide prevalence of obesity that is over 300 million. Obesity is not, as is sometimes implied, a condition that suddenly appeared within the last fifty years. The rate of obesity is, however, growing at an alarming pace, and has been for several decades. This has led to a similar increase in obesity-related illnesses, like type 2 diabetes, hypertension, and heart disease.

Why would evolution have left us with a preference for sweet foods, when it is these very same foods that make us fat and unhealthy? Part of the answer may lie in the fact that the environment in which our evolutionary ancestors lived didn’t have 64 oz. fountain sodas, frosting-covered donuts, and candy aisles. In their hunter-gatherer societies, food was much more scarce, so while we spend our days counting calories, they spent theirs searching for them. Sweet-tasting foods are usually an indication of high caloric content. They are also generally not poisonous, making them doubly valuable to a primitive food gatherer. So, a predilection for them would have been adaptive at one time, and may be an evolved mechanism. This hypothesis is reinforced by a widespread partiality for sweetness throughout much of nature.

A group of researchers from Duke University Medical Center have conducted a study, however, that calls into question the idea that a penchant for high-sugar foods is based on the ability to taste their sweetness. The group genetically engineered a line of mice that lack the ability to taste sweetness. They then exposed the mice to sugar water and water containing sucralose, a noncaloric sweetener. The “sweet-blind” mice demonstrated a preference for the actual sugar water. The preference appeared to be based not on sweetness, but calorie content.

This still fits in with the idea that the proclivity for high-calorie foods is an adaptive trait, but without the ability to taste sweetness as an indicator of the water’s calorie content, how did the mice know which water to drink? The researchers examined the brains of the mice and found that their reward system was activated by the caloric level of the water—independent of taste. The high-calorie sugar water raised dopamine levels and stimulated neurons in the nucleus accumbens, an area of the brain thought to be integral in reinforcing the value of rewarding experiences.

This activation of the reward system is one that seems to be separate from the hedonic aspect of pleasure. The affinity of the sweet-blind mice for high calorie water may represent the involvement of metabolic awareness in the reward system. This implies the brain’s understanding of "reward" is at a much deeper biological level than that which we normally associate with the word. It also is further indication of a separation between the hedonic and reinforcing aspects of the reward system (see the previous post on dopamine).

This finding could have real-world implications in helping to battle the obesity epidemic. If high-calorie foods are rewarding in and of themselves, it may help to explain our nation’s addiction to items that contain calorically fulsome additives, like high-fructose corn syrup. Reducing the prevalence of such additives could decrease the rewarding value of the food they are in, and thus reduce consumption.

It’s imperative that something is done soon to curb the rising rates of obesity. Our propensity toward heftiness may be partly due to a once evolutionarily adaptive trait that has become maladaptive in our modern environment. Thus, our difficulty in making the adjustment illustrates the power of genetics and evolution. But it should also remind us that evolution might be having a powerful effect right now. If so, it is being aided by fast food, mini-marts, and billions of dollars of advertising, and a society that may be too complacent to pay attention to the ramifications.

The Many Faces of Dopamine

2008-03-24T14:13:00.011-04:00

The history of dopamine is full of experimental surprises and paradigmatic shifts. For many years after its discovery, it was thought dopamine’s only role in the brain was in the synthesis of norepinephrine, which is made from dopamine with the help of the enzyme dopamine B-hydroxylase. Around the middle of the twentieth century, however, it began to be recognized as having important physiological effects in its own right, and by the mid 1960s it was found that low levels of it were correlated with Parkinson’s disease. Continued investigation of dopamine led to the realization that it is a neurotransmitter, with its own receptors and pathways, and that its influence on brain activity is profound.

When a link between dopamine transmission and rewarding experiences (e.g. eating, sex, drugs) was established, it caused many to understandably hypothesize that dopamine was responsible for our subjective experience of pleasure. This is perhaps when dopamine reached the height of its stardom, as it began to garner media attention as the “pleasure transmitter”. Its role was readily embraced by a populace who were anxious to discover what exactly was behind their persuasive urge to sneak a piece of chocolate, pursue a one-night stand, or indulge in recreational drug use.

But science eventually caught up with the hype when researchers began to notice that dopamine didn’t correlate exactly with pleasure. For one thing, hedonic reactions could be sustained even after the administration of a dopamine antagonist (which inhibits dopamine’s effects). Additionally, dopamine transmission seemed to occur around the time a reward was being enjoyed, but not always during. For example, dopaminergic neurons might be activated as a person reaches for a piece of chocolate, but not while it is in their mouth, indicating more of an anticipatory role than an hedonic one.

It was eventually suggested that dopamine’s role is not in experiencing pleasure per se, but in making the association between an external stimulus and a rewarding experience. In this way, dopamine could act as a reinforcer, prompting associative learning that allows an organism to remember stimuli that proved to be rewarding in the past, and attribute importance, or salience, to them. Dopamine may be involved in the “wanting” aspect of pleasurable things, but not necessarily the “liking” of them.

So what causes pleasure, then? Leknes and Tracey, in April’s issue of Nature Reviews Neuroscience summarize a current view of the neurobiological substrates of pleasure and pain. According to this perspective, dopamine is responsible for the motivation required to seek out a reward while endogenous opioid systems are accountable for our subjective experience of pleasure. Dopamine is needed for “wanting”, while opioids are necessary for “liking”.

These two substances interact in a comprehensive model of the experiences of reward and pain known as the Motivation-Decision Model. According to this paradigm, actions are accompanied by an unconscious decision-making process that is based primarily on 1) the homeostatic needs of an organism, 2) threats in the environment, and 3) the availability of rewards. In the Motivation-Decision Model, the importance of survival is weighed against possible pain, and a decision is made on whether to pursue a stimulus. Opioids are involved not only in the experience of the reward, but also in inhibiting pain to allow the achievement of a reward if it is considered valuable enough.

Thus, dopamine at the same time draws attention to a reward and cues opioid release to allow for the procurement of it. Attainment of the reward also results in opioid activity as a substrate of pleasure. It seems these two neurotransmitter systems have a complex interaction that may underlie our experience of pleasure, our motivation to obtain it, and also the ability to withstand some pain in order to achieve it.

Dopamine may even have a role in helping us to remember aversive stimuli, although this is still up for debate. Striatal dopamine neurons have been found to be inhibited below baseline levels during exposure to aversive stimuli. It is unclear, however, whether dopamine's role in pain processing involves perception of pain or pain-avoidance learning.

Opioid and dopaminergic systems are closely related anatomically, but exactly which regions mediate the pain and pleasure responses is not yet completely understood. The overall system seems to include the nucleus accumbens (NAc), pallidum, and amygdala. All three areas have been shown to be active in reward and/or pain processing.

Although the history of dopamine is not yet complete, its role has grown substantially from a humble precursor to norepinephrine to one of the major neurotransmitters involved in the experiences of pain and pleasure, experiences that we find inseparable from our understanding of life. A deeper comprehension of this system will have great implications for areas like addiction. It also may prove beneficial in treating disorders like depression or chronic pain, where an ongoing affliction results in a diminished ability to experience pleasure. And, it will probably reveal dopamine’s part in the activity of the brain to be an extremely diverse one, a far cry from a neurotransmitter precursor, or even the “pleasure transmitter”, of the brain.

Reference:
Leknes, S., Tracey, I. (2008). A common neurobiology for pain and pleasure. Nature Reviews Neuroscience, 9(4), 314-320. DOI: 10.1038/nrn2333

fMRI and Counterterrorism

2008-03-20T23:32:00.007-04:00

Bioethicists have for years been debating the conscientiousness of using neuroimaging techniques outside of a clinical setting, such as in courtroom situations or interrogations. These discussions are inevitable, as an fMRI visualization of brain activity seems—at least potentially—to be a much more precise indicator of hidden thoughts and emotions than the standard polygraph. Jonathan Marks, an associate professor of bioethics at Penn State recently drew attention to this debate by asserting that fMRI is being used by the United States government in the interrogation of terrorist suspects.

fMRI is a neuroimaging technique that was developed in the 1990s and has since become the preferred method of imaging brain activity. It involves placing the head of the subject in a donut-shaped magnetic device, which can detect subtle changes in electromagnetic fields. When an area of the brain is in use, blood flow is directed to that region. Hemoglobin, an oxygen-transporting protein in red blood cells, exhibits different magnetic properties when oxygenated as compared to when it is deoxygenated. This is how the fMRI detects the flow of oxygenated blood and, based on the resultant magnetic field, produces an image of which areas of the brain are being used. fMRI has been used to help us gain a better understanding of which brain regions are active during a number of different states, such as happiness, sadness, fear, and anger.

Marks, however, points out that fMRI technology is not reliable enough to be used as a lie detector, and warns our government using it could lead to further abuse of prisoners and human rights violations. He claims that the U.S. is using fMRI not only as a lie detector, but also to single out terror suspects for aggressive interrogation if it indicates they recognize certain names or stimuli (e.g. the name of a terrorist sect leader). Marks bases this allegation on previously unpublished statements made by a U.S. interrogator.

While fMRI may have the potential to one day be an accurate lie detector, most experts in the imaging field would agree that right now it isn’t reliable enough to be used outside of a clinical or laboratory setting. There are a number of reasons for this. One is that, although fMRI images currently have the best resolution neuroimaging can offer, those images don’t provide a complete view of the intricacies of brain activity. They are made up of pieces known as “volume picture elements”, or voxels. The smallest voxels an fMRI can make out are about the size of a grain of rice, and would include the activity of tens of thousands of neurons. While this is helpful in determining the stimulation of brain regions, it is not precise enough to break that activity down into the interaction of very small groups of neurons. Thus, it is far from providing a complete image of neuronal activity—at least far enough to make it an ethically questionable method to use to condemn or exculpate those whose brains are scanned by it.

More important, especially in the use of fMRI with terror suspects, is the fact that fMRI data is drawn from averages of groups of people in laboratory settings. Individual differences in brain activity could be significant, and could be even more drastic across cultures. Additionally, a subject’s baseline fMRI measurements could change over time or by setting. Marks suggests it could take up to weeks of testing to determine what any one person’s baseline neural activity is. Also, a subject who is undergoing the stress of being held by a hostile party may exhibit brain activity that is already much different than that obtained from a participant in a laboratory experiment.

This is not to say fMRI might not be able to one day be used as a lie detector. A group of researchers from the University of Pennsylvania conducted an fMRI study in 2002 to determine which areas of the brain were active while participants gave deceptive responses to questions. The results indicated that the anterior cingulate cortex and superior frontal gyrus were specifically associated with lying, causing the researchers to conclude there are specific neural correlates to deception that are recognizable by fMRI. Even the lead author of that study, however, cautions that fMRI technology is not at the point where it could be used to identify a liar with certainty. He points out that the slightest changes in the wording of a question could produce different neural responses.

Marks’ fear is that fMRI will be used to screen suspected terrorists, resulting in their subjection to aggressive interrogation techniques. These types of techniques can cause a suspect to admit to crimes he/she had no part in, just to end the torture. Thus, Marks’ asserts, the fMRI won’t aid in finding out the truth, it will just allow interrogators to feel more justified in using whatever tactic they feel necessary to extract the information they are looking for. He cites President Bush’s veto of legislation this month that would have banned aggressive interrogation by the CIA an indication this misuse of fMRI could go on unchecked.

fMRI is an amazing technology, and its value will probably continue to be reinforced over the next several decades (or until it is displaced by an even more precise method). But its current limitations in determining whether someone is lying or not are clear. It’s depressing to think that, while neuroimaging has led to better medical care and a significantly improved understanding of the brain, it may also have led to the torture of individuals, some who may have been erroneously singled out due to a misunderstanding (or disregard) of the limits of the technology.

Encephalon #41 is Ready for Your Viewing Pleasure

2008-03-17T22:03:00.004-04:00

Check out Encephalon #41 at Pure Pedantry. The blog carnival includes a number of great neuroscience posts from a similar number of different bloggers. Have a look...

Sea Cucumbers on the Brain

2008-03-16T17:55:00.009-04:00

Advancements in biomedical science come from the study of all different sorts of organisms, from humans to roundworms, fruit flies, and yes, even sea cucumbers. The authors of a recent study in Science suggest research involving the sea cucumber has potential for improving treatments for Parkinson’s disease, stroke, and spinal cord injuries. They speculate it may conceivably even be used in the development of flexible body armor or bullet-proof vests.

You might be wondering what it is about the sea cucumber that would make it an interesting organism to study, and how such an ostensibly mundane creature could possibly lead to intriguing breakthroughs in science. The answer lies in the skin of this echinoderm, which can transform from soft and pliable to rigid and inflexible in a matter of seconds.

The sea cucumber gets its name from its appearance, which consists of an elongated, stocky body that resembles the precursor of the pickle. It is a scavenger, sliding along the sea floor in tropical waters, living off of plankton and debris for food. Normally, it is pliable, using its flexibility to slither around rocks or position itself along lines of current to suck up potential food particles that may float by. If touched, however, its skin goes from supple to stiff. This defensive mechanism provides it with a temporary sort of body armor to protect it from predators. The transformation is enabled by a complex matrix of collagen fibrils and fibrillin microfibrils whose interaction can be changed by the release of macromolecules from effector cells. The effector cells are activated by touch.

A group of researchers at Case Western Reserve University in Cleveland investigated the mechanism underlying this transformation in the hopes of creating a nanocomposite material analogous to the sea cucumber dermis. Nanocomposites are products of nanotechnology that involve the insertion of nanoparticles into macroscopic materials. This can alter the function or diversity of the macroscopic material, for example by making it more conductive or, in this case, adjusting its rigidity.

The group used an elastic polymer and inserted into it a rigid cellulose nanofiber network, made up of cellulose whiskers taken from other sea creatures known as tunicates. The authors note that, once the mechanism is perfected, cellulose from renewable resources like wood and cotton could also be used. The interaction between the cellulose fibers is made through hydrogen bonds, which keep the material rigid when it is dry. When soaked in water, however, the cellulose fibers are separated as water preferentially forms hydrogen bonds with them. This causes the substance to become malleable.

Neat, right, but how does it apply to the brain? Well, currently there is a lot of interest in using intracortical microelectrode implants to measure and influence brain electrical activity. This brain pacemaker method has shown a great deal of promise in treating Parkinson's disease, pain, stroke, and spinal cord injuries, among other disorders. Unfortunately, however, with current procedures the electrode signals tend to diminish after a few months, causing the treatment to have questionable long-term usefulness. It is hypothesized that the reason the signal decays is due to the rigidity of the electrode, which damages surrounding cortical tissue, leading to the electrode’s corrosion when glial cells respond to the threat.

Thus, the authors of this study suggest the use of an electrode that resembles the nanocomposite material they designed, which could be made rigid for penetration of the outer layers of the brain, then more flexible when implanted in cortical tissue to avoid doing harm to its environment. The aqueous makeup of the cortex could be suitable to displace the hydrogen bonds made between cellulose fibers and cause the electrode to become pliable.

This is a valuable find for the promising area of deep-brain stimulation. The authors suggest its potential may extend beyond such biomedical applications if the mechanism can be designed to react to nonchemical stimuli, like electrical or optical triggers. This is where technology like body armor could be involved—flexible at one moment yet rigid and protective at the next. That type of application involves all sorts of other dimensions, however, and is a long way off. Regardless, this is quite a bit of potential to come out of an organism many people have only heard of due to its seemingly incongruous comparison to its vegetable counterpart.

Reference:

Capadona, J.R., Shanmuganathan, K., Tyler, D.J., Rowan, S.J., Weder, C. (2008). Stimuli-Responsive Polymer Nanocomposites Inspired by the Sea Cucumber Dermis. Science, 319(5868), 1370-1374. DOI: 10.1126/science.1153307

Unraveling the Mystery of Mania

2008-03-15T22:37:00.005-04:00

Bipolar disorder (BPD) is one of the most prevalent psychiatric disorders in the world, affecting close to six million people in the U.S. alone. It is characterized by severe shifts of mood between stages of depression and mania. The depression involves traditional symptoms of a depressive episode, such as hopelessness, loss of interest in daily activities, and disruption of sleeping patterns. The manic episodes are what you might consider the exact opposite of depression, manifesting as drastically increased energy, euphoria, lack of inhibition, and delusions of grandeur. Many psychiatrists believe BPD is underdiagnosed, but it is also a term that is overused colloquially (much like depression), at least in my experience. Often someone will refer to an acquaintance as bipolar, meaning he or she has frequent mood swings. BPD is marked by severe changes in mood that last for several days at a time, quite unlike the sudden shift your significant other might experience when he/she hasn’t had their coffee yet.

BPD involves a spectrum of symptoms, and sorting out the mechanisms behind its occurrence has been expectedly complicated. No single gene has been identified as being responsible for BPD, and its complexity has prohibited scientists from being able to recreate the disorder reliably in animals for study. Recently, however, a group of scientists from the National Institutes of Health (NIH) has identified a gene that seems to be related to manic states in mice.

The gene, GRIK2 (glutamate receptor, ionotropic, kainite 2), encodes for a glutamate receptor, specifically glutamate receptor 6 (GluR6). Glutamate is the predominant excitatory neurotransmitter in the central nervous system. GRIK2 has attracted a lot of attention in BPD research since it was found to be associated with suicidal ideation brought on by antidepressant treatment. People with BPD are more prone to treatment-induced suicidal ideation, leading the group at NIH to investigate this gene in regards to BPD.

The group created knockout (KO) mice that lacked the GRIK2 gene and compared their behavior with control mice. KO organisms are those that have been genetically engineered to carry an inoperable version of a gene. This allows researchers to juxtapose their behavior with that of other animals that have the gene, and thus isolate the effect that the gene has.

The KO mice exhibited behavior that was consistent with mania. This was measured with a battery of tests, which showed the mice to be more aggressive, more active, and less inhibited. They were also overly sensitive to amphetamine administration, and their hyperactivity was mitigated by the administration of lithium, a mood stabilizer and common treatment for BPD.

This research is important, as scientists may now have an animal model for the manic episodes of BPD. The group does point out, however, that it is unknown whether GRIK2 is involved in the cyclic nature of BPD, or if it causes the euphoric and mind-altering aspects of a manic episode. While there is still much to be understood about the disorder, this may be an integral step toward elucidating its perplexing mechanism.

Daisy, Daisy, Give Me Your Answer Do

2008-03-13T23:10:00.008-04:00

Even the most successful attempts at artificial intelligence (AI) always seem to lack certain essential qualities of a living brain. It is a formidable task to create a robotic or computerized simulation of a human that seems to display original desires or beliefs, or one that truly understands the desires and beliefs of others in the way people can. This latter ability, often referred to as “theory of mind”, is considered an integral aspect of being human, and the extent to which it has developed in us may be one thing that sets us apart from other animals. Reproducing theory of mind in AI is difficult, but a semblance of it has been demonstrated before with physical robots (click here for an example). Until now, however, it has never been recreated in computer generated characters.

A group of researchers at Rensselaer Polytechnic Institute (RPI) have developed a character in the popular computer game Second Life who uses reasoning to determine what another character in the game is thinking. The character was created with a logic-based programming RPI calls RASCALS (Rensselaer Advanced Synthetic Character Architecture for “Living” Systems). The program involves several levels of cognition, simple systems for low and mid-level cognition (like perception and movement), and advanced logical systems for abstract thought. The group believes they can eventually use RASCALS to create characters in Second Life that possess all the qualities of a real person, such as the capacity to lie, believe, remember, or be manipulative.

Second Life is a life-simulating game, similar in some ways to the popular game The Sims. Unlike the The Sims, however, Second Life involves a virtual universe (metaverse) where people can interact with one another in real-time through avatars they create for use in the game.

The character created by the group at RPI, Edd, appears to have reasoning abilities equivalent to those of about a four-year old child. To test these abilities, Edd was placed in a situation with two other characters (we’ll call them John and Mike). Mike places a gun in briefcase A in full sight of John and Edd. He then asks John to leave the room. Once he is gone, Mike moves the gun to case B, then calls John back. Mike asks Edd which case John will look in for the gun.

Does this sound familiar? It's an actual psychological test developed in the 1980s, originally known as the Sally-Anne test. The Sally-Anne test plays out the same scenario described above, only with dolls and a marble or ball (since its inception the test has been done with human actors as well). A child watches the Anne doll take a marble from Sally’s basket and put it in her box while Sally is not in the room. If the child, after watching the interaction, can guess when Sally returns that she will look in her basket for the marble, it demonstrates he or she has begun to form theory of mind. The child is able to understand that other people have thoughts and beliefs different from his or her own. They realize that when Sally re-enters the room she is unaware the marble has changed positions, so she will look in the spot where the marble originally was. The ability to make these types of attributions of belief usually develops at around age three to four in children.

Edd, the character from Second Life, is able to do the same. When Mike asks him in which case John will look for the gun, he will say case A—the case John saw the gun placed in (for the demonstration click here). And Edd is not programmed specifically to make this choice. Instead he “learns” from past mistakes that, if John cannot see the gun being moved he will not know it is in the other briefcase.

The research group at RPI see Edd as a first step in the creation of avatars on Second Life that can interact with humans in a manner unlike that of any simulated characters before, being able to understand and predict the actions of others, and act virtually autonomously. They see potential benefits of this technology in education and defense, as well as entertainment. IBM, a supporter of the research, has visions of creating holographic characters for games like Second Life, which could interact with humans directly.

This is all pretty amazing stuff, but for some reason HAL singing “Daisy Bell” keeps eerily replaying in my head as I write it.

This Study Sponsored by Krispy Kreme

2008-03-08T01:20:00.015-05:00

The brain’s motivational processes always provide an interesting area for research, as they underlie all of our “voluntary” behavior. Much progress has been made in understanding motivational areas of the brain since the advent of sophisticated neuroimaging techniques. Recently, a group of researchers using fMRI attempted to identify specific activity in the brain that takes place when a person shifts their attention to a relevant object in their environment (the first step in developing motivation to obtain the object).

The group focused on hunger, testing subjects at two separate occasions: once after eating as many Krispy Kreme donuts as they could (eight was the record), and another after fasting for eight hours. In each experimental condition, the subjects were then shown pictures, some of tools and others of donuts, while being scanned with fMRI.

As you might expect, the subjects who had just gorged themselves on donuts didn’t show increased activity in response to the donut pictures. But in those who fasted, images of donuts caused rapid activity throughout the limbic lobe—an area of the brain thought to be involved in identifying salient objects in one’s environment. Immediately after the donut was recognized, attentional mechanisms in the brain, involving the posterior parietal cortex, were also stimulated, demonstrating that the subject’s attention had been turned to the relevant object. These mechanisms seemed to work in conjunction with those that were used to gauge the importance of the object. Thus, the authors of the study suggest the posterior parietal and limbic lobe play an interactive role in identifying salient stimuli and immediately focusing one's attention on them.

This experiment provides further evidence for the concept that our brains are inherently organized to recognize aspects of our environment that are beneficial to us. Many believe the significance of certain types of stimuli is evolutionarily ingrained, meaning that our brains evolved to place importance on those that promote survival, such as food, water, or sex (which leads to dissemination of genetic information). This study goes a bit further to elucidate the mechanisms involved in the distribution of attention among salient and non-salient stimuli. If a hungry brain sees food, it will activate those attentional mechanisms to focus itself on that food, providing motivation to obtain it.

I suppose the greater task in our corpulent society right now, however, is to learn how to get people to avoid those Krispy Kreme donuts instead of to understand exactly how our brain focuses attention on them.

Genes and Happiness, or Free Will Revisited

2008-03-07T01:54:00.010-05:00

As I begin writing this post I can’t help but be reminded of the one I wrote a few weeks ago about the troubles one runs into when trying to reconcile present-day understandings of neuroscience and genetics with the traditional concept of free will. A team of researchers from the University of Edinburgh and the Queensland Institute of Medical Research recently conducted a study to investigate how much our subjective sense of happiness is dependent upon our genetic makeup (and thus personality style). Is our ability to be happy solely up to us ("us" being defined as hypothetical beings with complete free will), or is it constrained by the type of person we are, which is determined to a large extent by our genes?

To find out, the researchers studied a sample of 973 pairs of twins (365 monozygotic, or identical, and 608 dizygotic, or fraternal). Twin studies are an experimental method used in behavioral genetics to isolate the influence of genes on personality. Since monozygotic twins share 100% of their genes, behavior that is based primarily on genetic makeup can be assumed to be seen in both members of a pair. The actual observations can be compared with the phenotype of dizygotic twins, who only share about 50% of their genetic information. Similarities between monozygotic twins that aren’t as significant in the dizygotic twins can be assumed to have a prominent genetic basis. In this model, environmental effects are also considered, but the composition of the sample allows the effects of gene and environment to more easily be separated.

The researchers used a questionnaire called the Midlife Development Inventory (MIDI) to assess the personality of the participants. The scores were averaged across five dimensions that describe overall personality characteristics, known as the Five Factor Model (FFM). It consists of Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism. The FFM is a personality assessment tool that was developed in the early twentieth century. It has been refined numerous times, and been shown to be a reasonably accurate instrument for making generalized appraisals of personality.

Certain traits measured by the FFM have also been correlated with one’s sense of subjective well-being, especially Neuroticism, Extraversion, and Conscientiousness. The reasons why exactly are uncertain, and could be due to any number of factors involving how these traits affect one’s social interactions and lifestyle. For example, low Neuroticism may indicate emotional stability and Conscientiousness could denote self-restraint, both qualities which are often considered important in leading a contented life.

The researchers also conducted an interview to assess well-being, asking participants how satisfied they were with their life at present, how much control they felt they had over their lives, and how satisfied they were with life overall.

The group found that, as has been seen in the past, subjective well-being was correlated with the personality traits of the FFM. Specifically, it was negatively correlated with Neuroticism, and positively correlated with Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. In addition, the correlation between the FFM characteristics in monozygotic twins was significantly higher than in dizygotic twins, suggesting a genetic basis for the formation of these personality traits.

Subjective well-being was shared between the twins at a level correlated with that of their positive personality traits. What this suggests is the following: we are born with a particular genetic makeup that is deeply ingrained and difficult to change, regardless of experience. This makeup is translated into personality traits that can be broadly generalized into categories such as neurotic, extraverted, etc. Some of these traits end up being conducive to our happiness and well-being. The less neurotic an individual is, for example, the happier he or she tends to be. Since these attributes are genetically prescribed and predictive of our happiness, some would say the amount of happiness we are able to experience in life is limited to a great extent by our genetic makeup.

It is easy, however, to take this argument a bit too far. A headline today on sciencedaily.com, for example is “Genes Hold the Key To How Happy We Are, Scientists Say”. This is not really what the authors of this study are claiming. They instead are suggesting our genes provide us with a starting point, a set-point, of emotional stability, which we end up moving from in one direction or another based on our experiences. While it is important for some of us to understand how the limitations of our genetic makeup might handicap us when it comes to the enjoyment of life, it’s also necessary to point out that the environment can have drastic effects on who we are compared to our original constitutional makeup. People born with what might be considered an unfavorable personality assessment according to the FFM often come up with innovative ways to improve their life, and their outlook on it. So, do genes alone hold the key to how happy we are? I don’t believe so. But they may provide us with a rough outline, albeit one that we are able to constantly revise throughout our lives.

Of course, I may just be in a good mood today. I don’t think the post I wrote about neuroscience and free will a few weeks ago was so optimistic. Those revisions we make in that outline may themselves be constrained by genetic limitations on the options we are able to imagine…and the argument can go on and on…

Reference:

Weiss, A., Bates, T.C., Luciano, M. (2008). Happiness Is a Personal(ity) Thing: The Genetics of Personality and Well-Being in a Representative Sample. Psychological Science, 19(3), 205-210. DOI: 10.1111/j.1467-9280.2008.02068.x

Reading Minds With fMRI

2008-03-05T23:48:00.009-05:00

Well, it may not be mind reading just yet, but a computer model developed by a group of neuroscientists at the University of California, Berkeley, is perhaps one (tiny) step closer to that sort of technology. In a study to be published in tomorrow’s issue of Nature, the group describes the use of the computer model to accurately identify which photograph—out of a group of many—a subject had just looked at, based only on fMRI data. Even more impressively, the model worked with photographs the participants had never seen before.

Studies of this sort have been conducted in the past with success, but involved only simple patterns or basic object recognition. In the current study, two participants were shown 1750 photographs of various scenes and objects while their brain activity was measured with fMRI. Using the data from these fRMI scans, the researchers created a computer model to distinguish patterns of activity in the visual cortex that occurred in response to specific features of the photographs. For example, the model could be used to determine which areas are typically activated in response to lines, spherical shapes, or spots of dark shadowing. To do this, they divided the fMRI representation of the visual cortex into small cubes and used the model to examine how activity in each subsection changed in relation to different photographs.

After the initial fMRI data was analyzed with the computer model, the two subjects (also co-authors of the study) then viewed 120 photographs they had never seen before while being scanned again. The researchers used the model to predict what the brain activity of each subject would be as they viewed the novel pictures. For one subject, the model’s prediction matched the actual brain activity 92% of the time. For the other, it was accurate 72% of the time. By chance alone, it would have made the correct match only 0.8% of the time. One of the subjects then viewed a set of 1000 pictures with scenes more similar to one another to further test the specificity of the model. It was still accurate 82% of the time.

While the mention of mind reading above is, of course, a bit sensationalistic, this technology is still amazing, and perhaps a harbinger of strange things to come. If we can eventually predict patterns of brain activity in response to visual stimuli with precision, who is to say we will not one day be able to dissect more complex thought processes, or at least identify sharp distinctions, like when one is telling a lie vs. telling the truth? Such technology, if determined to be accurate, could have interesting ramifications.

This is all speculation about things that may happen in the distant future, however, and only tenuously related to the computer model discussed above. After all, the model is still limited to pictures from a known set. It could not be used to interpret fMRI data and reconstruct a semblance of what a person has seen, it can only match the activity to photographs it has been exposed to previously. Regardless, it is an area of research that is worth following closely, as it involves perhaps the most precise elucidation of cognitive processes we have yet to be privy to.

Experimental Evidence Supports Runner's High; Aromatherapy...Not So Much

2008-03-05T15:50:00.012-05:00

For a long time the idea that a “runner’s high” occurs after exercise of a long duration has been obvious to athletes. The physiological reasons behind it, however, have been much more of a mystery to scientists. The most prominent theory to explain it over the last twenty years or so has been the endorphin hypothesis, which suggests that prolonged strenuous activity releases endorphins, causing an elevation of mood and decrease in the perception of pain. The word endorphin comes from “endogenous”, meaning produced within the body, and “morphine”, an opiate known for its pain-mitigating properties. Thus, endorphins are like opiates created by our bodies, and can act as natural painkillers or induce euphoric feelings under certain circumstances.

The endorphin hypothesis has received a fairly high degree of support over the years, although it has never been confirmed experimentally—until now. A group of researchers from the Technical University of Munich and the University of Bonn recently conducted an experiment with ten athletes. They ran PET scans on the athletes at two separate times: at rest, and after a two-hour bout of endurance running.

In the PET, they used a radioactive opioidergic ligand 6-O-(2-[F] fluoroethyl)-6-O-desmethyldiprenorphine ([18F]FDPN). This substance binds to opiate receptors in the brain. If opiate receptors are in use by endorphins, the [18F]FDPN should be unable to bind to those receptors. Thus, if intense exercise produces endorphins, they will occupy opiate receptors, and, as compared to the PET scan at rest, there should be more [18F]FDPN in an unbound state, as its natural binding site will be filled by endorphins.

This is just what the researchers found. After the exercise, opioid receptors showed decreased availability (meaning they were bound to endorphins produced by the running). The level of euphoria as reported by the athletes was significantly increased, with higher levels inversely correlated with the availability of opiate receptors. The brain regions most affected were primarily in prefrontal and limbic areas, areas commonly associated with emotions.

The researchers hope to expand upon this study by searching for practical uses for the improved understanding of acitivity-induced endorphin binding. This could include investigating the specific benefits of exercise for those suffering from chronic pain, depression, or anxiety. They also are very interested in how genetic makeup affects opiate receptor distribution in the brain, and how this might affect addiction.

Another concept (albeit a less substantiated one than the occurrence of runner’s high) under investigation of late is the benefit of aromatherapy. Aromatherapy is an alternative medical practice that has been around for centuries, but has regained a great deal of popularity over the last couple of decades. It involves the inhalation of certain scents, such as lavender or lemon, which are purported to have a number of positive effects on one’s mood and health.

Researchers from Ohio State University put aromatherapy to the test in what is probably the most comprehensive study on the practice to date. Using 56 participants, some who advocated the use of aromatherapy and others who had no opinion, the researchers measured blood pressure, heart rate, healing ability, stress hormone levels, reaction to pain, and recorded self-report of mood over a three-day period of aromatherapy use. The participants were exposed to an odor suggested to be a stimulant (lemon), another purported to be relaxing (lavender), and water with no odor. Some of the participants were told what odors they would be subjected to, and what changes they might expect, while others were randomly placed in a blind category where no such information was given. The experimenters were all kept in a blind condition.

The lemon oil did induce an enhancement of mood based on self-report, although the lavender oil did not. Neither of the oils, however, had any effect on the numerous biochemical markers used to measure stress, healing ability, immune response, or pain tolerance.

The researchers who conducted the study are quick to point out this is not conclusive evidence there is no benefit to aromatherapy. As one of the authors stated, however, “…we still failed to find any quantitative indication that these oils provide any physiological effect for people in general”. It's something to keep in mind if you are thinking of buying any alternative medicine products that tout their immune-boosting, stress-relieving, and mood-enhancing qualities: are their claims backed by science, or just anecdotal evidence?

Diltiazem Reduces Cocaine Craving in Rats

2008-03-01T02:43:00.011-05:00

A seemingly unlikely candidate in the battle against cocaine addiction has emerged from work being done by researchers at Boston University School of Medicine and Harvard Medical School. The group administered diltiazem, a drug commonly used to treat hypertension, to cocaine-addicted rats, and found that it significantly reduced their cravings for cocaine.

Diltiazem is a type of drug known as a calcium (Ca2+) channel blocker. Ca2+ channels are voltage-gated ion channels, which when activated allow an influx of Ca2+ into a cell. This inflow of Ca2+ can exert any number of effects, depending on the cell. In neurons, it is often the trigger for the release of neurotransmitter-filled synaptic vesicles, which is the basis of communication between the nerve cells. Ca2+ channels also can be involved in hormone and gene expression. In the heart, they contribute to muscle contraction. Diltiazem limits the activity of Ca2+ channels, and reduces contraction of the heart muscle. This lowers the amount of oxygen the heart needs, which can alleviate symptoms of hypertension.

So what does this have to do with cocaine? Current models indicate drug addiction occurs due to neural reconfigurations caused by the memory-encoding activity of two neurotransmitters: glutamate and dopamine. Glutamate, the main excitatory neurotransmitter in the brain, is thought to encode specific sensory and motor information in cortical and thalamocortical areas, while dopamine seems to react in a more general sense to rewarding stimuli. The interaction of these two chemicals is believed to be responsible for intensifying the memory of drug use and all the stimuli related to it, leading to craving, repeated use of the drug, and addiction.

Ca2+ channels play an integral role in these neurotransmitters working together harmoniously. When they are blocked and brain Ca2+ decreased, the process is disrupted. This is what may account for the reduction of cocaine cravings in the rats.

This study is a promising one for the addiction field, as there are no effective drug therapies currently available for cocaine dependency. It also speaks volumes about how far our understanding of addiction has come. Once it was regarded simply as a choice made by degenerates who had no motivation to live a normal life. Eventually scientists found there are biological mechanisms underlying it that seem to, for the most part, preclude consciously choosing it as a lifestyle. As we come to understand those mechanisms more, the concept of addiction becomes at the same time more tangible and complex.

For example, dopamine was originally thought to be the substrate of pleasure in the brain. It now has a better understood, but more complicated role, of helping us to identify rewarding stimuli in our environment. This is a skill that is evolutionarily adaptive for obvious reasons. Fairly recently it was learned that glutamate is involved in the addiction process as well. Now that our understanding of the interaction between dopamine and glutamate is growing, we are beginning to understand addiction involves a series of synaptic changes made through associative learning, which result in an almost indelible imprinting of an addictive memory. And this expanding knowledge of the neuroscience of addiction all must be viewed against a backdrop of identified genetic patterns, which predispose certain people toward the disorder.

Although this view of addiction as having a neurobiological and genetic basis is commonly accepted science, it has yet to be embraced by a large portion of society, including governments who continue to use incarceration of addicts as their preferred method of dealing with the issue of drug use. Most of us have an addiction of some sort. It may be food, or cigarettes, shopping, or heroin. It’s important to remember, though, that all addictions, from the most minor to the most severe, are probably due to a similar process in the brain that has caused too much importance to be placed on the pursuit of a once-rewarding stimulus. So a crack addict is victim to the evolution and organization of the human brain’s reward system in the same way a shopoholic is. And for those who are lucky enough to not have an addiction, or at least a very damaging one, you might want to hesitate before you credit yourself too much or denigrate someone with an addiction. If the addict were born with your genes and your brain, chances are they wouldn’t be an addict either. It’s time we begin, as a society, recognizing addiction as a disorder instead of a reprehensible and prosecutable offense, in and of itself.

Good News for Ugly Babies

2008-02-27T22:53:00.010-05:00

Babies really have it made. They usually have at least one, and sometimes a coterie, of people in their life devoted to figuring out exactly what will make them happy, whether it be food, milk, a pacifier, etc. They also have the privilege of enjoying a warm, cooing welcome from almost anyone they encounter, be it a close relative or complete stranger. Not many of us have the ability to turn away from a smiling baby with cold indifference, and some will stop whatever they are doing just to walk over to tell the infant how cute he/she is.

Charles Darwin made the first scientific attempt at explaining the affinity most people have for babies. He suggested it involves an evolutionarily adaptive mechanism. Babies are the evolutionary goal of procreation realized. Considering the biological investment made in bearing a child, along with its individual helplessness, it would be adaptive for a species to be inclined to treat their young with a caring hand. Konrad Lorenz, a pioneer in explaining instinctive behavior, further elucidated on this idea, suggesting there are specific aspects of an infant’s facial features that automatically elicit a parental response, even from a non-parent.

Neuroimaging studies have indicated that parents do show increased activity in areas of the brain associated with rewarding events (nucleus accumbens, anterior cingulate, amygdala) when they see an infant’s face, even if it is not their own child. People who are already parents may be naturally more inclined toward positive feelings when seeing a baby’s face, however, as it could cause them to generate a pleasing comparison to their own child, or even just stem from their familiarity with infantile features. To determine if a predilection for infants is a universal trait, participants who aren’t parents would need to be included in such a study.

Recently, a group of researchers did just that, conducting a study that involved both parents and non-parents. They used magnetoencephalography, an imaging technique that measures magnetic fields produced by the brain’s electrical patterns (quite possibly the future of neuroimaging), to image brain activity while participants viewed unfamiliar adult and infant faces (interspersed with other symbols). The faces were closely matched in expression and attractiveness to prevent these characteristics from playing a confounding role in the study.

They found that when infant faces were viewed, before normal activity in the brain associated with seeing a human face occurred (in an area called the fusiform face area), there was a surge of activity in the medial orbitofrontal cortex. The medial orbitofrontal cortex has been implicated in a number of previous studies in the perception of rewarding stimuli. This activity occurred only when viewing infant faces, and had an extremely rapid onset—about 130 ms after seeing the face. The speed of the response indicates it was probably non-conscious.

This finding seems to add support to Darwin and Lorenz’s theories of an instinctual preference for the features of infants. The authors of the study note it also may have some clinical importance, specifically in cases of postnatal depression. One of the most troublesome symptoms of postnatal depression is the tendency a mother can acquire to be unresponsive to her child. This coldness sometimes makes a crying infant even more uneasy instead of being pacified when their mother approaches. Links between depression and the cingulate cortex have been suggested, and the cingulate cortex is strongly connected to the medial orbitofrontal cortex.

The researchers plan to do follow-up studies to investigate if differences in levels of parenting experience, gender, or specific infant features might affect this reaction. But the indication that the initial response seems to be non-conscious implies there may be a neural reward mechanism in place that is specific to seeing an infant. It is easy to understand why such a trait would be adaptive for a parent to have, as the more solicitous parents are toward their offspring the better their progeny’s chances of survival. It also makes sense that the trait would become widespread, as in tribal groups kin selection could play a large role in making infant survival important. Thus, it could have eventually become a response almost all people, parent and non-parent alike, shared. I suppose no one should be surprised that another concept espoused by Darwin may one day help us to better understand human nature.

Reference:

Kringelbach, M.L., Lehtonen, A., Squire, S., Harvey, A.G., Craske, M.G., Holliday, I.E., Green, A.L., Aziz, T.Z., Hansen, P.C., Cornelissen, P.L., Stein, A., Fitch, T. (2008). A Specific and Rapid Neural Signature for Parental Instinct. PLoS ONE, 3(2), e1664. DOI: 10.1371/journal.pone.0001664

Understanding Memory at the Molecular Level

2008-02-25T22:01:00.010-05:00

Probably the most extensively researched facet of cognition, memory has proven to be a process that is as difficult to unravel as it is essential to the human experience. Monumental developments in memory research are occurring regularly, however, although they are often under the public radar as they are only pieces of a puzzle we are still incapable of fully assembling. Regardless, the work being done on these pieces will one day allow for an understanding of memory so extensive it will seem to have little in common with our traditional conceptions of what memory is.

An important share of that work is being done at The Scripps Research Institute. A group of researchers there have been focusing their studies on the molecular mechanisms of memory. Last year, they developed a transgenic mouse with genes that cause neurons activated within a particular timeframe to be tagged with a fluorescent marker. Using this mouse, the group demonstrated that the same neurons used during the learning of a fear response are activated during retrieval of the memory. The number of neurons activated also correlated with the intensity of the response, indicating a steady relationship between experience and neural representation. This work helped to elucidate the structure of neural networks involved in memory consolidation and retrieval.

The group then turned their attention to the mechanism involved in long-term memory formation. Receptors for glutamate, the primary excitatory neurotransmitter in the central nervous system, are essential for long-term potentiation (LTP), which is the enhancement of synaptic communication thought to underlie long-term memory formation. It has been suggested that LTP may be the result of the integration of AMPA glutamate receptors (AMPARs) into the synapse that is strengthened. The additional receptors would make the neuron more sensitive to glutamate, leading to LTP.

It has been shown that protein synthesis in neuronal cell bodies is necessary for consolidating memories as well. Thus, it was hypothesized that proteins made in the soma (cell body) are involved in the insertion of AMPARs into synapses associated with memory, resulting in quicker transmission at these synapses and the capacity for memory recall. What has been unclear, however, is exactly how the proteins synthesized in the soma cause plasticity to occur only at the specific synapses associated with a memory.

A popular explanation for this process involves something called synaptic tagging. In this scenario, neuronal stimulation causes the creation of a synaptic tag, a kind of signpost on the neuron that is used to attract proteins necessary for plasticity (such as proteins involved in forming AMPARs). This tagging would occur only at synapses involved in processing the LTP-inducing stimuli, and thus could account for the localization of memory to specific groups of neurons.

The researchers at The Scripps Institute, Naoki Matsuo, Leon Reijmers, and Mark Mayford, again used transgenic mice, this time to investigate the concept of synaptic tagging. They engineered mice to express a subunit of the AMPAR, referred to as GluR1, fused to a green fluorescent protein. They suppressed expression of this gene through the use of doxycycline until the experiment. They then exposed some of the mice to a fear-conditioning program, where they learned to associate foot shock with a particular environment. GluR1 is necessary for the formation of AMPARs. Thus, new AMPAR formation was measurable after the fear conditioning by examining dendritic spines of hippocampal brain slices for fluorescence.

Dendritic spines are regions that protrude from dendrites, where synapses are located and input from other neurons received. There are three morphological types: thin, stubby, and mushroom-shaped.

As they expected, the researchers found an increased proportion of fluorescent GluR1 subunits on the dendrites of hippocampal neurons in those mice that underwent the fear conditioning. Specifically, the fluorescent GluR1 was found on the mushroom-shaped spines, and not in significant amounts on the other spines. It seems a mechanism that resembles synaptic tagging plays a role in directing GluR1-containing AMPARs to mushroom spines.

This study is important for a number of reasons. Understanding the morphological changes that result in LTP is necessary in developing a working physiological model of memory. This study provides insight into the mechanism of these changes and makes our understanding of the memory process a little more concrete. In addition, synaptic modifications that lead to behavioral changes are thought to underlie a number of human tendencies. The successful use of transgenes in this memory study could thus provide a basis for their use in studying these other behaviors affected by neuronal enhancement, e.g. addiction.

Reference:

Matsuo, N., Reijmers, L., Mayford, M. (2008). Spine-Type-Specific Recruitment of Newly Synthesized AMPA Receptors with Learning. Science, 319, 1104-1107. DOI: 10.1126/science.1149967

Why Some People Didn't Give Up on Gene Therapy

2008-02-22T22:05:00.013-05:00

Gene therapy, a treatment for disease that involves the insertion of healthy or disease-fighting genes into a person's cells, has undergone something of a roller coaster ride of public approval. Although hotly contested from its inception due to suggested ethical and methodological flaws, its first use in 1990 on four-year old Ashanti DeSilva to alleviate the symptoms of a rare immune disorder seemed successful. The next decade, however, instead of being one of vindication for gene therapy advocates, was fraught with disappointment due both to technical problems with its application, and to grossly unethical handling of its use in people.

In 1999, Jesse Gelsinger, an eighteen-year old with a genetically inherited liver disease, died in a clinical trial for gene therapy. Subsequent investigations found that the researchers involved in the study acted unscrupulously in a number of ways, such as not reporting serious side effects experienced by other patients and not disclosing that monkeys had died after similar treatment in previous studies. This provided more ammunition for opponents of gene therapy. Then, in a clinical trial in the beginning of this decade two children developed leukemia-like symptoms, leading to a temporary ban on clinical trials for the method.

Clinical trials were resumed, but as you can see scientists studying gene therapy have had many obstacles to overcome in getting people to focus on the potential of the treatment, and the successes it has had. Thus, news coming from researchers at the Cedars-Sinai Medical Center will likely be reason for gene therapy proponents to celebrate.

The group recently completed a study using gene therapy in rats to attack glioblastoma (GBM), the most common type of brain cancer. GBM is especially lethal, with a prognosis of six to twelve months of life after diagnosis. It is also extremely hard to treat, as, by the time it is diagnosed it has usually spread to other brain areas, making it difficult to surgically remove a tumor without leaving cancer cells behind. The blood-brain barrier, a safety mechanism that prevents toxins in the blood from entering the brain, stops chemotherapeutic agents from getting to tumor cells in effective amounts. Dendritic cells, which are essential to the immune process as they present foreign antigens on their cell surface to stimulate the immune response, do not naturally occur in the brain. Thus, the tumor in GBM grows unchecked by the immune system. This growth also usually causes behavioral changes and cognitive deficits as the tumor affects other areas of the brain.

The scientists at Cedars-Sinai, using a viral vector (a virus used as a vehicle to carry genetic material), sent two proteins to the cancer cells in the rats’ brains. One of the proteins attracted dendritic cells to the brain, which resulted in an immune response that attacked the cancer cells. Another protein, when combined with an antiviral medication (ganciclovir), also killed tumor cells.

The study found this treatment increased survival to about 70%. In addition, any behavioral or cognitive deficits that were caused by the growing tumors disappeared after the tumor was destroyed. The ability to generate an immune response to the cancer cells was also retained by the rat's immune system. Thus, when cancer cells were re-introduced later on, the rat's immune system was able to kill them off on its own.

Obviously, the implications of having a successful treatment for this type of tumor are tremendous, not only for the management of brain cancer, but also for cancer research in general. Phase I clinical trials for the therapy have been scheduled to begin this year. Unfortunately, even if all goes well in clinical trials, this treatment is still years away from being utilized in practice due to the structure of FDA guidelines for drug development. It is, however, a new bright spot on the horizon for gene therapy. It should also be cause for excitement for everyone, gene therapy advocate or not, as it may represent a crucial step toward treating cancer, one disease that has often eluded even our best efforts to do so in the past.

Encephalon Blog Carnival

2008-02-21T00:47:00.003-05:00

For those of you who don't already know, the revival of Encephalon is complete and posted at Sharp Brains. The carnival is a collection of neuroscience and psychology postings from 24 bloggers (including one from yours truly). Check it out if you haven't already!

Human Flocking Behavior with a Shaky Segue into Mirror Neurons

2008-02-19T23:52:00.013-05:00

On occasion, I will be in a public place like an airport, sports stadium, or bar/club, and I’ll pause to look at the sea of people that I’m part of. I then usually start to feel being human is a little less significant than we are inclined to think it is, as I get caught up making zoologically comparative observations. In the case of the airport or large event, I often consider how we resemble herds of cattle, moving in one direction or another with the urging of signs or velvet ropes instead of sheepdogs (or sometimes even with security guards barking at us much like a sheepdog would). When at a bar or club, I’m prone to make comparisons to the courtship displays of various animals, like the ostentatious demonstration of the male peacock, or the male fruit fly’s persistent pursuit of a mate.

A group of scientists at the University of Leeds recently published a study that inevitably leads one to similar comparisons. It focuses on flock-like behavior in humans. The researchers conducted their experiments in a large hall with groups of people that varied in size. A number of people in the group were given specific directions about which walking route to follow, the rest were left uninformed, to amble about on their own. They also weren't told that directions were given out to anyone. The participants in the group weren’t allowed to communicate with one another, by speech or gesture.

The study found that the uninformed individuals tended to follow those who had been given directions, even though they were a comparative few to the many. In fact, the researchers observed that as the number of people in the group was increased, the less informed participants were needed to create a following. The largest groups of 200 or more only needed about 10 people walking in a specific direction to cause the rest of the group to fall in behind them. The followers, when interviewed afterward, often didn’t seem to be aware they were being led.

You might be wondering what this all has to do with neuroscience and the answer is: no one knows. This was a behavioral study, and the authors didn’t speculate on the brain regions that might be involved. Although suggesting their involvement in this type of flocking behavior is purely speculative, it seems like as good a time as any to bring up the subject of mirror neurons.

Mirror neurons were first discovered in experiments with macaque monkeys. A group of researchers led by Giacomo Rizzolatti were using electrodes to measure brain activity while the monkeys engaged in motor tasks, like picking up pieces of food. They unexpectedly found that some of the neurons were activated not only when the monkeys picked up the food, but also when they saw someone else (experimenter or another monkey) pick it up. After this finding, areas were identified in the human brain that may play a similar role. They include regions of the inferior frontal cortex and parietal lobe.

Since this discovery much excitement has surrounded the concept of mirror neurons. As these neurons seem to be specifically activated when watching another person perform a goal-directed action, some have suggested they may underlie our ability to understand that other people have intentions. This could mean they are the foundation for empathy, imitation, and communication. Some studies have even indicated malfunctioning mirror neurons may contribute to autism.

The truth is (as is usually the case with the brain), mirror neurons aren’t going to be that easy to figure out. Nor will they be a magic bullet that will conveniently explain a panoply of human behavior. They are part of a complex system that we have a very vague understanding of at this point. We can only speculate about their involvement in much larger reactions like empathy and language. They do seem to play a role in perceiving intention, however, and thus have an intriguing potential when it comes to understanding human behavior, as so much of it is based on knowing that we are surrounded by other intentional agents.

So, to get back to the flocking study, it doesn’t have a specific connection to neuroscience—yet. Just remember, however, if you are standing in line among hundreds to get to your gate at the airport, or being herded through the turnstile at the sports stadium, or observing the human courtship rituals at a club with a sense of detachment, and these sights seem surreal or slightly dehumanizing to the comparative biologist in you, and you begin thinking how similar we are to cattle, or sheep, you may not be far off base—and you’re not alone.

Sisyphus and Science, or History Repeats Itself

2008-02-17T21:17:00.005-05:00

Researchers working at the Harvard Stem Cell Institute (HSCI) published a paper online last week in Cell Stem Cell discussing advances they’ve made in trying to coax adult cells to revert to embryonic stem cell-like states, without viruses or oncogenes (cancer-causing genes). They have outlined the molecular process involved in this nuclear reprogramming, something which up until now has been a very nebulous sequence of events. Being able to reprogram cells without viruses or oncogenes is crucial, as their involvement prohibits the use of the resultant embryonic stem cells (ESC) in humans.

While it is important to understand this process, a great amount of time and research money is being spent trying to convert adult cells to ESCs when there are somewhere around ½ a million frozen embryos sitting in fertility clinics around the country. When a woman undergoes in vitro fertilization (IVF), several embryos are created from the fertilization process. After a few days, the embryos are inspected and the healthiest few are selected for transfer (the actual number transferred varies with the age of the patient and the laws of the country where the procedure is done). The patient can then decide what to do with the remaining embryos: freeze (cryopreserve) them, donate them to research, or dispose of them. Many patients, thinking of the potential for life (or for future IVF procedures) the blastocysts possess, have an understandably difficult time making the decision to donate them to research or have them disposed of (for an interesting article on the difficulty of this decision, go here). Thus, the embryos are frozen and there they stay, sometimes indefinitely.

But, due to George W. Bush’s fanatical opposition of stem cell legislation, scientists can’t get research funding from the government to use even those frozen embryos that patients have chosen to donate to science. They remain untouched, alongside the hundreds of thousands of others, as the top scientists in the country try to figure out ways to make ESCs out of adult cells.

Ironically, IVF itself was the focus of political and ethical debates for years, attacked with the same arguments being used against ESC research. Now, however, it is a commonly accepted practice. And, while IVF provides infertile couples or women with the ability to have children—an amazing blessing for these people—ESCs have potential to be used in the treatment of any disease that involves the degradation of tissue. This would include Parkinson’s, Alzheimer’s, type I diabetes, spinal cord injuries, or stroke (to name a few). Thus, ESCs might be able to provide some blessings of their own.

While the advancements of the researchers at HSCI are great, I can’t help but wonder what type of developments we would be seeing if scientists didn’t have to focus on this hurdle of turning adult cells into ESCs, when there are hundreds of potential ESC lines just waiting out there to be created from frozen embryos. It’s like being tied down to a chair in the middle of the grocery store and dying of starvation.

Can Neuroscience and Free Will Coexist?

2008-02-15T23:05:00.028-05:00

Studying neuroscience involves dissecting individual behaviors and separating them into their biological components. For example, imagine yourself sitting in front of the television as dinner time is nearing. You grow hungrier as you wait for the show you are watching to come to end, then when it does you get up and go to the kitchen to make something to eat. If an interviewer were to later ask you why you got up to eat at that moment, you might reply “I was hungry, so I decided to have dinner”.

From a neuroscience standpoint, the answer might be a little more complex. As the food you ate for lunch became completely digested, the glucose and insulin levels in your blood began to fall. The lower blood insulin level was detected by your hypothalamus, which sent signals to various cortical areas (a vaguely understood process) providing the impetus to obtain food. The cortex then activated the basal ganglia, leading to the initiation of a motor movement (through the corticospinal tract), which carried you to your refrigerator.

A glaring difference between the two explanations for your behavior is that one involves choice, while the other consists of the perfunctory satisfaction of a biological drive. Do you decide it is time to eat, or do you feel a biological urge to consume food since your blood glucose levels have fallen and your body is in need of replenishment? Deciding to eat is reminiscent of a human action motivated by free will, while being biologically driven to replenish energy stores is suggestive of automatic, reflexive behavior we are usually more comfortable ascribing to drosophila or lab rats.

Of course in this situation the truth seems to lie somewhere in between. You didn’t have to get up to eat at that second (you weren’t starving), you chose to. At the same time it was due in part to your need to satisfy a biological drive. Other questions about neuroscience and choice, however, can get a little more difficult. If genetic influences and brain aberrations underlie drug use and addiction, how constrained by their biological makeup is someone in making a decision to abstain from using drugs if they are exposed to them? Suppose genetic influences can be shown to lead to biochemical effects that strongly incline someone towards aggressiveness, shyness, studiousness, self-restraint, risk-taking, etc.? How much free will do we have when it is impinged upon by genes, neurons, neurotransmitters, and so on?

Roy F. Baumeister addresses the issue of free will in the context of present-day biology and psychology in a recent article in Perspectives on Psychological Science. Baumeister affirms that nonconscious processes play a prodigious role in behavior. He also, though, acknowledges our ability to choose within the boundaries of those automatic processes. The scenario above is an example of this type of choice. You delay the initiation of your movement to the kitchen until you have finished watching your television show. While not deterministic in its definition, however, this is a very limited version of free will. It is not so much a question of "if" you will go to the kitchen, but "when". The outer realm of possibility might involve you ordering pizza instead of microwaving leftovers, but the predominant goal of obtaining food will be achieved somehow, within a reasonable amount of time.

Baumeister suggests this circumscribed free will is the product of natural selection. He postulates that the primary driving force behind human social evolution was cultural adeptness. This would include an array of skills and behavior, such as the ability to comply with norms, follow rules, act morally, postpone gratification, and pursue long-term goals. The evolution of self-control, Baumeister hypothesizes, might be the first step in selection for cultural competence. As human culture developed, it became more saturated with information. Intelligent choice (free will) may have been selected for as a necessary means to process culturally relevant information, and act on it in a manner compatible with social mores. For example, the ability to curb your hunger may seem trivial when it involves waiting until the end of a television show. It could have been important, though, in a hunter-gatherer society where food was scarce. Here it might have meant restraining yourself from grabbing your tribesmen’s portions from out of their hands when you were done with yours, a transgression that would have been severely punished.

If self-control were such an important selective pressure, Baumeister argues, it probably should be a biologically expensive skill. He points to experiments by Gailliot et al., which demonstrate low blood glucose levels to be associated with poor performance on self-control tasks. After drinking a glass of lemonade with sugar, performance was restored. Baumeister suggests self-control warrants the use of large amounts of biological energy due to its adaptiveness. Not only does it improve decision-making abilities, but it has been correlated with success, likability, and health—an evolutionary goldmine.

This is all fine and good, but if free will is limited, and (to add insult to injury) a simple biological product of descent with modification, why the adamant human belief in freedom of choice? Why that unshakable part of us that says: we are not drosophila! We are not rats! We are different, we are people! Baumeister speculates belief in free will may have become so strong because it is beneficial to a healthy society. Envision a social order where we are not held responsible for our actions. Or imagine trying to trust and cooperate with others when you know there is no moral imperative pushing them to act a certain way. It would be disastrous. Belief in free will could keep a society healthy, even if that free will was, in actuality, limited.

Thus, according to Baumeister’s view, free will is largely illusory. We are primarily ruled by biological drives, and free will is our way of moderating those impulses to keep them from being socially discordant, and thus counterproductive. We are so quixotically convinced of our freedom of choice due to separate, but related, selection pressures that are necessary for the existence of functional societal groups.

Studying neuroscience and/or genetics will inevitably lead one into such intellectual morasses. It is difficult to imagine that debates about personal responsibility won’t become more intense as our knowledge of genetic and biological predisposition grows. Perhaps that knowledge will lead to a better understanding of free will and our inclination to believe in it. Until then what our reality consists of—free will, determinism, or somewhere in between—is up for debate. Choose whichever you’re most comfortable with.

Reference:

Baumeister, R.F. (2008). Free Will in Scientific Psychology. Perspectives on Psychological Science, 3(1), 14-19. DOI: 10.1111/j.1745-6916.2008.00057

Further Proof "Junk DNA" Has Value

2008-02-12T23:25:00.006-05:00

The prevalence of noncoding regions of DNA in the genome of humans and many other eukaryotic organisms has long been a subject of controversy. DNA is composed of alternating areas called exons and introns. When DNA is transcribed to mRNA (the first step of protein synthesis), the introns (from "intragenic regions") are spliced out before the final mRNA sequence is formed. The exons become part of the mRNA and can code for amino acids involved in protein formation. The function of introns has been a mystery, and their ostensible superfluousness has caused some to refer to them as “junk DNA”.

Numerous hypotheses have been developed to explain the existence of introns. Some have suggested they are merely relics of old genes that no longer have any use to us, and thus have become non-functional. Others have postulated that junk DNA provides a buffer around integral genes to save them from being cut when portions of chromosomes “cross over” in meiosis. But many other scientists have not been satisfied with the suggestion that such a large portion of a genome (by some estimates up to 97%) would have a passive, or even meaningless, role.

Included in that group is a team of researchers at the University of Pennsylvania School of Medicine, who have discovered an important role in cellular function that is played by an intron. In 2005, they found that dendrites, the branch-like arms of a neuron that receive input from other neural cells, have the ability to splice mRNA. This was previously thought to occur only in the nucleus of cells. More recently, the group discovered an mRNA outside the nucleus that contains an intron. The mRNA encodes for a protein important to the functioning of the dendrite.

When the group removed the intron from the mRNA and left a spliced RNA molecule in the cell, the electrical properties of the cell became irregular. They believe the intron plays an integral role in guiding the mRNA to the dendrite, and may be involved in determining how many mRNAs are brought there to form electrically conducting channels. To serve this function, the intron may be spliced out of the mRNA by the dendrite and then incorporated into the dendrite itself. The details are not yet certain, but what is clear is this particular intron has an essential role in the cell, thus bringing the moniker “junk DNA” further into question, and inviting more research into the greater part of our genome.

Autism May Involve Limited Awareness of Self

2008-02-11T21:27:00.000-05:00

As the prevalence of autism continues to rise—for reasons that are still unknown—researchers are frantically trying to understand the disorder. Autism consists of a spectrum of behaviors, such as repetitive or ritualistic behavior, self-injury, impaired language ability, and limited communication skills. One of the most commonly held views on autism has been that those who are afflicted have a decreased capacity to feel empathy, or to understand that other people have their own mental states, desires, and intentions. Neuroimaging studies with autistic individuals have seemed to support this idea.

Other studies have indicated there is a diminished ability to recognize self in the autistic mind as well. A neuroimaging study released this week supports that hypothesis. The experiment used fMRI and a relatively new technique called hyperscanning to measure brain activity of autistic and non-autistic adolescents as they played an interactive game together. Hyperscanning is an imaging method that allows multiple people to be scanned with fMRI simultaneously as they communicate with one another.

The researchers compared the fMRI images to images they had taken of athletes’ brains as they imagined themselves taking part in athletic activities. They found this focus on “self” caused high activity in the cingulate cortex, an area previously implicated in self-awareness and social interaction. This area was also highly activated in the non-autistic participants in the game as they thought about what action they would take. It contrasted with a different pattern of activity that occurred when they thought about the actions of their partner. Although the autistic participants were able to play the game effectively, they showed much lower levels of stimulation in the cingulate cortex. The activity was also negatively correlated with the severity of their autistic symptoms (the more severe the symptoms the lower the activity).

All of the autistic participants in the study were considered high functioning, with normal or high normal intelligence quotients. The research group plans to conduct more imaging experiments in the future with autistic individuals who have lower IQs. For now, this experiment may shed more light on the brain mechanisms underlying autism. It also adds more complexity to the problem, however, as it appears a deficit in the awareness of others may not be all that’s involved.

Baby Math Geeks

2008-02-10T20:25:00.000-05:00

There are certain abilities that humans develop with such universality it seems as if our brains might be specifically designed to acquire them. One example is language. About fifty years ago, most psychologists believed children learned language by imitating the adults around them, then refined it by receiving feedback about the accuracy of their utterances. Famous linguist Noam Chomsky was the first to point out, however, that children have an ingenious ability to create sentences they’ve never heard before, and the speed with which they pick up their native language is much quicker than any realistic learning curve. Chomsky posited there must be something inherent in the architecture of our brains that expedites learning language at a young age. Since Chomsky’s contributions to what became the cognitive revolution in psychology, a great deal of research has been done that supports the theory that people have a natural inclination toward acquiring language. Children will develop language abilities along the same general timeline regardless of the opportunities they have to learn from adult examples (excluding cases of severe isolation or abuse).

Some believe the concept of number also has an innate origin. Neuroimaging studies have indicated there are specific brain areas, primarily in the parietal lobe, that are associated with counting objects. These areas have been shown to be active during counting tasks in children as young as four years old. Behavioral experiments have demonstrated that even 6-9 month old infants have some basic understanding of numerical concepts (such as knowing if you have one object and add another you should end up with two objects, not one). This proclivity to understand numbers at such a young age might indicate that the human brain is organized to facilitate the learning of numerical concepts, just as it is with language.

The imaging evidence for a numerical region in the parietal lobe comes primarily from adults and children four or older. A group of researchers, Veronique Izard, Ghislaine Dehaene-Lambertz, and Stanislas Dehaene, wanted to determine if this localization of numerical function existed in three-month-old infants. They used electroencephalography (EEG), which measures electrical activity of the brain through electrodes placed on the scalp, to ascertain which areas of the infants’ brains were active while they watched animal-like objects on a black background. Sometimes the objects would change in appearance, other times they would differ in number.

The group found a clear distinction in brain activity between viewing object appearance and object number. When the type of the objects was changed, activity was recorded in the temporal cortex. This corresponds to regions associated with object differentiation in adults and older children. When the number of the objects was changed, however, there was activity in a network that spread from the parietal to the prefrontal lobe. This network is similar to that seen in object number recognition in adults and older children.

These results indicate there may be an inborn mechanism in the brain for understanding numerical concepts. This shouldn’t be too shocking, as it seems an understanding of numbers would be crucial to evolutionary survival (what’s more dangerous: one predator or four?). Nevertheless, it is important to remember that the concept of being born with a mind like a tabula rasa maintained its popularity throughout most of the last century. Experiments like this one suggest there are at least some basic guidelines for us to follow on that slate we are born with.

Reference:

Izard, V., Dehaene-Lambertz, G., Dehaene, S. (2008). Distinct Cerebral Pathways for Object Identity and Number in Human Infants . PLoS Biology, 6(2), e11. DOI: 10.1371/journal.pbio.0060011