Rare mutations that knock-out the function of monoamine oxidase a gene have long been known to give rise to developmental changes that increase the propensity of males to engage in aggressive behavior. The effects of so-called natural variants – that may slightly reduce or increase the amount of activity of the MAOA protein – can be harder to understand since they are less-definitive and perhaps more easily masked or influenced by the environment and developmental mileu. Nevertheless, the role of natural, common variation in the maoa gene and its relation to aggressive behavior in boys remains of interest – witness a news report today, “‘Warrior Gene’ Linked To Gang Membership, Weapon Use: FSU Study”.
Rather than debate the validity and merits of such sensational headlines, it may be more productive to understand how & why naturally occurring genetic variation might influence the development of the brain in a way that makes it more difficult for adolescents and adults to control their aggressive impulses. Clearly, healthy males have a predisposition to act out moreso than females, which – while at odds with our modern societal norms – comes along with our evolutionary legacy and phylogenetic relationship to other primates and mammals where male aggression is the rule. In this sense, the really exciting story, is not whether there is something amiss with schoolboys who carry certain genetic variants of maoa, but how such variants work over the course of normal brain development and why, in terms of our own evolutionary history, we carry such variants.
That male-male aggression can be a means to differentiate male fitness and – via sexual selection in females – reduce mutational load, has been widely shown across the sexually-reproducing biome. Thus, while variants such as the high expression 4-repeat VNTR in maoa have likely been helpful, rather than hurtful, in the establishment and survival of our noble species, it may be a difficult task to prove such a proposition. As Stephen Jay Gould once wrote, “Thus, we are presented with unproved and unprovable speculations about the adaptive and genetic basis of specific human behaviors: why some (or all) people are aggressive, xenophobic, religious, acquisitive, or homosexual” (Our Natural Place, p. 243). Nevertheless, we may learn a bit about ourselves as we relate genetic variation to both cognitive science and to rigorous phylogenetic analysis.
One great example of a recent paper that covers the link from genes to cognition is, “MAO A VNTR polymorphism and variation in human morphology: a VBM study” by Cerasa et al., [PMID: 18596609]. Here the team investigates the structure of the human male brain using a method known as voxel-based-morphometry (VBM) that allowed them to ask where in the brain one might observe grey-matter changes that are correlated to genotype? After an analysis of 33 high-maoa-expressing males vs. 26 low-expressing males, the team found that only in the orbitofrontal cortex were such associations significant. This, as noted by the team, is of interest, since the orbitofrontal cortex is an area of the brain that is known to regulate impulsivity. In this study, the high-expressing males had lower levels of grey matter in the orbitofrontal cortex, a result that is in-line with a previous finding – however it remains somewhat out of trend with earlier findings showing that smaller orbitofrontal cortex volumes (without respect to genotype) are associated with higher impulsivity and findings that show that boys with the high-expression form of MAOA were less likely to engage in aggressive behavior.
Clearly, this little bit of the genome containing the MAOA-VNTR has a complex – but interesting story to tell. The gene does not seem to show any evidence for recent positive selection, so perhaps the role of maoa and its effects on aggression were worked out long before our lineage came along. Indeed, now we must learn to bear our genetic legacy proudly and humanely. Good luck!
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One of the most well-studied genetic polymorphisms in the behavioral- psychiatric- cognitive-genetics area is the 5HTT-LPR, a short repeating sequence that mediates the transcriptional efficiency of the serotonin transporter. Given the wide-ranging effects of 5HTT on the developing and mature nervous system, it is perhaps not surprising that variation in 5HTT levels can have wide-ranging effects on brain structure, function and behavior (see here and here for 2 of my own posts on this). One of the latest findings has to do with the issue of “functional connectivity” or the degree to which 2 separate brain regions co-activate and interact with each other – this type of functional interaction and integration of brain systems being a good thing.
Earlier studies have shown that individuals who carry the “short” allele at the 5HTT-LPR show less coupling of their frontal cortex (perigenual anterior cingulate cortex) with their amygdala – which perhaps indicates that their frontal cortex has a harder time regulating the amygdala. This may be a mechanistic explanation for why such people have been found to be more prone to anxiety. A new study by Pachecco et al., seems to support this mechanistic account - however, they confirm the coupling model using a different neuroimaging modality – which makes the paper especially interesting. In their article, “Frontal-Limbic White Matter Pathway Associations with the Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism” [doi: 10.1523/JNEUROSCI.0896-09.2009] use a method known as diffusion tensor imaging, a modality that is particularly sensitive to white matter tracts that are known to function as high-speed interlinks between disparate areas of the brain. They find that a particular tract – the left frontal uncinate fasciculus - is differentially formed, and is less so, in carriers of the short allele. The authors suggest that the association of the 5HTT-LPR with functional connectivity may be somewhat due to the white matter tracts that connect separate brain regions. Interestingly, the finding was not seen in other white matter tracts (fasciculi) – which suggests that the genetic polymorphism is interacting with other – yet to be identified – factors (environment perhaps?) that lead to such a specific difference.
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One of the difficulties in understanding mental illness is that so many aspects of mental life can go awry – and its a challenge to understand what abnormalities are directly linked to causes and what abnormalities might be consequences or later ripples in a chain reaction of neural breakdown. Ideally, one would prefer to treat the fundamental cause, rather than only offer palliative measures for symptoms that arise from tertiary neural inefficiencies. In their research article entitled, “Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk“, [doi: 10.1176/appi.ajp.2008.08020261] (audio link) Rasetti and colleagues explore this issue.
Specifically, they focus on the function of the amygdala and its role in responding to, and processing, social and emotional information. In schizophrenia, it has been found that this brain region can be somewhat unresponsive when viewing faces displaying fearful expressions – and so, the authors ask whether the response of the amygdala to fearful faces is, itself, an aspect of the disorder that can be linked to underlying genetic risk (a type of core, fundamental cause).
To do this, the research team assembled 3 groups of participants: 34 patients, 29 of their unaffected siblings and 20 demographically and ethnically matched control subjects. The rationale was that if a trait – such as amygdala response – was similar for the patient/sibling comparison and dissimilar for the patient/control comparison, then one can conclude that the similarity is underlain by the similarity or shared genetic background of the patients and their siblings. When the research team colected brain activity data in response to a facial expression matching task performed in an MRI scanner, they found that the patient/sibling comparison was not-similar, but rather the siblings were more similar to healthy controls instead of their siblings. This suggests that the trait (amygdala response) is not likely to be directly related to core genetic risk factor(s) of schizophrenia, but rather related to apsects of the disorder that are consequences, or the state, of having the disorder.
A follow-up study using a different trait (prefrontal cortex activity during a working memory task) showed that this trait was similar for the patient/sibling contrast, but dissimilar for the patient/control contrast – suggesting that prefrontal cortex function IS somewhat linked to core genetic risk. Congratulations to the authors on this very informative study!
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Posted in Actin, ARHGAP18, CDC34, DLPFC, GTPase, RSRC1, TGF-alpha, tagged ARHGAP18, CDC34, DLPFC, Frontal lobe, Functional magnetic resonance imaging, Mental disorder, Mental health, RHO, RSRC1, schizophrenia, Stem cell, TGFa on February 5, 2009 |
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One of the mental functions many of us take for granted is memory – that is – until we’re at the grocery store. If you’re like me, you dart out of the house confident that you don’t need a list since you’re just going to “pick up a few things” – only to return home and discover (hours later when you’re comfortably ensconced on the couch) that you forgot the ice cream. Damn, why can’t I have a more efficient working memory system ? What’s the matter with my lateral frontal cortex ? Can I (should I) blame it on my genes ? What genes specifically ?
One group recently reported the use of the so-called BOLD-response (blood oxygen level dependent) as a means to sift through the human genome and identify genes that mediate the level of brain activity in the lateral frontal cortex that occur during a working memory task – somewhat akin to remembering a list of groceries. Steven Potkin and associates in their paper, “Gene discovery through imaging-genetics: identification of two novel genes associated with schizophrenia” [doi: 10.1038/mp.2008.127] examine the level of brain activity in 28 patients with schizophrenia (a disorder where mental function in the lateral frontal cortex is disrupted) and correlate this brain activity (difference between short and long list) with genetic differences at 100,000 snps spread across the autosomes.
They identify 2 genes (that pass an additional series of statistical hurdles designed to weed-out false positive results) RSRC1 and ARHGAP18, heretofore, never having been connected to mental function. Although neither protein is neuron or brain-specific in its expression, ARHGAP18 is a member of the Rho/Rac/Cdc42-like GTPase activating (RhoGAP) gene family which are well known regulators of the actin cytoskeleton (perhaps a role in synaptic plasticity ?) and RSRC1 is reported to bind to actin homologs. Also, RSRC1 may play a role in forebrain development since it is expressed in cdc34+ stem cells that migrate under the control of TGF-alpha (As an aside, yours truly co-published a paper showing that TGF-alpha is regulated by early maternal care – possible connection ? Hmm). A last possibility is a role in RNA splicing which many SR-proteins like RSRC1 function in – which also could be important for synaptic function as many mRNA’s are stored in synaptic terminals.
The authors’ method is completely novel and they seem to have discovered 2 new points from which to further explore the genetic basis of mental disability. It will be of great interest to see where the research leads next.
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One of the weird things about chronic pain is that it can sometimes be more “in your brain” than, say “in your back” or “in your elbow“. Take for example, a phenomenon known as phantom limb pain – where individuals who lose a limb, can still complain of feeling pain in that very missing limb. As described here, it is possible to “unlearn” this pain – which is a learning process involving changes in synaptic connectivity in the brain.
Where then, and how, might pain and learning related to chronic pain be happening “in your brain” rather than in your back or elbow. Well, a recent paper from Min Zhuo’s lab at the University of Toronto have reported some new insights into synaptic mechanisms of pain. In their recent paper [doi:10.1186/1744-8069-4-40], “Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex” they evaluate the role of presynaptic glutamamte release in a brain region known as the anterior cingulate cortex – a region whose activity is well-known to correlate with reports of pain.
One of the cool tricks they used to evaluate the role of pre- vs. post-synaptic actions of glutamate was to use mice that carry a G-protein coupled receptor from the sea slug (Aplysia) which can respond to octopamine (a chemical not normally found in mouse brains) to activate glutamate release pre-synaptically. When mice were administered octopamine in the cingulate cortex, became more sensitive to chronic pain. This identifies a very specific biochemical pathways and brain area for which pharmacologic and behavioral therapeutics might be designed for the treatment of chronic pain.
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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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Image via Wikipedia Nowadays, as many folks peer into the vast tangled thicket of their own genetic code, they, as I, assuredly wonder what it all means and how best to ascertain their health risks. One core theme that emerges from repeated forays into one’s own data is that many of us carry a scads of genetic risk for illness, but somehow, find ourselves living rather normal, healthy lives. How can this be ? A recent example of this entails a C/T snp (c) located in the 5′ flanking region of the neuregulin 1 gene which has been repeatedly associated with schizophrenia. Axel Krug and colleagues recently reported in their paper, “Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals” that T/C variation at this snp is associated with activation of the frontal cortex in healthy individuals. Participants were asked to keep track of a series of events and respond to a particular event that happened “2 events ago” . These so-called n-back tasks are not easy for healthy folks, and demand a lot of mental focus – a neural process that depends heavily on circuits in the frontal cortex. Generally speaking, as the task becomes harder, more activity in the frontal cortex is needed to keep up. In this case, individuals with the TT genotype seemed to perform the task while using somewhat less activity in the frontal cortex, rather than the risk-bearing CC carriers. As someone who has tried and failed to succeed at these tasks many times before, I was sure I would be a CC, but the 23andMe data show me to be a non-risk carrying TT. Hmmm … maybe my frontal cortex is just underactive.
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Image via Wikipedia Like most parents, I enjoy watching my children develop and marvel at the many similarities they bear to myself and my wife. The reshuffling of physical and behavioral features is always a topic of discussion and is the definitive icebreaker during uncomfortable silences with the inlaws. In some cases, the children are blessed with the better traits, but in other cases, there’s no option but to cringe when, “Look – wow, he really has your nose – hmmm”, is muttered. Most interesting, is the unfolding of patterns of behavior that unfold slowly with age. Differences in temperament and personality can instill great pride in parents but also can be a grating source of friction. One of my F1′s has recently taken to sessions of shrill, spine rattling, screaming which I hope will pass soon.
Why ? Many parents ask. “Have WE been raising him/her to do this ? – surely that’s what the neighbors must think”. “Is it something in the family ? I heard Aunt Marie was a bit of a screamer as a child – hmmm.”
In one of several of their landmark studies on the genetic regulation of pediatric brain development, Jay Giedd and colleagues, now provide in their recent paper, “Variance Decomposition of MRI-Based Covariance Maps Using Genetically-Informative Samples and Structural Equation Modeling”, a core framework on the relative contribution of genes vs. environment for the developing cortex. The paper is part of an ongoing longitudinal study of pediatric brain development at the Child Psychiatry branch at NIMH. Some 600 children participated – including identical twins, fraternal twins, siblings and singleton children.
The team used an analytical approach known as MACAAC (Mapping Anatomical Correlations Across the Cerebral Cortex) to ask how much does the variation in a single part of the brain co-vary with other parts ? Then the team used structural equation modeling to explore how much this co-variation might differ across identical twins vs. fraternal vs. siblings vs. age-matched singleton children. In locations where there is an high genetic contribution to co-variation in cortical thickness, identical twins should co-vary more tightly than fraternal twins or siblings etc. In this way, the team were able to parse out the relative influence of genes vs. environment to the developing brain.
In general terms, the team reports that a single genetic factor accounts for the majority of variation in cortical thickness, which they note may be consistent with a major mechanism of development of cortical layers involving the migration of neurons along radial glia. Genetic co-variances across separate locations in the brain were highest in the frontal cortex, middle temporal gyrus and left supramarginal gyrus. Interestingly, when environmental covariations were observed, they were usually restricted to just one hemisphere, while genetic covariations were often observed bilaterally.
Figure 5 of this paper is really incredible, it shows which areas of the cortex are more influenced by genes vs. environment. If I can just find the areas involved in screaming, the next time one of my neighbors looks askance at my F1, I’ll be able to explain.
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Every student can recall at least one stereotypical professor who – while brilliant – kept the students amused with nervous and socially inept behavior. Let’s face it, if you’re in academia, you’re surrounded by these – uh, nerds – and, judging by the fact that you are reading (not to mention writing) this blog right now – probably one of them. So, its natural to ask whether there might be a causal connection between emotionality, on the one hand, and cognitive performance on the other. Research on the neuromodulator serotonin shows that it plays a key role in emotional states – in particular, anxiety. Might it exert effects on cognitive performance ? In their paper, “A functional variant of the tryptophan hydroxylase 2 gene impacts working memory: A genetic imaging study“, (DOI: 10.1016/j.biopsycho.2007.12.002) Reuter and colleagues use a genetic variation a G to T snp (rs4570625) in the tryptophan hydroxylase 2 gene, a rate limiting biosynthetic isoenzyme for serotonin to evaluate its effect on a cognitive task. They ask subjects (who are laying in an MRI scanner) to perform a rather difficult cognitive task called the N-back task where the participant must maintain a running memory queue of a series of sequentially presented stimuli. Previous research shows that individuals with the GG genotype show higher scores on anxiety-related personality traits and so Reuter and team ask whether these folks activate more or less of their brain when performing the N-back working memory task. It turns out that the GG group showed clusters of activity in the frontal cortex that showed less activation than the TT group. The authors suggest that the GG group can perform the task using by recruiting less of their brains – hence suggesting that perhaps there just might be a genetic factor that accounts for a possible negative correlation between efficient cognitive performance and emotionality.
My 23andMe profile shows a GG here – nerd to the hilt – what will I use the rest of my PFC for ? Something else to worry about.
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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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Posted in COMT, DLPFC, Dopamine, Frontal cortex, Orbitofrontal cortex, Parahippocampal gyrus, Posterior parietal cortex, tagged 23andMe, Dopamine, Frontal lobe, Functional magnetic resonance imaging on January 1, 2008 |
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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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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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Behavioral geneticists are fond of noting that more than half of the risk for mental illness is heritable, and, fonder of the number of specific risk factors that have been identified. What is much less well known however is how these heritable factors interact with the environment to potentiate risk. Psychiatrists, on the other hand, rightly point out that children and adults who experience traumatic and social stress are also at greater risk for psychiatric illness. Indeed, brain imaging has shown a number of anatomical regions where activity declines in subjects and patients alike who experience trauma or other difficult experience. In their recent paper, “Stress-induced changes in primate prefrontal profiles of gene expression,” Karssen and colleagues take a major step towards bridging the gene-by-experience puzzle and examine how gene expression changes in response to socially stressful experience. Using a squirrel monkey model, an experimental group of males was subjected to intermittent social separation and also exposure to new roommates – conditions known to elevate cortisol levels. Using a (note the caveat here) human microarray platform and several signal analysis protocols, the investigators present several hundred genes differentially (interestingly mostly down-regulated) expressed in the frontal cortex. So – the question begs – were any of the genes identified in the Karssen study the same, or in the same pathways, as known genetic risk factors ? Yes – well sort of. The authors present several genes, including a few involved in GABA signaling, that had previously been linked via gene expression studies to mood disorders in humans. Certainly, these are attractive candidates for family- and population-based association studies.
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The DISC1 mouse is a major step forward in a translational research path towards understanding how genes contribute to the risk of complex mental disorders such as schizophrenia. The latest mouse (see PNAS - Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans by Hikida et al.) attempts to replace the normal mouse gene with a human mutation. The deficits parallel human abnormalities in a remarkable way. Note, however, that Joseph Gogos and colleagues (including my one-time boss Maria Karayiorgou) have shown (see PNAS -Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice by Hiroko et al.) that an ostensibly normal mouse inbred strain (normal, that is, if you’re inbred for one, and a mouse, for another) carries a truncated form of DISC1. Both of these mouse models show deficits in frontal cortex dependent behaviors but, together, they also demonstrate how the many interacting genes in the background can modify and ameliorate the effects of a single mutation. Do the genes that modify DISC1 in mice modify risk in humans?
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