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Posts Tagged ‘Genetics’

ruler - STUPID INCOMPETENT MANUFACTURERS
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One of the difficult aspects of understanding mental illness, is separating the real causes of the illness from what might be secondary or tertiary consequences of having the illness.  If you think about a car whose engine is not running normally, there may be many observable things going wrong (pinging sound, stalling, smoke, vibration, overheating, loss of power, etc.) – but, what is the real cause of the problem?  What should be done to fix the car? – a faulty sparkplug or timing belt perhaps?  Such is often the problem in medicine, where a fundamental problem can lead to a complex, hard-to-disentangle, etiology of symptoms.  Ideally, you would fix the core problem and then expect the secondary and tertiary consequences to normalize.

This inherent difficulty, particularly in mental illness, is one of the reasons that genetic research is of such interest.  Presumably, the genetic risk factors are deeper and more fundamentally involved in the root causes of the illness – and hence – are preferable targets for treatment.  The recent paper, “Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability” [Arch Gen Psychiatry. 2009;66(5):467-477] seeks to ascertain whether one aspect of schizophrenia – a widespread and well-documented thinning of the neocortex – is due to genetic risk (hence something that is closer to a primary cause) or – rather – if cortical thinning is not due to genetics, and so more of a secondary consequence of things that go wrong earlier in the development of the illness.

To explore this idea, the team of Goldman et al., did something novel.  Rather than examine the differences in cortical thickness between patients and control subjects, the team evaluated the cortical thickness of 59 patients and 72 unaffected siblings as well as 196 unrelated, matched control participants.  If the cortical thickness of the siblings (who share 50% of their genetic variation) was more similar to the patients, then it would suggest that the cortical thinning of the patients was under genetic control and hence – perhaps – a biological trait that is more of a primary cause.  On the other hand, if the cortical thickness of the siblings (who share 0% of their genetic variation) was more similar to that of the healthy control participants, then it would suggest that cortical thinning was – perhaps more of a secondary consequence of some earlier deficit.

The high-resolution structural neuroimaging allowed the team to carefully assess cortical thickness – which is normally between a mere 2 and 4 millimeters – across different areas of the cortex.  The team reports that, for the most part, the cortical thickness measures of the siblings were more similar to the unrelated controls – thus suggesting that cortical thickness may not be a direct component of the genetic risk architecture for schizophrenia.  Still, the paper discusses several candidate mechanisms which could lead to cortical thinning in the illness – some of which might be assessed in the future using other imaging modalities in the context of their patient/sibling/control experimental design.

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caliban missing miranda
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“A devil, a born devil, on whose nature
Nurture can never stick; on whom my pains,
Humanely taken, all, all lost, quite lost
And as with age his body uglier grows,
So his mind cankers.”

So says the wizard Prospero about the wretched Caliban in Shakespeare’s The Tempest (Act IV, Scene I, lines 188 – 192).  Although Shakespeare was not a neuroscientist (more to his credit!), his poignant phrase, “on whose nature, Nurture can never stick”  strikes the very core of the modern debates on the role of genes and personal genomes, and perhaps reminds us that our human experience is delicately balanced amidst the interaction of genes and environment.

Among the some 20,500 genes in the human genome (yes, this is the latest estimate from Eric Lander this past weekend) one particularly amazing gene stands out.   CACNA2D1 the alpha-2/delta-1 subunit of the voltage-dependent calcium channel complex (which also binds to the widely-prescribed drug Gabapentin) encodes a protein who, in conjunction with other related subunits, forms a calcium channel to mediate the influx of calcium ions into neurons when membrane polarization occurs.  In the recent article, “Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis” [doi:10.1016/j.cell.2009.09.025] Eroglu and colleagues reveal that this single gene – initiates the development of synapses – the dynamic structures whose ever changing interconnections make us who we are – that allow “nurture to stick” as it were.

More on the biology of CACNA2D1 and its interactions with its ligand – Thrombospondins – to come.

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SfNneuroblogbadge Phrenological thinking, a popular pseudoscientific practice in the 1800’s suggested that the structure of the head and underlying brain held the clues to understanding human behavior.  Today, amidst the ongoing convergence of developmental science, molecular & biochemical science and systems-dynamical science (to name just a few), there is – of course – no single or agreed-upon level of analysis that can provide all the answers.  Circuit dynamics are wonderfully correlated with behavior, but they can be regulated by synaptic weights.  Also,  while developmental studies reveal the far reaching beauty of neuronal circuitry, such elegant wiring is of little benefit without healthy and properly regulated synaptic connections.  Genes too, can be associated with circuit dynamics and behavior, but what do these genes do?  Perchance encode proteins that help to form and regulate synapses? Synapses, synapses, synapses.  Perhaps there is a level of analysis – or a nexus – where all levels of analysis intersect?  What do we know about synapses and how these essential aspects of brain function are formed and regulated?

With this in mind I’ve been exploring the nanosymposium, “Molecular Dynamics and Regulation at Synapses” to learn more about the latest findings in this important crossroads of neurobiology.  If you’re like me, you sort of take synapses for granted and think of them as being very tiny and sort of generic.  Delve a while into the material presented at this symposium and you may come to view the lowly synapse – a single synapse – as a much larger, more complex, ever changing biochemical world unto itself.  The number of molecular players under scrutiny by the groups presenting in this one session is staggering.  GTPase activating proteins, kinases, molecular motors, receptors, proteases, cell adhesive proteins, ion channels and many others must interact according to standard biochemical and thermodynamic laws.  At this molecular-soup level, it seems rather miraculous that the core process of vessicle-to-cell membrane fusion can happen at all – let alone in the precise way needed to maintain the proper oscillatory timing needed for Hebbian plasticity and higher-level circuit properties associated with attention and memory.

For sure, this is one reason why the brain and behavior are hard to understand.  Synapses are very complex!

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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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Many thanks to Dr. Christina S. Barr from the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism-Laboratory of Clinical and Translational Studies, National Institutes of Health Animal Center for taking the time to comment on her team’s recent publication, “Functional CRH variation increases stress-induced alcohol consumption in primates” [doi:10.1073/pnas.0902863106] which was covered here.  On behalf of students and interested readers, I am so grateful to her for doing this!  Thank you Dr. Barr!

For readers who are unfamiliar with the extensive literature on this topic, can you give them some basic background context for the study?

“In rodents, increased CRH system functioning in parts of the brain that drive anxious responding (ie, amygdala) occurs following extended access to alcohol and causes animals to transition to the addicted state.  In rodent lines in which genetic factors drive increased CRH system functioning, those animals are essentially phenocopies of those in the post-dependent state.  We had a variant in the macaque that we expected would drive increased CRH expression in response to stress, and similar variants may exist in humans.  We, therefore, hypothesized that this type of genetic variation may interact with prior stress exposure to increase alcohol drinking.”

Can you tells us more about the experimental design strategy and methods?

“This was a study that relied on use of archived NIAAA datasets. The behavioral and endocrine data had been collected years ago, but we took a gene of interest, and determined whether there was variation. We then put a considerable amount of effort into assessing the functional effects of this variant, in order to have a better understanding of how it might relate to individual variation. We then genotyped archived DNA samples in the colony for this polymorphism.”

“I am actually a veterinarian in addition to being a neuroscientist- we have the “3 R’s”. Reduce, refine, and replace…..meaning that animal studies should involve reduced numbers, should be refined to minimize pain/distress and should be replaced with molecular studies if possible.  This is an example of how you can marry use of archived data and sophisticated molecular biology techniques/data analysis to come up with a testable hypothesis without the use of animal subjects. (of course, it means you need to have access to the datasets….;)”

How do the results relate to broader questions and your field at large?

“I became interested in this system because it is one that appears to be under intense selection.  In a wide variety of animal species, individuals or strains that are particularly stress-reactive may be more likely to survive and reproduce successfully in highly variable or stressful environments. Over the course of human evolution, however, selective pressures have shifted, as have the nature and chronicity of stress exposures.  In fact, in modern society, highly stress-reactive individuals, who are no less likely to be eaten by a predator (predation not being a major cause of mortality in modern humans), may instead be more likely to fall susceptible to various-stress related disorders, including chronic infections, diabetes, heart disease, accelerated brain aging, stress-related psychiatric disorders, and even drug and alcohol problems. Therefore, these genetic variants that are persistent in modern humans may make individuals more vulnerable to “modern problems.”

I do hope this helps. Let me know if it doesn’t, and I will try to better answer your questions.”

THANK YOU AGAIN VERY MUCH DR. BARR!!

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Science IS fun … props to Francis Collins for going out on a limb for the younger crowd on the Colbert Report.

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creb1According to Joseph LeDoux, “One of the most important contributions of modern neuroscience has been to show that the nature/nurture debate operates around a false dichotomy: the assumption that biology, on one hand, and lived experience, on the other, affect us in fundamentally different ways” (ref).  Indeed.  While I know not where the current debate stands, I’d like to point to a fantastic example of just how inextricably linked the genome is to the environment.  In their recent paper, “A Biological Function for the Neuronal Activity-Dependent Component of Bdnf Transcription in the Development of Cortical Inhibition” [doi:10.1016/j.neuron.2008.09.024]  Hong et al., ask what happens when you take away the ability of a given gene to respond to the environment.  This is not a traditional “knockout” experiment – where the gene is inactivated from the moment of conception onwards – but rather a much more subtle type of experimental manipulation.  What happens when you prevent nurture from exerting an effect on gene expression?

The team focused on the BDNF gene whose transcription can be initiated from any one of eight promoter sites (I-XIII).  These sites vary in activity depending on the phase of development and/or the tissue or type of cell – all of which make for a complex set of instructions able to turn the BDNF gene on and off in precise developmental and/or tissue-specific ways.  In the case of promoter IV, it appears to be triggered in the cortex in response to Ca++ release that occurs when neurons are firing – a phenomena called, “neuronal activity dependent transcription” – a top example of how the environment can influence gene expression.  Seeing as how BDNF promoter IV is important for this type of environment-induced gene expression, the team asked what happens when you remove this particular promoter?

To do this, the team constructed – keep in mind that these are – mice that contain mutations in several of the Calcium (Ca++) response elements in the promoter IV region.  They introduced point mutations so that the Ca++ sensitive protein CREB could not bind to the promoter and activate gene expression.  OK, so what happens?

Firstly, the team reports that the mutant mice are more or less indistinguishable from controls in appearance, gait, growth rate, brain size and can also reproduce and transmit the mutations.  WOW! Is that one strike AGAINST nurture? The team then shows that BDNF levels are more than 50% reduced in cultured neurons, but that levels of other immediate early genes are NOT affected (as expected).  In living animals, the effects were similar when they asked how much gene expression occurs in the sensory cortex when animals are exposed to light (after an extended period of darkness).  OK, so there are few effects, so far, other than lower levels of nurture-induced BDNF expression – hmmm. Looking more closely however, the team found that the mutant mice generated lower levels of inhibitory neuron activity – as measured by the firing of miniature inhibitory postsynaptic currents.  Follow-on results showed that the total number of inhibitory neurons (parvalbumin and NPY + GABAergic cells) was no different than controls and so it would seem that the activity dependence of BDNF is important for the maintenance of inhibitory synapses.

Hence, the team has found that what “nurture” does (via the BDNF promoter IV in this case) is to exert an effect on the connectivity of inhibitory neurons.  Wow, thanks mother nurture!  Although it may seem like an obscure role for something as important as THE environment, the team points out that the relative balance of excitation-to-inhibition (yin-yang as covered here for Rett syndrome) is crucial for proper cognitive development.

To explore the notion of inhibory/excitation balance further, check out this (TED link) video lecture, where Michael Merzenich describes this imbalance as a “signal-to-noise” problem wherein some children’s brains are rather noisy (due to any number of genetic/environmental reasons – such as, perhaps, poorly maintained inhibitory connections).  This can make it harder to develop and function in life.  Perhaps someday, the genetic/environment research like that of Hong and colleagues will inform the rehabilitative strategies developed by Merzenich.

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The homunculus (argument) is a pesky problem in cognitive science – a little guy who might suddenly appear when you propose a mechanism for decision making, spontaneous action or forethought  etc. – and would take credit for the origination of the neural impulse.  While there are many mechanistic models of decision making that have slain the little bugger – by invoking competition between past experience and memory as the source of new thoughts and ideas – one must always tread lightly, I suppose, to be wary that cognitive mechanisms are based completely in neural properties devoid of a homuncular source.

Still, the human mind must begin somewhere.  After all, its just a ball of cells initially, and then a tube and then some more folds, layers, neurogenesis and neural migration  etc. before maturing – miraculously – into a child that one day looks at you and says, “momma” or “dada”.  How do these neural networks come into being?  Who or what guides their development toward that unforgettable, “momma (dada)” moment?  A somewhat homuncluar “genetic program” – whose instructions we can attribute to millions of years of natural selection?  Did early hominid babies say “momma (dada)?  Hmmm. Seems like we might be placing a lot of faith in the so-called “instructions” provided by the genome, but who am I to quibble.

On the other hand, you might find that the recent paper by Akhtar et al., “Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function” [doi:10.1523/jneurosci.0097-09.2009] may change the way you think about cognitive development.  The team explores the function of two very important epigenetic regulators of gene expression – histone deacetylases 1,2 (HDAC1, HDAC2) on the functionality of synapses in early developing mice and mature animals.  By epigenetic, I refer to the role of these genes in regulating chromatin structure and not via direct, site-specific DNA binding.  The way the HDAC genes work is by de-acetylating – removing acetyl groups – thus removing a electrostatic repulsion of acetyl groups (negative charge) on histone proteins with the phosphate backbone of DNA (also a negative charge).  When the histone proteins carry such an acetyl group, they do NOT bind well to DNA (negative-negative charge repulsion) and the DNA molecule is more open and exposed to binding of transcription factors that activate gene expression.  Thus if one (as Akhtar do) turns off a de-acetylating HDAC gene, then the resulting animal has a genome that is more open and exposed to transcription factor binding and gene expression.  Less HDAC = more gene expression!

What were the effects on synaptic function?  To summarize, the team found that in early development (neonatal mouse hippocampal cells) cells where the HDAC1 or 2 genes were turned off (either through pharmacologic blockers or via partial deletion of the gene(s) via lentivirus introduction of Cre recombinase) had more synapses and more synaptic electrical activity than did hippocampal cells from control animals.  Keep in mind that the HDACs are located in the nucleus of the neuron and the synapses are far, far away.  Amazingly – they are under the control of an epigenetic regulator of gene expression;  hence, ahem, “epigenetic puppetmasters”.  In adult cells, the knockdown of HDACs did not show the same effects on synaptic formation and activity.  Rather the cells where HDAC2 was shut down showed less synaptic formation and activity (HDAC1 had no effect).  Again, it is amazing to see effects on synaptic function regulated at vast distances.  Neat!

The authors suggest that the epigenetic regulatory system of HDAC1 & 2 can serve to regulate the overall levels of synaptic formation during early cognitive development.  If I understand their comments in the discussion, this may be because, you don’t necessarily want to have too many active synapses during the formation of a neural network.   Might such networks might be prone to excitotoxic damage or perhaps to being locked-in to inefficient circuits?  The authors note that HDACs interact with MecP2, a gene associated with Rett Syndrome – a developmental disorder (in many ways similar to autism) where neural networks underlying cognitive development in children fail to progress to support higher, more flexible forms of cognition.  Surely the results of Akhtar et al., must be a key to understanding and treating these disorders.

Interestingly, here, the controller of these developmental phenotypes is not a “genetic program” but rather an epigenetic one, whose effects are wide-spread across the genome and heavily influenced by the environment.  So no need for an homunculus here.

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Lonely child
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For humans, there are few sights more heart-wrenching than an orphaned child (or any orphaned vertebrate for that matter).  Isolated, cold, unprotected, vulnerable – what could the cold, hard calculus of natural selection – “red in tooth and claw” – possibly have to offer these poor, vulnerable unfortunates?

So I wondered while reading, “Functional CRH variation increases stress-induced alcohol consumption in primates” [doi:10.1073/pnas.0902863106].  In this paper, the authors considered the role of a C-to-T change at position -248 in the promoter of the corticotropin releasing hormone (CRH or CRF) gene.  Its biochemical role was examined using nuclear extracts from hypothalamic cells, to demonstrate that this C-to-T nucleotide change disrupts protein-DNA binding, and, using transcriptional reporter assays, that the T-allele showed higher levels of transcription after forskolin stimulation.  Presumably, biochemical differences conferred by the T-allele can have a physiological role and alter the wider functionality of the hypothalamic-pituitary-axis (HPA axis), in which the CRH gene plays a critical role.

The authors ask whether primates (rhesus macaques) who differ in genotype (CC vs. CT) show any differences in physiological stress reactivity – as predicted by differences in the activity of the CRH promoter.  As a stressor, the team used a form of brief separation stress and found that there were no differences in HPA function (assessed by ACTH and Cortisol levels) in animals who were reared by their mothers.  However, when the stress paradigm was performed on animals who were reared without a mother (access to play with other age-matched macaques) there were significant differences in HPA function between the 2 genetic groups (T-alleles showing greater release of stress hormones).  Further behavioral assessments found that the peer reared animals who carried the T-allele explored their environment less when socially separated as adults (again no C vs. T differences in maternally reared animals).  In a separate assessment the T-carriers showed a preference for sweetened alcohol vs. sweetened water in ad lib consumption.

One way of summarizing these findings, could be to say that having no mother is a bad thing (more stress reactivity) and having the T-allele just makes it worse!  Another way could be to say that the T-allele enhances the self-protection behaviors (less exploration could be advantageous in the wild?) that arise from being orphaned.  Did mother nature (aka. natural selection) provide the macaque with a boost of self-preservation (in the form of a T-allele that enhances emotional/behavioral inhibition)?  I’m not sure, but it will be fun to report on further explorations of this query.  Click here for an interview with the corresponding author, Dr. Christina Barr.

—p.s.—

The authors touch on previous studies (here and here) that explored natural selection on this gene in primates and point out that humans and macaques both have 2 major haplotype clades (perhaps have been maintained in a yin-yang sort of fashion over the course of primate evolution) and that humans have a C-to-T change (rs28364015) which would correspond to position -201 in the macaque (position 68804715 on macaque chr. 8), which could be readily tested for similar functionality in humans.  In any case, the T-allele is rare in macaques, so it may be the case that few orphaned macaques ever endure the full T-allele experience.  In humans, the T-allele at rs28364015 seems more common.

Nevertheless, this is yet another – complicated – story of how genome variation is not destiny, but rather a potentiator or life experience – for better or worse.  Related posts on genes and early development (MAOA-here), (DAT-here), (RGS2-here), or just click the “development tag“.

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Within the genetic news flow, there is often, and rightly so, much celebration when a gene for a disease is identified.  This is indeed an important first step, but often, the slogging from that point to a treatment – and the many small breakthroughs along the way – can go unnoticed. One reason why these 2nd (3rd, 4th, 5th …) steps are so difficult, is that in some cases, folks who carry “the gene” variant for a particular disorder, do not, in fact, display symptoms of the disorder.

Huh? One can carry the risk variant – or many risk variants – and not show any signs of illness?  Yes, this is an example of what geneticists refer to as variable penetrance, or the notion of carrying a mutation, but not outwardly displaying the mutant phenotype.  This, is one of the main reasons why genes are not deterministic, but much more probablistic in their influence of human development.

Of course, in the brain, such complexities exist, perhaps even moreso.  For example, take the neurological condition known as dystonia, a movement disorder that, according to the Dystonia Medical Research Foundation, “causes the muscles to contract and spasm involuntarily. The neurological mechanism that makes muscles relax when they are not in use does not function properly. Opposing muscles often contract simultaneously as if they are “competing” for control of a body part. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures.”  Presently there are more than a dozen genes and/or chromosomal loci that are associated with dystonia – two of the major genes, DYT1 and DYT6 – having been identified as factors in early onset forms of dystonia.  Now as we enter the era of personal genomes, an individual can assess their (own, child’s, preimplantion embryo’s!) genetic risk for such rare genetic variants – whose effects may not be visible until age 12 or older.  In the case of DYT1, this rare mutation (a GAG deletion at position 946 which causes a loss of a glutamate residue in the torsin A protein) gives rise to dystonia in about 30-40% of carriers.  So, how might these genes work and why do some individuals develop dystonia and others do not?  Indeed, these are the complexities that await in the great expanse between gene identification and treatment.

An inspection of the molecular aspects of torsin A (DYT1) show that it is a member of the AAA family of adenosine triphosphatases and is related to the Clp protease/heat shock family of genes that help to properly fold poly-peptide chains as they are secreted from the endoplasmic reticulum of the cell – a sort-of handyman, general purpose gene (expressed in almost every tissue in the body) that sits on an assembly line and hammers away to help make sure that proteins have the right shape as they come off their assembly linesNot much of a clue for dystonia – hmm.  Similarly, the THAP domain containing, apoptosis associated protein 1 (THAP1) gene (a.k.a. DYT6) is also expressed widely in the body and seems to function as a DNA binding protein that regulates aspects of cell cycle progression and apoptosis.  Also not much an obvious clue to dystonia – hmm, hmm.  Perhaps you can now see why the identification of “the gene” – something worth celebrating – can just leave you aghast at how much more you don’t know.

That these genes influence an early developmental form of the disorder suggests a possible developmental role for these rather generic cogs in the cellular machinery.  But where? how? & why an effect in some folks and not others?  To these questions, comes an amazing analysis of DYT1 and DYT6 carriers in the article entitled, “Cerebellothalamocortical Connectivity Regulates Penetrance in Dystonia” by Argyelan and colleagues [doi: 10.1523/JNEUROSCI.2300-09.2009]. In this article, the research team uses a method called diffusion tensor imaging (sensitive to white matter density) to examine brain structure and function among individuals who carry the mutations but either DO or DO NOT manifest the symptoms. By looking at white matter tracts (super highways of neural traffic) throughout the brain the team was able to ask whether some tracts were different in the 2 groups (as well as a group of unaffectd, non-carriers).  In this way, the team can begin to better understand the causal pathway between these run-of-the-mill genes (torsin A and thap1) and the complex pattern of muscle spasms that arise from their mutations.

To get right to the findings, the team has discovered that in one particular tract, a superhighway known as “cerebellar outflow pathway in the white matter of lobule VI, adjacent to the dentate nucleus” (not as quaint as Route 66) that those participants that DO manifest dystonia had less tract integrity and connectivity there compared to those that DO NOT manifest and healthy controls (who have the most connectivity there).  Subsequent measures of resting-state blood flow confirmed that the disruptions in white matter tracts were correlated with cerebellar outflow to the thalamus and – more importantly – with activity in areas of the motor cortex.  The correlations were such that individuals who DO manifest dystonia had greater activity in the motor cortex (this is what dystonia really comes down to — too much activity in the motor cortex).

Thus the team were able to query gene carriers using their imaging methods and zero-in on “where in the brain” these generic proteins exert a detrimental effect.  This seems to me, to be a huge step forward in understanding how a run-of-the-mill gene can alter brain function in such a profound way.  Now that they’ve found the likely circuit (is it the white matter per se or the neurons?), more focus can be applied to how this circuit develops – and can be repaired.

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1/365 [dazed & confused]
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pointer to: Daniel MacArthur and Neil Walker’s (@ Genetic Future bog) in-depth coverage of various critiques on the recent back-to-back-to-back Nature magazine trifecta (covered here) on GWAS results for schizophrenia.  Rough going for the global corsortia and a major f**king bummer for folks like myself who have been hoping that these vast studies would provide a solid basis for genome-based cognitive intervention strategies in the future.  Some of the discussion in the comments section points to the weakness in the diagnostic criteria, which is a topic also covered here recently.

Perhaps there is hope in the brain systems / imaging-based approaches that are taking off as genome technology spreads into cognitive and imaging science. Tough to scan 10’s of thousands of people however. Double F**K!

I guess DSM-based psychiatric genetics is just about dead for the time being.  The announcement of the soon to shutter deCODE Genetics and its 5-year stock price captures the failure of this endeavor.

decode1

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“B-b-book”? you say – as in words printed – on paper?  Yes, its a book, “The Genetics of Cognitive Neuroscience” for which my colleagues and I contributed chapter 5. Despite the 15th century medium, the collection of ideas and expertise assembled by the editors makes the book a great intoduction to this evolving topic.

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Its not often that Nature magazine publishes a triple-back-to-back-to-back, so take note if you’re interested in the genetics of mental illness. The 3 papers – [doi:10.1038/nature08185] involving 3,322 individuals with schizophrenia and 3,587 controls, [doi:10.1038/nature08186] 4,999 cases and 15,555 controls and [doi:10.1038/nature08192] 8,008 cases and 19,077 controls – are as massive and powerful as any genome-wide effort to-date.  The results?  Overall a common result showing linkage to the major histocompatibility complex or so-called ‘MHC genes’ located on chromosome 6.  What to these genes do? and what’s the relevence to mental illness?

Here’s a quickie immunology primer on the biological function of the major histocompatibility genes.  They encode proteins whose molecular function is display short peptides on the surface of aptly named antigen presenting cells in the immune system (think of your hand as an MHC protein holding onto an apple (the short peptide) and holding it out or presenting it to someone (an Helper T-Cell).  This act of “presentation” is done so that the Helper T-Cells can determine whether such peptides are “self” or “non-self”.  If such displayed peptides are non-self (such as a virus, endotoxin or bacterium), then the helper T-Cells will sound the alarm and initiate a T- or B-Cell based immune response aimed specifically at the offending invader.  The movies below show the MHC proteins in their place displaying antigen peptides on the cell surface for binding with a helper T-Cell.


So, what does this have to do with mental illness? Although there are other non-immunological genes interspersed among the MHC genes, there is good reason to begin to explore the role of external infection and early development.  The authors of one paper note that,  “Schizophrenia patients are more likely, compared to the general population, to have been born in the winter or the spring. Although infections such as influenza and measles have been proposed as a possible mechanism for this distortion, a clear association between infectious agents and schizophrenia has not been demonstrated.”

The more we know, the more we don’t know.  Hopefully more early environment data will be analyzed.

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labyrinthine circuit board lines
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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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Human chromosome 15
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One way to organize the great and growing body of research into autism is via a sort-of  ‘top-down’ vs. ‘bottom-up’ perspective.  From the ‘top-down’ one can read observational research that carefully catalogs the many & varied social and cognitive attributes that are associated with autism.  Often times, these behavioral studies are coupled with neurochemical or neuroimaging studies that test whether variation in such biomarkers is correlated with aspects of autism.  In this manner, the research aims to dig down into the physiology and biochemistry of the developing brain to find out what is different and what differences might predict the onset of autistic traits.  At the deepest biological level – the bedrock, so to speak – are a number of genetic variations that have been correlated with autism.  These genetic variants permit another research strategy – a ‘bottom-up’ strategy that allows investigators to ask, “what goes wrong when we manipulate this genetic variant?”  While proponents of each strategy are painfully aware of the limitations of their own strategy – oft on the barbed-end of commentary from the other side – it is especially exciting when the ‘top-down’ and ‘bottom-up’ methods find themselves meeting in the agreement in the middle.

So is the case with Nakatani et al., “Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism” [doi: 10.1016/j.cell.2009.04.024] who created a mouse that carries a 6.3 megabase duplication of a region in the mouse that luckily happens to be remarkably conserved in terms of gene identity and order with the 15q11-13 region in humans – a region that, when duplicated, is found in about 5% of cases with autism.  [click here for maps of mouse human synteny/homology on human chr15] Thus the team was able to engineer mice with the duplication and ask, “what goes wrong?” and “does it resemble autism in any kind of meaningful way (afterall these are mice we’re dealing with)?

Well, the results are rather astounding to me.  Most amazing is the expression of a small nucleoar RNA (snoRNA) – SNORD115 (mouse-HBII52) – that function in the nucleolus of the cell, and plays a role in the alternative splicing of exon Vb of the 5HT2C receptor.  The team then found that the editing of 5HTR2C was altered in the duplication mice and also that Ca++ signalling was increased when the 5HTR2C receptors were stimulated in the duplication mice (compared to controls).  Thus, a role for altered serotonin function – which has been a longstanding finding in the ‘topdown’ approach – was met midway and affirmed by this ‘bottom-up’ approach!  Also included in the paper are descriptions of the abberant social behaviors of the mice via a 3-chambered social interaction test where duplication mice were rather indifferent to a stranger mouse (wild-type mice often will hang out with each other).

Amazing stuff!

Another twist to the story is the way in which the 15q11-13 region displays a phenomenon known as genomic-imprinting, whereby only the mother or the father’s portion of the chromosome is expressed.  For example, the authors show that the mouse duplication is ‘maternally imprinted’ meaning that that pups do not express the copy of the duplication that comes from the mother (its expression is shut down via epigenetic mechanisms that involve – wait for itsnoRNAs!)  so the effects that they report are only from mice who obtained the duplication from their fathers.  So, if you by chance were wondering why its so tough to sort out the genetic basis of autism – here’s one reason why.  On top of this, the 5HTR2C gene is located on the X-chromosome which complicates the story even more in terms of sorting out the inheritance of the disorder.

Further weird & wild is the fact that the UBE3A gene (paternally imprinted) and the genetic cause of Angelman Syndrome sits in this region – as does the SNRPN gene (maternally imprinted) which encodes a protein that influences alternative RNA splicing and also gives rise to Prader-Willi syndrome.  Thus, this tiny region of the genome, which carries so-called “small” RNAs can influence a multitude of developmental disabilities.  Certainly, a region of the genome that merits further study!!

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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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