Posted in 5HTT, DARPP32, DLPFC, Dopamine, Frontal cortex, MAOA, tagged Biology, Brain, Eukaryotic, Functional magnetic resonance imaging, Gene, Genetic diversity, Genetics, MAOA on July 31, 2009 |
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Amidst a steady flow of upbeat research news in the behavioral-genetics literature, there are many inconvenient, uncomfortable, party-pooping sentiments that are more often left unspoken. I mean, its a big jump – from gene to behavior – and just too easy to spoil the mood by reminding your colleagues that, “well, everything is connected to everything” or “that gene association holds only for that particular task“. Such may have been the case often times in the past decade when the so-called imaging-genetics literature emerged to parse out a role for genetic variation in the structure and functional activation of the brain using various neuroimaging methods. Sure, the 5HTT-LPR was associated with amygdala activation during a face matching task, but what about other tasks (and imaging modalities) and other brain regions that express this gene. How could anyone (let alone NIMH) make sense out of all of those – not to mention the hundreds of other candidate genes poised for imaging-genetic research?
With this in mind, it is a pleasure to meet the spoiler-of-spoilers! Here is a research article that examines a few candidate genetic polymorphisms and compares their findings across multiple imaging modalities. In his article, “Neural Connectivity as an Intermediate Phenotype: Brain Networks Under Genetic Control” [doi: 10.1002/hbm.20639] Andreas Meyer-Lindenberg examines the DARPP32, 5HTT and MAOA genes and asks whether their associations with aspects of brain structure/function are in any way consistent across different neuroimaging modalities. Amazingly, the answer seems to be, yes.
For example, he finds that the DARPP32 associations are consistently associated with the striatum and prefrontal-striatal connectivity – even as the data were collected using voxel-based morphometry, fMRI in separate tasks, and an analysis of functional connectivity. Similarly, both the 5HTT and MAOA gene promoter repeats also showed consistent findings within a medial prefrontal and amygdala circuit across these various modalities.
This type of finding – if it holds up to the spoilers & party poopers – could radically simplify the understanding of how genes influence cognitive function and behavior. As suggested by Meyer-Lindenberg, “features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure.” He suggests that dynamic causal modeling of resting state brain function may be a powerful approach to understand the role of a gene in a rather global, brain-wide sort of way. I hope so and will be following this cross-cutting “connectivity” approach in much more detail!
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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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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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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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Daniel Weinberger and company have a new installment in-press at Biological Psychiatry in their epic program to untangle the genetic basis of schizophrenia – “Heritability of Brain Morphology Related to Schizophrenia: A Large-Scale Automated Magnetic Resonance Imaging Segmentation Study.” Like all complex illness, schizophrenia is regulated by a variety of environmental sources (perinatal complications, stress & substance abuse are a few) and equally regulated by heritable factors. Although several specific genes for schizophrenia have been painstakingly identified, the genes are expressed widely throughout the brain – making it difficult to pinpoint where in the brain the gene interacts with the environment to exert its detrimental effects. To solve this problem, Weinberger and colleagues pioneered a method known as imaging-genetics where they look at how individual genetic differences correlate with differences in brain structure or functional activity (if you ever have a chance to volunteer for an fMRI brain imaging study – go for it – it’ll be one of the top 10 weirdest experiences of your life). In their latest report, the team pioneers a new “fully-automated whole brain segmentation” technique to show that the genetic factors that put individuals at risk may be functioning vis-a-vis the hippocampus and neocortex. This narrows the search space a lot! and is a major step forward in beginning to localize where in the brain the genetic risk originates.
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