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Archive for the ‘Striatum’ Category

Splitting in defense of my DRD2 alleles

Posted in Dopamine, DRD2, Striatum, Substantia nigra, Uncategorized, tagged , on April 7, 2011| Leave a Comment »

As a big fan of black and white photography, I’m intrigued by the concept of “Splitting” or so-called “black and white” thinking.  It’s something we all do to different degrees … when we avoid dealing with the “shades of gray” and group things in our life into “all good” or “all bad” groups.

Psychologists have considered this cognitive tendency to be a normal part of cognitive development (eg. good guys vs. bad guys), a response to stress, and also a part of various psychopathologies (funny, how psychiatrists have a tendency to group us into the “normal” and “abnormal”, huh?).

Is there anything wrong with seeing the world in black and white?  Perhaps, if you label mildly annoying people as “bad”, you’ll soon have no friends … but otherwise, I’m not sure.  Simplicity can be soothing.

I mean, our brains have a strong tendency to work at the extremes … for example, when it comes to cognition and movement.  We’re wired with so-called striatonigral (Go) and striatopallidal (NoGo) neural pathways that are engaged when cognition is transduced into action.  In the primal world of our ancestors, we didn’t survive very long if we danced around fretfully pondering the costs and benefits of running, or not running, from saber tooth tigers!  So, it’s no surprise, that we’re inherently uncomfortable in the wishy-washy, indecisive, muddling middle ground when making a decision.  We want to “go” or “freeze”, “do it” or “don’t”, “good” or “bad” … just make a f**king decision already.

Here’s a link to some current research on the “Go” and “NoGo” brain systems … and their genetic underpinnings (eg. the DRD2 protein is active when we are flummoxed with uncertainty which keeps us lingering in the NoGo state). Hey, our genome got us here … in one piece … it helped us stay alive … that’s not necessarily a bad thing.

thanks for the pic amadeus

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Coping with the shifting sands of development one grain at a time

Posted in SAPAP3, Striatum, tagged , , , , , , , , , , on February 22, 2010| Leave a Comment »

03230052.JPG
Image by mbrownstone via Flickr

Walter Dean Myers, an author of The Young Landlords and many other classic coming of age novels once remarked, “The special place of the young adult novel should be in its ability to address the needs of the reader to understand his or her relationships with the world, with each other, and with adults.”  Indeed, the wonderful elaborations of psychosocial development that occur during the teenage years makes for a vivid and tumultuous time – worthy of many a book – especially those like Myers’ that so help adolescents to cope.  During this time, a child’s brain and body is supplanted by adult systems, which, from a physiological point of view, place the adolescent’s mind and body at the mercy of thousands of shifting biochemical processes.  Such a notion of the shifting sands of adolescence were brought to mind while reading a research article focused on one – just one single example – of biochemical change.

The paper entitled, “Cortico-striatal synaptic defects and OCD-like behaviors in SAPAP3 mutant mice” [doi: 10.1038/nature06104] points out that mice who lack the function of the post-synaptic density scaffolding protein encoded by the SAPAP3 gene display excessive grooming and other behaviors reminiscent of obsessive compulsive disorder – a condition that frequently emerges during adolescence.  One of the main findings of the paper is that a normal developmental shift of NR2B –> NR2A subunits of the NMDA receptor does NOT seem to occur – rendering the SAPAP3 mutant mice with an immature form of NMDA receptor.  The authors suggest that this may be the underlying reason for the aberrant behavior, and were able to normalize the mutant mice by re-introducing SAPAP3 protein via a lentiviral-mediated expression vector placed in the striatum.

Gosh.  This NR2B –> NR2A shift is just one example – one grain – in the shifting biochemical sands of development.  Just one of thousands.  How did my brain ever make it through?

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RARB says I was born when my late born striosomal cells were born

Posted in Basal Ganglia, RARB, Striatum, tagged , , , , , , , , , , , , on February 5, 2010| Leave a Comment »

Novelty candles may be used.
Image via Wikipedia

Everyone has a birthday right. Its the day you (your infant self) popped into the world and started breathing, right?  But what about the day “you” were born – that is – “you” in the more philosophical, Jungian, spiritual, social, etc. kind of a way when you became aware of being in some ways apart from others and the world around you.  In her 1997 paper, “The Basal Ganglia and Cognitive Pattern Generators“, Professor Ann Graybiel writes,

The link between intent and action may also have a quite specific function during development. This set of circuits may provide part of the neural mechanism for building up cognitive patterns involving recognition of the self. It is well documented that, as voluntary motor behaviors develop and as feedback about the consequences of these behaviors occurs, the perceptuomotor world of the infant develops (Gibson 1969). These same correlations among intent, action, and consequence also offer a simple way for the young organism to acquire the distinction between actively initiated and passively received events. As a result, the infant can acquire the recognition of self as actor. The iterative nature of many basal ganglia connections and the apparent involvement of the basal ganglia in some forms of learning could provide a mechanism for this development of self-awareness.

As Professor Graybiel relates the “self” to function in the basal-ganglia and the so-called cortico-thalamic basal-ganglia loops – a set of parallel circuits that help to properly filter internal mental activity into specific actions and executable decisions – I got a kick out of a paper that describes how the development of the basal-ganglia can go awry for cells that are born at certain times.

Check out the paper, “Modular patterning of structure and function of the striatum by retinoid receptor signaling” by Liao et al.   It reveals that mice who lack a certain retinoic acid receptor gene (RARbeta) have a type of defective neurogenesis in late-born cells that make up a part of the basal ganglia (striatum) known as a striosome.  Normally, the authors say, retinoic acid helps to expand a population of late-born striosomal cells, but in the RARbeta mutant mice, the rostral striosomes remain under-developed.   When given dopaminergic stimulation, these mutant mice showed slightly less grooming and more sterotypic behaviors.

So when was “my self’s” birthday?  Was it when these late-born striosomal cells were, umm, born?  Who knows, but I’m glad my retinoic acid system was intact.

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Indulging my inner rat over a few drinks

Posted in ADH1C, Amygdala, Caudate nucleus, CDH13, GATA4, Striatum, tagged , , , , , , , , , , , , , on November 16, 2009| Leave a Comment »

Where da rodents kick it
Image by Scrunchleface via Flickr

A recent GWAS study identified the 3′ region of the liver- (not brain) expressed PECR gene (rs7590720(G) and rs1344694(T)) on chromosome 2 as a risk factor for alcohol dependency.  These results, as reported by Treutlein et al., in “Genome-wide Association Study of Alcohol Dependence” were based on a population of 487 male inpatients and a follow-up re-test in a population of 1024 male inpatients and 996 control participants.

The authors also asked whether lab rats who – given the choice between water-based and ethanol-spiked beverages over the course of 1 year – showed differential gene expression in those rats that were alcohol preferrers vs. alcohol non-preferring rats.  Among a total of 542 genes that were found to be differentially expressed in the amygdala and caudate nucleus of alcohol vs. non-alcohol-preferring rat strains,  a mere 3 genes – that is the human orthologs of these 3 genes – did also show significant association with alcohol dependency in the human populations.  Here are the “rat genes” (ie. human homologs that show differential expression in rats and association with alcohol dependency in humans): rs1614972(C) in the alcohol dehydrogenase 1C (ADH1C) gene, rs13273672(C) in the GATA binding protein 4 (GATA4) gene, and rs11640875(A) in the cadherin 13 (CDH13) gene.

My 23andMe profile gives a mixed AG at rs7590720, and a mixed GT at rs1344694 while I show a mixed CT at rs1614972, CT at rs13273672 and AG at rs11640875.  Boooring! a middling heterozygote at all 5 alcohol prefer/dependency loci.   Were these the loci for chocolate prefer/dependency I would be a full risk-bearing homozygote.

 

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3D brain atlas gets comprehensive genetic makeover

Posted in Basal Ganglia, Cingulate cortex, Striatum, Superior temporal cortex, tagged , , , , on October 7, 2009| Leave a Comment »

morph_slicer_demoThe brain is a wonderfully weird and strange organ to behold.  Its twists and folds, magnificent, in and of themselves, are even moreso when we contemplate that the very emotional experience of such beauty is carried out within the very folds.  Now consider the possibility of integrating these beauteous structure/function relationships with human history – via the human genome – and ask yourself if this seems like fun.  If so, check out the recent paper, “Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study” [doi:10.1016/j.neuroimage.2009.09.043].

Here the research team – members of the Biomedical Informatics research Network – have carried out the largest and most comprehensive known twin study of brain structure.  By performing structural brain imaging on 404 male twin pairs (important to note here that the field still awaits a comparable female study), the team examined the differences in identical (MZ) vs. fraternal (DZ) pair correlations of the structure of some 96 different brain regions.  The authors now provide an updated structural brain map showing what structures are more or less influenced by genes vs. environment. Some of the highlights from the paper are that genes accounted for about 70% of overall brain volume, while in the cortex, genes accounted for only about 45% of cortical thickness.  Much of the environmental effects were found to be non-shared, suggesting, as expected, that individual experience can have strong effects on brain structure.  The left and right putamen showed the highest additive genetic influence, while the cingulate and temporal cortices showed rather low additive genetic influences (below 50%).

If you would like to play around with a free brain structure visualization tool, check out Slicer 3D, which can be obtained from the BIRN homepage or directly here.  I had fun this morning digitally slicing and dicing grey matter from ventricles and blood vessels.

slicer

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Beauty is in the ventral striatum of the beholder

Posted in Dopamine, Striatum, tagged , on September 16, 2008| Leave a Comment »

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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Genetic ski patrol up and down the inverted U

Posted in Dopamine, DRD2, Frontal cortex, Striatum, tagged , on March 14, 2008| Leave a Comment »

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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Humans & li’l birdies share genetic pathway for speech

Posted in FOXP2, Striatum, tagged , on December 26, 2007| Leave a Comment »

Zebra Finch (Taeniopygia guttata)Image via Wikipedia The evolution of language sometimes seems like a sort of jewel in the evolutionary crown of homo sapiens. Evidence of positive selection in the verbal dyspraxia FOXP2 gene, is often discussed with amazement and a reverential tone befitting this special evolutionary achievement. Enter the humble zebra finch – who’s songs and language articulation could teach Sinatra a thing or two. Haesler and colleagues use short-hairpin RNAs to interfere with the zebra finch homolog of FOXP2 in a brain area known as ‘area x’ (functionally equivalent to the human striatum) where the gene is upregulated during the late summer when males must belt out their best version of Strangers in the Night to woo the females. In their paper, “Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X“, (DOI) the research team finds that young zebra finches with lower expression of FOXP2 have difficulty learning new songs and are less able to articulate specific sounds and lyrical blurbs. These difficulties are much like the difficulties experienced by human children who carry mutations in FOXP2.

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GPR6 teaches B.F. Skinner that actions have consequences

Posted in G-protein, GPR6, Striatum, tagged , , , , , , , , on November 24, 2007| Leave a Comment »

B.F.Image via Wikipedia

I’m not sure what Skinner would have thought, but its clear that, nowadays, mechanisms of behavior can be understood in terms of dynamic changes in neural systems and, furthermore, that individual differences in these neural dynamics are heavily regulated by genetic variation. Consider the recent paper by Lobo et al., “Genetic control of instrumental conditioning by striatopallidal neuron–specific S1P receptor Gpr6” (DOI). The authors use molecular genetics to seek out and find key genetic regulators of a specific and fundamental form of learning – operant or instrumental conditioning, pioneered by B.F. Skinner – wherein an individual performs an act and, afterwards, receives (+ or -) reinforcing feedback. This type of learning is distinct from classical conditioning where, for example, Pavlov’s dogs heard a bell before dinner and eventually began to salivate at the sound of the bell. In classical conditioning, the cue comes before the target, whereas in operant conditioning, the feedback comes after the target. Interestingly, the brain uses very different neural systems to process these different temporal contingencies and Lobo and company dive straight into the specific neural circuits – striatopallidal medium spiny neurons – to identify genes that are differentially expressed in these cells as compared to other neurons and, in particular, striatonigral medium spiny neurons. The GPR6 gene was found to be the 6th most differentially expressed gene in these cells and resultant knockout mice, when placed in an operant chamber, were much faster than control animals in learning the bar press association with a sugar pellet reward. The expression of GPR6 in striatopallidal cells predicts that they should have a normal function in inhibiting or slowing down such associations, so it makes sense that the GPR6 knockout animals are faster to learn these associations. This is one of the first genes whose function seems specifcially linked to a core cognitive process – Skinner might have been impressed after reading the paper.

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rs6265 (A) is my bodyguard

Posted in BDNF, Nucleus accumbens, Striatum, Ventral tegmental area, tagged , , on November 19, 2007| Leave a Comment »

It’s generally not fun to be browbeaten, bullied, bulldozed or downright oppressed – by the schoolyard bully or perhaps the micromanaging boss – in any form. While we’ve all been there – sometimes with initial feelings of sorrow, mopiness, lethargy, etc. – all part of the normal adaptive response to just pack-it-in and withdraw, the effects of social stress in some individuals can be quite profound and serious. The recent paper, “Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions” by Krishnan and company (DOI) provides some insight into mechanisms of social stress and how several genetic factors are implicated in the regulation of activity of a particular synapse linking the ventral tegmental area (VTA) and nucleus accumbens (NAc). Of particular interest is the protective effect of a single G to A nucleotide change (rs6265) in the brain derived neurotrophic factor (BDNF) that leads to a valine to methionine amino acid substitution at position 66, a portion of the protein thought to play a role in cytoplasmic trafficking. As reported, transgenic mice that carry the human form of the poorly secreted Met/Met form of BDNF did not suffer a typical withdrawl, depression-like syndrome when subjected to a paradigm of chronic social defeat as compared to defeated Val/Val (highly secreted form) mice. In correspondence with this finding, higher levels of BDNF were found in the NAc in human cases of human depression. The authors’ work provides a new mechanistic model for regulation of VTA-NAc synaptic activity that makes testable predictions about complex behaviors and avenues for prevention and remediation of one of life’s unpleasant, but inevitable, tribulations.

…darn-it !  my 23andMe profile shws that I am a C/C valine/valine … how depressing 😦

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