January 21, 2008 by dendrite
Synaptic formation involves a complex series of steps including cellular movement, membrane specialization, molecular recognition, recruitment of pre- & postsynaptic docking proteins and accompanying receptors, reuptake & recycling factors. When individual components of this process are structurally unsound or misformed, it is easy to imagine that the process of synapse formation can go awry. To investigate this possibility, Fabrichny and colleagues evaluate the structure of key molecular complex that is known to influence the risk of autism spectrum disorder – a developmental disorder where synapse formation processes are known to be misregulated. In their paper, “Structural Analysis of the Synaptic Protein Neuroligin and Its b-Neurexin Complex: Determinants for Folding and Cell Adhesion”, (DOI) provide and in-depth x-ray structural assessment of a neuroligin (NLGN3/4) in complex with its target, beta-neurexin (NRXB1). This particular trans-synaptic molecular docking event is necessary for proper synapse formation and mutations in the neuroligin and neurexin genes appear to be associated with autism and mental retardation. One mutation associated with autism, Cys451Arg, is actually remote from the neurexin docking site, and rather causes problems by causing the neuroligin to get hung up in the endoplasmic reticulum. Another mutation, Gly99Ser, is located at the surface in a turn preceding the short b3 strand, and its mutation does not seem to affect folding or binding. As noted by the authors, Val403Met however, “participates in the tight parallel packing of the a2 helix onto the four-helix bundle and a mutation of this residue by a bulkier side chain may affect correct folding of the C-terminal domain and prevent formation of the functional neuroligin dimer.” This mutation then, unlike the other mutations, seems to play a more direct role in the structure of the docking event. Same disorder, same gene – different molecular mechanisms !
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Posted in NLGN3/4, NRXB1 | Tagged autism, Mental disorder | Leave a Comment »
January 14, 2008 by dendrite
Image via Wikipedia Twin studies are oft used to gauge the role of the genome in behavioral science. A recent report, “Nature versus Nurture in Ventral Visual Cortex: A Functional Magnetic Resonance Imaging Study of Twins” by Polk et al., (DOI) shows that brain activity during early stages of visual processing is more similar in twins vs. unrelated subjects across several object categories such as faces, houses, pseudowords and a control category consisting of -ok- chairs? When the brain activity of identical vs. fraternal twins was examined, the activity associated with faces showed the greatest difference in similarity of activity compared to other categories. Its always fun to speculate about why the genome might weigh-in more heavily when it comes to face processing – certainly an important skill for our primate order.
Posted in Visual cortex | Tagged Functional magnetic resonance imaging, Twin | Leave a Comment »
January 5, 2008 by dendrite
Image via Wikipedia Brain images with red and yellow splotches of activity are now ubiquitous in the psychology literature and well on their way, via neuromarketing, to bamboozling consumers everywhere (eg. this splotch shows that 2/3 people really do prefer Pepsi !). When inappropriately used, fMRI methods can devolve quickly into a high-tech form of phrenology with concomitant hucksters (not unlike recent reports of consumer fraud in genetic testing) and, despite its ubiquity and potentcy as a research tool, the molecular basis for the fMRI signal has remained somewhat mysterious. Generally, when neurons fire, local blood-flow increases and the paramagnetic form of deoxyhemoglobin can be distinguished from the nonmagnetic oxygenated form using the electromagnetic scannner. Hence, splotches that indicate more blood flow (or Brain Oxygen Level Dependent – BOLD reponse) can be a proxy for neural activity. The connection between neuronal firing and blood flow, however, is not necessarily simple nor easily ignored. Amazingly, a recent report from Takano and colleagues, “Astrocyte-mediated control of cerebral blood flow” (DOI) shows that a single master regulatory gene, cyclooxygenase-1 (COX-1) is sufficient to regulate blood flow in response to neural activity. Takano and a team led by Maiken Nedergaard show that astrocytes have their hands wrapped around neural synsapses and their feet wrapped around capillaries. When the astrocytes sense synaptic firing (glutamate spillover) they signal to the capillaries and contractile pericyte cells to relax and vasodilate. Using a series of pharmacologic blockers, the team tested a number of candidate regulatory pathways and found that only COX-1 blockade affected vasodilation in response to neural activity. The work of this research team greatly improves the understanding of the fMRI method and provides a well constrained framework through which to understand fMRI data and, moreover, the interplay between brain imaging and genetic data. Hopefully the basic research will stay one step ahead of the hucksters.
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Posted in COX1, White matter | Tagged Functional magnetic resonance imaging, Neuroeconomics | Leave a Comment »
January 2, 2008 by dendrite
Image via Wikipedia Among complex biological datasets, human genomic and functional imaging of the brain are right up there with the most fearsome wild & hairy beasts. Initial attempts to begin to tame the pair of these beasts by cross-relating the two forms of data have employed highly focused, hypothesis-testing strategies – for good reason – any exploratory association study would require a prohibitively large subject population. Liu and colleagues, in their paper, “Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA” (DOI) provide a new statistical approach to parsing out meaningful neuroanatomical and genetic components from such complex datasets. The authors record brain activity data while subjects attempt to pick out auditory oddball sounds (beep-beep-beep-beep-beep-boop-beep-beep-). As reported, an analysis of the MRI data and a SNP array consisting of 384 SNPs from 222 genes revealed 10 SNPs that were associated with specific patterns of brain activity. Several SNPs were identified (rs3087454 and rs1355920 are located in the nicotinic acetylcholine receptor-7 (CHRNA7) subunit, rs7520974 is located in the muscarininc acetylcholine receptor-3 (CHRM3) subunit while rs885834 is located in the choline acetyl transferase (CHAT) gene) that would explain the known role of acetylcholine in parietal lobe function, a brain region commonly activated in auditory oddball perception tasks. The method – far beyond this author’s sophistication – nevertheless, seems to output data that is well supported by other forms of converging evidence.
Posted in acetylcholine, CHAT, CHRM3, CHRNA7, Parietal cortex | Tagged Functional magnetic resonance imaging | Leave a Comment »
January 1, 2008 by dendrite
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 !
Posted in COMT, DLPFC, Dopamine, Frontal cortex, Orbitofrontal cortex, Parahippocampal gyrus, Posterior parietal cortex | Tagged 23andMe, Dopamine, Frontal lobe, Functional magnetic resonance imaging | Leave a Comment »
December 28, 2007 by dendrite
Mouse models of complex neurological illness are a powerful means to dissect molecular pathways and treatment paradigms. Current mouse models for the tremors and movement difficulties seen in Parkinson disease include genes such as parkin, alpha-synuclein, LRRK2, PINK1 and DJ-1. These models however, do not show the motor control problems and spontaneous degeneration of dopamine neurons as seen in PD in human patients. A new mouse model as reported by Kittappa and colleagues, unlike previous models, does, however, show amazing verisimilitude to PD. In their paper, “The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age” (DOI) the authors find that mice with only a single copy of the foxa2 gene acquire motor deficits and a late-onset degeneration of dopamine neurons. The age-related spontaneous cell death preferentially affects dopamine producing neurons in the substantia nigra that are affected in PD. The link between genetic risk and environmental exposure to oxidative toxins, a known risk factor in PD, is remarkably straightforward as foxa2 appears to be a regulator of superoxide dismutase, a potent protective scavenger of damage-inducing free radicals. More amazingly still, the authors demonstrate that foxa2 plays a key role in the birth of dopamine neurons – thus opening up new therapeutic possibilities of simultaneously producing new neurons and blocking apoptotic death of old ones. This fox brings new hope for treatment !
Posted in Dopamine, FOXA2 | Tagged Development, Neuron, Parkinson's disease | Leave a Comment »
December 26, 2007 by dendrite
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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Posted in FOXP2, Striatum | Tagged evolution, language | Leave a Comment »
December 25, 2007 by dendrite
Image by koolkao via Flickr Damage to the human brain, ie. loss of cells due to programmed or non-programmed cell death is presently considered to be an irreversible fate. Many a skilled neurosurgeon can place new neurons or stem cells into damaged areas, but that does little good unless those cells are able to sprout new axons and dendrites that migrate outward – sometimes very long distances – and make the proper synaptic connections and re-establish functional neural networks. Presumably, the instructions that tell a cell where, and how far to go, and whom to synapse with when you get there, are a mix of autonomous and pre-programmed genetic instructions but also environmentally determined (turn left when you see the McDonald’s at the globus pallidus). Kelsch and team, in their open-access paper, “Distinct Mammalian Precursors Are Committed to Generate Neurons with Defined Dendritic Projection Patterns” (DOI) show that, for a certain type of neuron at least, the instructions are pre-programmed. The research team found that granule cell precursor cells in a part of the mouse brain called the olfactory bulb, show distinct patterns of where dendritic trees connect with other cells – in either deep layers of the cortex or superficial layers. These cells maintain their layer-specific patterns of dendritic connectivity even after transplantation suggesting that all the instructions needed are contained within the nucleus of the cell. Further understanding of the specific genetic instructions contained therein opens new roadways for the repair of brain damage.
Posted in Olfactory bulb | Tagged Neuron, Stem cell | Leave a Comment »
December 21, 2007 by dendrite
Image by dbking via Flickr Amidst the excitement of new personalized genome services, the Economist reports on fraudsters found peddling ‘personalized supplements’ based on bogus genetic testing results. This is an extreme, tragicomic example to be sure, but highlights some of the issues that can arise when confronting one’s genetic blueprint. A recent paper by Stephanis et al., “Impact of Schizophrenia Candidate Genes on Schizotypy and Cognitive Endophenotypes at the Population Level” (DOI) shows that in a population of healthy individuals, those that carry common variants (such as rs760761, rs1018381, rs2619522) located in the dysbindin (DTNBP1) gene, a risk factor for schizophrenia, show minor cognitive impairments such as decreased attentional capacity, worse performance on memory tasks, and alterations in schizotypal beliefs and experiences. Thus, it would seem that, common genetic variation associated with a complex psychiatric disorder can confer minor cognitive impairment in healthy individuals. As personalized genome services proliferate, healthy individuals will begin to recognize that they carry genetic risk for all kinds of ailments – mental illness included. I admit to having cringed somewhat when typing out the blunt title of this post – fraudsters notwithstanding.
Posted in DTNBP1 | Tagged 23andMe, Genetic testing, Mental disorder, Personalized medicine, schizophrenia | Leave a Comment »
December 18, 2007 by dendrite
Image via Wikipedia The Wall Street Journal just ran a piece on the growing use of electro-convulsive (“shock”) therapy in elderly patients suffering from severe depression. While the clinical evidence may show this approach is effective – albeit scary – it is notable that another study published on the same day by Hunsberger et al., entitled, “Antidepressant actions of the exercise-regulated gene VGF ” (DOI). This paper reveals that a number of genes possessing antidepressant-like properties are induced by exercise. Yes, good old fashioned walkin’ and sweatin’. A few clinical trials have shown that, in older people especially, exercise is just as effective as anti-depressant medications. Furthermore, exercise seems to increase neurogenesis in the hippocampus in a manner that is parallel to anti-depressants. One of the genes induced by exercise, a growth factor named VGF, produces anti-depressant responses when administered into the mouse brain, while +/- hemizygous VGF animals show increased physiological and behavioral signs of stress. The authors point to the role of structural synaptic changes in long-term relief of depression, rather than short term increases in serotonin, but -ironically – note that VGF would be a great candidate for drug development. Hmmm, seems like I’ll skip the meds and the electrodes, and get to sweatin’ with a Richard Simmons video.*
*For the record, I do not currently own a Richard Simmons video.
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Posted in Hippocampus, VGF | Tagged Antidepressant, exercise, Major depressive disorder, Mental health | Leave a Comment »
December 14, 2007 by dendrite
Image via Wikipedia Many of the unpleasant feelings and physiological changes associated with fear and anxiety can be traced back to a tiny brain region known as the amygdala. Neuroimaging studies often find this region abnormally active in people having difficulty down-regulating negative emotions. It is no surprise then, that when genes that regulate innate fear and the reactivity of this brain region are identified there is much hope for future medications that might target these biochemical pathways and relieve emotional suffering. So it is that Coryell and colleagues identify such a gene, ASIC1a, the acid sensing ion channel 1a, and report in their paper, “Targeting ASIC1a Reduces Innate Fear and Alters Neuronal Activity in the Fear Circuit” (DOI) and report that more expression of this gene results in mice with more innate fear and, that less expression or blockade of this gene results in less innate fear. The gene appears expressed in a well-studied fear circuit including the cingulate cortex, the amygdala and the bed nucleus of the stria terminalis, so any type of pharmacologic manipulation would be predicted to affect the entire fear circuit. The normal function of ASIC1a – a proton sensor – is presumably to regulate pH within and/or across cell membranes. Such changes in pH are known to affect synaptic transmission in a manner such that lower pH inhibits NMDA channels and higher pH activates NMDA channels, so it is possible that the effects of ASIC1a on fear may be ultimately due to effects on synaptic plasticity. An exciting candidate not to be feared.
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Posted in Amygdala, ASIC1a, Cingulate cortex, Glutamate, Stria terminalis | Tagged Emotion, medication, Neuron | Leave a Comment »
December 11, 2007 by dendrite
It has long been known that complex neuropsychiatric and neurodevelopmental illnesses have familial patterns of inheritance and that concordance in identical twins is greater than in fraternal twins. The genetic influences of mental illness – whilst apparent – do not, however, provide clues about which genes, of the 20,000 or so to choose from, confer risk. Hallucinations, mania, mood-swings, paranoia, disorganized thinking – to describe some of the difficulties that patients experience – do not immediately suggest specific candidate molecules. In an effort then, to pinpoint the specific neural processes that go awry in one particular complex mental illness, the The Consortium on the Genetics of Schizophrenia has published a landmark analysis of 183 nuclear families consisting of affected and unaffected siblings to address this problem. In their paper, “Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia” (Arch Gen Psychiatry. 2007;64(11):1242-1250) the team examine so-called endophenotypes, often consisting of cognitive assessments designed to engage discrete, anatomically characterized neural networks in order to zero-in on where in the brain the genetic risk exerts an effect. The critical point the authors make is that these endophenotypes must be shown to be reliable, stable, and, most importantly, heritable. In other words, while many neural proceeses may go awry in schizophrenia, not all of these processes will have been influenced by genetic factors. Hence the analogy to carving up the complex system (turkey) along the proper genetic lines (joints). Their analysis showed that a great many of their candidate endophenotypes are indeed heritable, such as pre-pulse inhibition of the startle response, the antisaccade task for eye movements, Continuous Performance Test, California Verbal Learning Test, Letter-Number Sequencing test, Abstraction and Mental Flexibility, Face Memory, Spatial Memory, Spatial Processing, Sensorimotor Dexterity, and Emotion Recognition. Other processes such as suppression of the P50 ERP was not found to be heritable, and thus may not be a process that is affected by genetic risk. Interestingly, as reported by the authors, “The genetic correlations observed between the CVLT and LNS, between Abstraction and Mental Flexibility and Spatial Memory, and between Spatial Processing and the antisaccade task, CPT, LNS, and Abstraction and Mental Flexibility were significant at the P .001 level and remained significant after correction for multiple testing. These results suggest that overlapping genetic architecture (pleiotropy) underlies some of these endophenotypes”. Further dissection of these validated endophenotypes may therefore yield more specific neural processes, and perhaps specific synaptic connections, that would more readily provide clues to the molecular players in these complex developmental disabilities.
Posted in Uncategorized | Tagged Development, Mental disorder, schizophrenia, Twin | Leave a Comment »
December 7, 2007 by dendrite
- Image by pfv. via Flickr
The acquisition of language in humans remains a complex and fascinating mystery from both a neuro- and evolutionary-biological perspective. Attempts to identify genetic regulators of neural processes that are involved in language acquisition have the potential to shed light, not only on the natural history of homo sapiens, but also, to help understand the complex neurodevelopmental disorder, Autism, often associated with profound language impairments. So, it is very exciting to read, “Genome-wide analyses of human perisylvian cerebral cortical patterning” by Abrahams et al., (DOI) who examined human gene expression in frontal vs. superior temporal cortex at a developmental period where neurogenesis and neuronal migration are particularly active. The authors went looking for differential gene expression during a critical developmental time point and in a critical brain region – since the superior temporal cortex is an area that is reliably activated by linguistic tasks as well as social cognition tasks. According to the article, a total of 345 differentially expressed genes were identified, with 61 enriched and 284 down-regulated in superior temporal cortex across two microarray platforms, with 13 genes identified by both microarray array platforms. One of the genes identified is LDB1, a regulator of the asymmetrically expressed LIM domain-only 4 (LMO4) a known mediator of calcium-dependent transcription in cortical neurons and known to regulate thalamocortical connectivity. Another gene, CNTNAP2, a member of the neurexin transmembrane superfamily of proteins that mediate cellular interactions in the nervous system has been previously associated with autism. Both of these genes seem to have important developmental roles and should provide access to the fine-scale wiring that occurs during the development of neural networks involved in language.
Posted in CNTNAP2, LDB1, Superior temporal cortex | Tagged autism, Development, language | 1 Comment »
December 2, 2007 by dendrite
Image via Wikipedia There is rightly much ado over the recent stem cell breakthrough. Indeed, who wouldn’t want to have an eternal supply of sprightly new cells to swap in to replace run-down geezer cells. Swapping in a neuron, however, is not quite so simple, as these cells are highly differentiated with far reaching projections and specific connections that have been pruned based on a lifetime of experience (ie. memories). Such is the dilemma of a neuron – how to stay fit and maintain that luxuriant bushy morphology and experience-pruned connectivity for 100 years or more ? Wu and company, in their recent paper, “Regulation of Dendritic Development by Neuron-Specific Chromatin Remodeling Complexes” (DOI) show that neurons employ specialized SWI/SNF-like chromatin remodeling machinery to maintain dendritic arbor. Neurons from mice lacking BAF53b showed poor activity-dependent dendritic growth which is an amazing and profound result. This is because the dendrites are far, far, far away from the nucleus and yet, remodeling of nuclear DNA is exerting regulatory control over activity-dependent morphology changes. Beautiful bodies and smart as well !
Posted in BAF53b, SWI/SNF | Tagged Epigenetics, Neuron, Stem cell | Leave a Comment »
November 28, 2007 by dendrite
Image via Wikipedia Just stumbled across this great free resource – NeuroMorpho – man ! neurons are really fun to look at. NeuroMorpho hyper-links up digital reconstructions from several thousand different cell types across many species with information on function, size, connectivity and neural simulation tools. The cell above is a Von Economo neuron, one of the few known specializations to hominoid cortical microcircuitry. Weird and wild to ponder that without this little cell, I lose my sense of “self”.
Posted in Uncategorized | Tagged Spindle neuron | Leave a Comment »
November 24, 2007 by dendrite
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.
Posted in G-protein, GPR6, Striatum | Tagged Addiction, B.F. Skinner, Basal Ganglia, Cognition, Dopamine, Genetics, inhibition, Neuron, Operant conditioning | Leave a Comment »
November 21, 2007 by dendrite
Comparisons of human genome variation within and across closely related species have great potential to reveal ways in which the brain and mind of modern humans may or may not have differed from our hominid ancestors. Such comparisons have recently revealed a great many genomic targets of natural selection, some of which are expressed in the developing brain, and, hence, might provide clues to the mental life of our ancestors. Variation in two such candidates ASPM (rs964201) and MCPH1 (rs2442496) arose approximately 50,000 years ago and show strong positive selection in the lineage leading to humans. What do these genes and common variants do ? Do they affect language acquisition ? Social behavior ? Intelligence ? Any type of process that might smack of something uniquely ‘human’ ? In their paper [DOI], “Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort“, Dobson-Stone et al., used structural MRI to determine whether differences in whole brain volume or grey matter volume might relate to either or both of these variants. Although no evidence was found that relate these common variants (rare mutations can cause microcephaly) their methodological approach seems like a fantastic strategy for gaining insights into our human origins.
Posted in ASPM, MCPH1 | Tagged evolution, language | Leave a Comment »
November 19, 2007 by dendrite
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 😦
Posted in BDNF, Nucleus accumbens, Striatum, Ventral tegmental area | Tagged 23andMe, Emotion, Mental health | Leave a Comment »
November 14, 2007 by dendrite
Image via Wikipedia From time to time, it just seems hopeless to adhere to a reductionist strategy in the area of psychiatry and psychology. How, indeed, can our infinitely complex mind be understood in terms of tiny chemical bits ? Just when you’re ready to give up and bid adieu to Descartes and his mechanisms, along comes a reinvigorating paper like Professor Morgan Sheng’s, “Synaptic Accumulation of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of PSD-95” (DOI). This paper demonstrates that the the addition and removal of a single – that’s right, a single – phosphate group to Serine 295 of the PSD-95 protein is sufficient to activate or inhibit the recruitment of synaptic proteins such as AMPA receptors and potentiate excitatory post-synaptic current. Given that many complex mental illnesses are associated with synaptic deterioration, there seems to be great therapeutic significance to this finding. [Neuron, Vol 56, 488-502, 08 November 2007]
Posted in AMPA receptor, Glutamate, PSD95 | Tagged Genetic testing, Mental disorder | Leave a Comment »
November 7, 2007 by dendrite
Image via Wikipedia Can you recall that certain classmate who’s eyelids would slowly close during Genetics 101 lecture, followed by head-whips and finally unconscious, enviable slumber (if you can’t, then perhaps this classmate was you) ? Participants in the Framingham Heart Study were able to fill out questionnaires on daily sleep habits and measures of sleepiness and the resultant genome scan as reported in, “Genome-wide association of sleep and circadian phenotypes” by Gottlieb et al., (DOI) provide some amazing candidates. Of several, rs324981 (Asn107Ile substitution in the putative ligand-binding pocket of the neuropeptide S receptor, NPSR1) was found to be associated with bedtime. I’d happily comment more on the biochemistry of this gene family, but I must have slept through that lecture.
Posted in NPSR1 | Tagged Mental health, Sleep | Leave a Comment »
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