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Archive for the ‘Dopamine’ Category

Mother and Child
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The roles of nature and nurture in child development have never been easy to disentangle.  Parents, in particular, seem to know this all too well, when it comes to their own children.  For example, when one of my children throws a tantrum, my wife can be mercilessly quick to point out that “those are your genes at work “.  I for one, can’t help but admire Mother Nature’s sense of justice (or is it humor?) as I’m forced to grapple with an unreconcilable 5-year old.  What can I do?  How can I get some type of optimal gene-by-environment (parenting style) going here?  Afterall, they are MY genes (expressed in said unreconcilable 5-year old) right?  Can I break out of the infinitely recurrent loop of me (my genes) trying to positively interact with my child (also my genes).  What’s a stubborn parent of a stubborn child to do?

In thinking about this, it was great to read a recent article by Lee and colleagues entitled, “Association of maternal dopamine transporter genotype with negative parenting: evidence for gene x environment interaction with child disruptive behavior” [doi: 10.1038/mp.2008.102].  In this article, the team examined how children (4 to 7 years old)  interacted with their mothers during a session where they were induced to cooperate in tasks involving free play with specific toys, tasks involving organizing items in a room and several pencil and paper tasks.  A set of observations were made (through 1-way glass) on aspects of parenting (negative feedback or contact, positive feedback and encouragement, and, total number of maternal commands).

In principle, the complexities of whose genes & behavior is influencing whose in such a situation are vast.  The authors point out that such interactions can be divided into passive GxE wherein children with certain genes (lets say genes for stubborness) may have inherited those genes from parents who exhibit a stubborn (negative) parenting style – hence leading to correlations in child genotype and parenting style.  Alternatively, such correlations can occur when a child (perhaps a stubborn child) evokes negative parenting response from a parent who did not (as my wife claims) transmit said stubborness genes – an example of an evocative GxE interaction.  In this study, the team examined the mother’s genotype at a 40-bp repeat polymorphism in the 3’UTR of the dopamine transporter (DAT) gene.  This is an apt candidate gene, since animal models of DAT loss-of-function show disrupted maternal behavior.

As an initial step, the team evaluated whether maternal genotype was correlated with maternal parenting style.  They found that the 10-repeat allele of the DAT gene was associated with more of a negative style of parenting.  However, the association of the 10-repeat allele of DAT was rather stronger in mothers whose children were categorized as disruptive than among mothers whose children were categorized as compliant – an example of an interaction of the mother’s genotype with her child’s disruptive behavior (which itself may be due to genes inherited by her – and so on – and so on).

Hard to pin down the genetic blame somewhere here.  Maddening actually.  Maddening enough to make dealing with my unreconcilable 5-year old seem a simple and welcoming task.

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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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The selection and dosing of medication in psychiatry is far from scientific – even though a great deal of hard science goes into the preclinical design and clinical development. One reason, among many, has to do with the so-called ‘inverted-U-shaped’ relationship between the dose of a psychoactive compound and an individuals’ performance. Some folks show dramatic improvement with a given dose (their system may be functioning down at the low side of the inverted U mountain and hence, and added boost from medication may send their system up in performance), while others may actually get worse (those who are already at the peak of the inverted U mountaintop). How can a psychiatrist know where the patient is on this curve – will the medication boost raise or topple their patient’s functioning ? Some insight comes in the form of a genetic marker closely linked to the DRD2 gene, that as been shown to predict response to a dopaminergic drug.

Michael Cohen and colleagues, in their European Journal of Neuroscience paper (DOI: 10.1111/j.1460-9568.2007.05947.x) entitled, “Dopamine gene predicts the brain‘s response to dopaminergic drug” began with a polymorphism linked to the DRD2 gene wherein one allele (TaqA1+) is associated with fewer DRD2 receptors in the striatum (these folks should show improvement when given a DRD2 agonist) while folks with the alternate allele (TaqA1-) were predicted to show a falling off of their DRD2 function in response to additional DRD2 stimulation. The research team then asked participants to perform a cognitive task – a learning task where subjects use feedback to choose between a ‘win’ or ‘not win’ stimulus – that is well known to rely on proper functioning of DRD2-rich frontal and striatal brain regions.

Typically, DRD2 agonists impair reversal learning and, as expected, subjects in the low DRD2 level TaqA1+ genetic group actually got “more” impaired – or perseverated longer on rewarding stimuli and required more trials to switch on the go and figure out which stimulus was the “win” stimulus. Similarly, when differences in brain activity between baseline and positive “you win” feedback was measured, subjects in the drug treated, TaqA1+ genetic group showed an increase in activity in the putamen and the medial orbitofrontal cortex while subjects in the TaqA1- showed decreases in brain actiity in these regions. The authors suggest that the TaqA1+ group generally has a somewhat blunted response to positive feedback (sore winners) but that the medication enhanced the frontal-striatal reaction to positive feedback. Functional connectivity analyses showed that connectivity between the frontal cortex and striatum was worsened by the DRD2 agonist in the TaqA1+ genetic group and improved in the TaqA1- group.

Although the interpretations of these data are limited by the complexity of the systems, it seems clear that the TaqA1 genetic marker has provided a sort of index of baseline DRD2 function that can be useful in predicting an individual’s relative location on the theoretical inverted-U-shaped curve.

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Holiday time is full of all things delicious and fattening. Should I have a little chocolate now, or wait till later and have a bigger dessert ? Of course, this is not a real forced choice (in my case, the answer too often seems – alas – “I’ll have both!”), but there are many times in life when we are forced to decide between ‘a little now’ or ‘more later’. Sometimes, its clear that the extra $20 in your pocket now would be better utilized later on, after a few years of compound interest. Other times, its not so clear. Consider the recent ruling by the Equal Employment Opportunity Commission, which allows employers to drop retirees’ health coverage once they turn 65 and become eligible for Medicare. Do I save my resources now to provide for my geezerdom healthcare spending, or do I enjoy (spend) my resources now while I’m young and able ? How do I make these decisions ? How does my life experience and genome interact to influence the brain systems that support these computations ? Boettiger and company provide some insight to these questions in their paper, “Immediate Reward Bias in Humans: Fronto-Parietal Networks and a Role for the Catechol-O-Methyltransferase 158Val/Val Genotype(DOI). The authors utilize an assay that measures a subject’s preference for rewards now or later and use functional brain imaging to seek out brain regions where activity is correlated to preferences for immediate rewards. Dopamine rich brain regions such as the posterior parietal cortex, dorsal prefrontal cortex and rostral parahippocampal gyrus showed (+) correlations while the lateral orbitofrontal cortex showed a (-) correlation. Variation in the dopaminergic enzyme COMT at the rs165688 SNP also showed a correlation with preferences for immediate reward as well as with brain activation. The authors’ results suggest that improving one’s ability to weigh long-term outcomes is a likely therapeutic avenue for helping impulsive folks (like me) optimize our resource allocation. I have not yet had my genome deCODEd or Google-ed, but strongly suspect I am a valine/valine homozygote.

Indeed it seems I am a GG (Valine/Valine) at this site according to 23andMe !

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Fred Sanford
Image by Thomas Hawk via Flickr

Mouse models of complex neurological illness are a powerful means to dissect molecular pathways and treatment paradigms. Current mouse models for the tremors and movement difficulties seen in Parkinson disease include genes such as parkin, alpha-synuclein, LRRK2, PINK1 and DJ-1. These models however, do not show the motor control problems and spontaneous degeneration of dopamine neurons as seen in PD in human patients. A new mouse model as reported by Kittappa and colleagues, unlike previous models, does, however, show amazing verisimilitude to PD. In their paper, “The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age(DOI) the authors find that mice with only a single copy of the foxa2 gene acquire motor deficits and a late-onset degeneration of dopamine neurons. The age-related spontaneous cell death preferentially affects dopamine producing neurons in the substantia nigra that are affected in PD. The link between genetic risk and environmental exposure to oxidative toxins, a known risk factor in PD, is remarkably straightforward as foxa2 appears to be a regulator of superoxide dismutase, a potent protective scavenger of damage-inducing free radicals. More amazingly still, the authors demonstrate that foxa2 plays a key role in the birth of dopamine neurons – thus opening up new therapeutic possibilities of simultaneously producing new neurons and blocking apoptotic death of old ones. This fox brings new hope for treatment !

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Deep-fried onion rings arranged in a line on a...Image via Wikipedia To go out tonight or stay home? Hillary or Barack? Curly fries or onion rings? How do I make these important choices and why will others decide differently? Although there are many reasons for not stressing-out and over-thinking one’s decisions (except for really important choices like curly fry vs. onion ring), it turns out that variation in your genome, in particular, 3 dopaminergic genes (DARPP-32, DRD2 and COMT: rs907094, rs1800496, rs4680) are influencing your tendency to ‘go for it’ or not to go for it. Frank and colleagues, in their paper, “Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning“, give an in-depth treatment of the neurobiology underlying decision making and reinforcement learning. After carefully reviewing the basic biology of dopaminergic synapses and selecting 3 candidate genetic variants, they find that each is associated with an independent aspect of decision making in a learning paradigm. The paper is an excellent example of how genetic variation can be linked to specific neural processes. Now bring on the curly fries – no wait – the onion rings.

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