Posts Tagged ‘Dopamine’

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pointer to: Computational Models of Basal Ganglia Function where Kenji Doya provides computational explanations for neuromodulators and their role in reinforcement learning. In his words, “Dopamine encodes the temporal difference error — the reward learning signal. Acetylcholine affects learning rate through memory updates of actions and rewards. Noradrenaline controls width or randomness of exploration. Serotonin is implicated in “temporal discounting,” evaluating if a given action is worth the expected reward.”

This type of amazing research provides a pathway to better understand how genes contribute to how the brain “works” as a 3-dimensional biochemical computational machine.

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MFrankIf you’re interested in the neurobiology of learning and decision making, then you might be interested in this brief interview with Professor Michael Frank who runs the Laboratory of Neural Computation and Cognition at Brown University.

From his lab’s website: “Our research combines computational modeling and experimental work to understand the neural mechanisms underlying reinforcement learning, decision making and working memory. We develop biologically-based neural models that simulate systems-level interactions between multiple brain areas (primarily basal ganglia and frontal cortex and their modulation by dopamine). We test theoretical predictions of the models using various neuropsychological, pharmacological, genetic, and neuroimaging techniques.”

In this interview, Dr. Frank provides some overviews on how genetics fits into this research program and the genetic results in his recent research article “Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation”. Lastly, some lighthearted, informal thoughts on the wider implications and future uses of genetic information in decision making.

To my mind, there is no one else in the literature who so seamlessly and elegantly interrelates genetics with the modern tools of cognitive science and computational neurobiology.  His work really allows one to cast genetic variation in terms of its influence on neural computation – which is the ultimate way of understanding how the brain works.  It was a treat to host this interview!

Click here for the podcast and here, here, here for previous blog posts on Dr. Frank’s work.

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A column of the cortex
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Here’s a new addition to a rapidly growing list of findings for the valine-to-methionine substitution in the COMT gene (rs4680).  The paper, “Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents” by Shaw and colleagues at the NIMH [doi:10.1038/mp.2008.121] finds that when genotype was used as a regressor for cortical thickness measures in children (8-14 years of age) significant associations were found in the right inferior frontal gyrus and the right superior/middle temporal gyrus (in both areas, the met/met group had thicker cortex).  The team notes that the findings in the frontal cortex were expected – as many others have found associations of COMT with this brain area using other imaging modalities.  However, the temporal lobe finds are something new.  No speculations on the mechanisms/implications are provided by the researchers on this new finding, but known interconnectivities of these two brain regions exist – perhaps supporting aspects of language, memory and/or other cognitive processes?

Perhaps the findings provide a clue to an important role that genes may play in the development of cognitive function.

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In 1802, in a letter to then Secretary of the Treasury, Albert Gallatin, Thomas Jefferson warned that, “If the American people ever allow private banks to control the issue of their money, first by inflation and then by deflation, the banks and corporations that will grow up around them (around the banks), will deprive the people of their property until their children will wake up homeless on the continent their fathers conquered.” (source)  Although the US now does have a central government bank, Jefferson’s warning still chillingly echoes through our current crisis as we teeter on this very brink.

The reasons why the US financial system lies stricken now (not to mention many times before) are complex for sure, but for a neuroscience & genetics buff like myself, its fun to consider the underlying mechanisms of human biology and behavior within a macroeconomic framework.  What role for the brain and human nature? How does our understanding of human social and emotional behavior reconcile with the premise of so-called “rational” behavior of investors and consumers in a marketplace? Can we regulate and design a debacle-proof economic system that accounts for human social and emotional influences on otherwise rational behavior? Luckily, if you are interested in these questions, you need only to pick up a copy of “Animal Spirits: How Human Psychology Drives the Economy, and Why It Matters for Global Capitalism” by George Akerlof and Robert Shiller, who cover this very topic in great detail and provide a broad framework for neuropsychological research to inform macroeconomic policy.  A lofty and distant goal indeed, but perhaps the only way forward from such spectacular wreckage of the current system.

One such aspect of so-called “animal  spirits” could be, for example – fear – which has been blamed many times for financial panics and is covered in great measure by Akerlof and Shiller.  During the depths of the great depression, FDR famously tried to shake people loose from their animal spirits by suggesting “Only Thing We Have to Fear Is Fear Itself” (listen to the audio).   As another example, consider the chart at the top of the post – a 5yr trace of the VIX an index of volatility in the price of stock options over time.  In a bull or a bear market, when there are clear economic signals that stock prices should rise or fall, the VIX is rather low – since people feel relatively certain about the overall direction of the market.  Note however, what happened in the fall of 2008, when the heady days of the housing boom ended and our current crisis began – the VIX rockets toward 100% volatility – indicating rather dramatic swings in future earnings estimates and hence, tremendous uncertainty about the future direction of the market.  Indeed, for high flying investors (who may reside in tall buildings with windows that open) the VIX is sometimes referred to as the fear index.

What – in terms of brain mechanisms – might underlie such fear – which seems to stem from the uncertainty of whether things will get better or worse?  What do we know about how humans react to uncertainty and how humans process uncertainty?  What brain systems and mechanisms are at play here? One recent report that uses genetic variation as a tool to peer into such brain mechanisms suggests that dopamine signaling modulates different brain areas and our propensity to respond in conditions of low and high uncertainty.

In their article, “Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation“, [doi:10.1038/nn.2342] Michael Frank and colleagues examine individual differences in a so-called exploration/exploitation dilemma.  In their ‘‘temporal utility integration task’’, individuals could maximize their rewards by pressing “stop” on a rotating dial which can offer greater rewards when individuals press faster, or when individuals learn to withold and wait longer, and, in a third condition when rewards are uncertain.  The authors liken the paradigm to a common life dilemma when there are clear rewards to exploiting something you know well (like the restaurant around the corner), but, however, there may be more rewards obtained by exploring the unknown (restaurants on the other side of town).  In the case of the VIX and its massive rise on the eve of our nations financial calamity, investors were forced to switch from an exploitation strategy (buy housing-related securities!!!) to an exploration strategy (oh shit, what to do?!!).

The neurobiological model hypothesized by Frank and colleagues predicts that the striatum will be important for exploitation strategies and find supporting data in gene associations with the striatally-enriched DARPP-32 gene (a marker for dopamine D1-dependent signalling) and DRD2 for the propensity to respond faster and slower, respectively, in the exploitative conditions (rs907094 & rs1800496).  For the exploratory conditions, the team found an association with the COMT gene which is well-known to modulate neural function in the prefrontal cortex (rs4680). Thus, in my (admittedly loose) analogy, I can imagine investors relying on their striata during the housing boom years and then having to rely more on their prefrontal cortices suddenly in the fall of 2008 when it was no longer clear how to maximize investment rewards.  Egregious bailouts were not yet an option!

Click here and here to read more breakthrough neuroeconomics & genetic research from Michael Frank and colleagues.  Here and here for more on Shiller and Keynes.

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Nuclear receptor related 1 protein
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Yesterday, there were some grumblings on the nomination of Francis Collins to the head of NIH.  Some folks feel that the genome-wide, genome-everything approach to medicine has somewhat over-promised and under-delivered in its promise to elucidate the molecular pathways of human disease.  In the field of mental health, the whole-genome era is just now dawning and ever more, ever larger studies are reporting the results of GWAS and other global sweeps for genetic risk.  So, its fair to ask whether the whole-genome approach hath bourne the promised fruit.  Exactly, how much of the overall risk of illness can we account for using the present genetic knowledge? I’d like to know & will be working to track this “bottom line” statistic in the future.

However, I suspect that the numbers may be humbling.  In part, because of the tricky ways in which the genome interacts with the pre- & post-natal environment during development.  For example, consider the recent paper by Saijo et al. “A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death” [doi 10.1016/j.cell.2009.01.038].  Here the team considers neurodegenerative processes and how the tissues of the brain cope with unwanted oxidative pro-inflammatory damage.  Specifically, the team shows that Nurr1, a so-called orphan nuclear receptor that is known to regulate the development of midbrain dopamine neurons, actually has another function – one that occurs inside the microglia of the brain (special macrophage-like cells of the brain that can clear infection – ideally without harming surrounding neural circuitry).  The team injected (into the midbrain) an evil, bacteria-like, oxidative sludge known as lipopolysaccharide (LPS) which triggers a full-blown immunologic alarm that often has the unwanted side-effect of inducing the death of dopaminergic neurons.  This is very BAD – as it creates a Parkinsonian condition – but, nevertheless is something that our bodies and brain must cope with throughout our life-cycle since we’re always being exposed to bacteria and other pathogens.  The team finds that the cytotoxic response of microglia is repressed by Nurr1 such that when Nurr1 expression is blocked,  the microglia are more active and then, unfortunately, cause more collateral damage to the dopaminergic cells in their efforts to clear the LPS.  So it seems that Nurr1 helps to save dopaminergic neurons by dampening down the normal inflammation response systems that – when faced with foreign infections – can cause collateral damage in their efforts to clear the infection.  Wow, so Nurr1 helps to give birth to dopamine neurons and to keep them safe from harm. Such a gene, is one I’d hope would work well.  Not surprisingly, mutations in Nurr1 have been associated with the risk of Parkinson’s Disease.

More interestingly, the way in which Nurr1 seems to carry out its regulation of this very common type of gene-x-environment (infection) interaction is through a so-called CoREST repressor complex which is implicated in various epigenetic forms of gene regulation – which can have long-lasting effects on cells, perhaps long-after the infection has cleared.

Thus, just this one story around little, itty bitty DNA binding factor Nurr1, who, alone can’t account for more than a hair’s worth of genetic risk, may, in fact, play a critical role in the onset of complex mental illness.  It would seem perhaps that identifying genetic risk factors may only be the beginning of a long, complex search for the biological roots of mental disability – where genes and environment weave intractable tales.

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U.S. Treasury Secre...

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Amidst the current economic panic, I’m feeling more shocked than usual when listening to the flip-flopping, falsehoods, fabrications, backstepping, about-facing and unabashed spin-doctoring spewing forth from the news media. If watched long enough, one may even develop empathy for Henry Paulson who carries the weight of the global economy on his shoulders. Nevertheless, what do we know about making mistakes ? Not necessarily global financial catastrophies, but little everyday mistakes. Why do some of us learn from our mistakes ? What’s going on in the brain ? Enter Michael Frank, Christopher D’Lauro and Tim Curran, in their paper entitled, “Cross-task individual differences in error processing: Neural, electrophysiological and genetic components” [Cognitive, Affective, & Behavioral Neuroscience (2007), 7 (4), 297-308]. Their paper provides some amazing insight into the workings of human error-processing.

It has been known for some time that when you make a mistakke – oops! – mistake, that there are various types of electrical current that emanate from the frontal midline (cingulate cortex) of your brain.  The so-called error related negativity (ERN) occurs more strongly when you are more focused on being correct and also seems to be more strong in people with certain personality traits (apparently not news commentators or politicians) while the error positivity (Pe) occurs more strongly when you become consciously aware that you made an error (perhaps not functioning in news commentators or politicians). Perhaps the ERN and Pe are basic neural mechanisms that facilitate an organisms adaptive ability to stop and say, “hey, wait a minute, maybe I should try something new.” The Frank et al., paper describes a relation between learning and dopamine levels, and suggests that when dopamine levels dip – as happens when our expectations are violated (“oh shit!, I bought stock in Lehman Brothers) – that this may facilitate the type of neural activity that causes us to stop and rethink things. To test whether dopamine might play a role in error processing, the team examined a common variant (rs4680) in the catechol-o-methyl transferase gene, a gene where A-carriers make a COMT enzyme that is slower to breakdown dopamine (a bulky methionine residue near the active site) than G-allele-carriers. Subjects performed a learning task where correct responses could be learned by either favoring positive feedback or avoiding negative feedback as compared to neutral stimuli. The team suspected that regardless of COMT genotype, however, there would be no COMT association with learning strategy, since COMT influences dopaminergic activity in the frontal cortex, and not in the striatum, which is the region that such reinforcement learning seems to be stored.

Interestingly, the team found that the error positivity (Pe) was higher in participants who were of the A/A genotype, but no difference in genetic groups for the error related negativity (ERN). This suggests that A/A subjects deploy more attentional focus when they realize they have made an error. Lucky folks ! My 23andMe profile shows a GG at this site, so it seems that when I make errors, I may have a normal ERN, but the subcortical dopamine that dips as a result does not (on average) result in much greater attentional focus. Oh well, I guess its the newsmedia pool for me.

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2nd third of 19th centuryImage via Wikipedia

You see a masterpiece while I see splatters of paint on a canvas. Why – in neural terms – do we see the same painting and feel so subjectively different ?

Understanding the neural crosstalk between visual inputs (the raw neural activity generated in the retina) and our complex internal states (needs, desires, fears etc.) of an organism is a research problem that is long on philosophy but rather difficult to address experimentally. Professors P. Read Montague and Brooks King-Casas provide a conceptual overview to how such neural crosstalk might be collected, analyzed and understood in terms of basic computational processes that underlie human decision making. In their article, “Efficient statistics, common currencies and the problem of reward-harvesting“, [doi: 10.1016/j.tics.2007.10.002] they provide an historical review of some of the major conceptual frameworks and give examples of how basic research in the area of reinforcement learning (dopamine serves as a reinforcement signal since it is released in the ventral striatum when you get more than you were expecting) might serve as a core cellular mechanism underlying the inter-linking of incoming sensory information with internal states.  Dr. Montague’s book on decision making is also a fun experience & great introduction to the burgeoning area of neuroeconomics.

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