Posted in acetylcholine, Cingulate cortex, GABA, Glutamate, tagged acetylcholine, AMPA, Cingulate, Emotion, evolution, Gene expression, Major depressive disorder on January 8, 2009|
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OK, there’s not really a “coolest” part of the brain, but, some areas are pretty darn weird & wild. Consider the cingulate cortex (shown here). Electrical stimulation of the pACC region in humans can produce overwhelming fear – even a feeling that death is imminent – while stimulation of white matter tracts adjacent to area 25 can relieve treatment resistent depression. Activity in the MCC region is often associated – not with emotion – but with motor planning and selection of actions. Stimulation of this area evoked the feeling of “I felt something, as though I was going to leave.” Interestingly, this region also contains a unique type of large neuron known as a von Economo cell, found in humans and Bonobo chimpanzees, but not other primate species – leading some to speculate that this area must contribute to something that makes us uniquely human. The PCC and RSC regions seem to be involved in how your brain computes where you are in 3-dimensional space, since activity in the PCC rises when participants mentally navigate pathways and routes of travel or assess the “self-relevance” of sensory stimuli, while lesions in RSC lead to topographic disorientation. Whew, that’s a lot of functionality ! Indeed, with so many functions, its not surprising that this region is often linked to mental illness of all sorts. In schizophrenia, for example, patients have difficulty controlling their actions (MCC regions have been implicated) as well as their emotions (ACC regions have been implicated) and maintaining a coherent sense of “self” (PCC & RSC regions have also been implicated).
Since we know that this brain region is implicated in mental illness and we know that mental illness arises – in part – due to genetic risk, it is of interest to begin to understand how genetic factors might relate to the development of structure, connectivity and function of the 4 sub-regions of the cingulate cortex. With this in mind, it was great to see a recent paper from Brent Vogt and colleagues at the Cingulum Neurosciences Institute [doi: 10.1002/hbm.20667] which has begun to examine differential gene expression in these 4 subregions ! They examined the expression of an array of neurotransmitter receptors (at the protein level actually) and asked whether the expression of the receptors was able to differentiate (as lesions, activity and architectonics do) the 4 subregions. In a word – yes – with the ACC region showing highest AMPA receptor expression and lowest GABA-A receptor expression. This was very different from the MCC region which had the lowest AMPA receptor expression while PCC had the highest cholinergic M1 receptor expression.
This seems a great foundation for future studies that will continue to dissect the many interconnected – yet separable – functions of the cingulate cortex. The “holy grail” of which might be to understand the evolutionary origins of the von Economo cells which are unique to our human lineage. The genome encodes the story – we just need to learn to read it aloud.
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Image by Getty Images via Daylife Psychiatrists and families that cope with mental illness have long been aware of far reaching familial risk. Although the new genomics greatly accelerates the identification of specific risk alleles; the direct functional and mechanistic connections between these tiny bits of nucleic acid and large-scale changes in neural activity and behavior is more often a matter of hand waving than hard science. Monory et al., in their article, “Genetic Dissection of Behavioural and Autonomic Effects of d9-Tetrahydrocannabinol in Mice” (doi:10.1371/journal.pbio.0050269) provide an excellent example of how to relate the effects of a given gene (the CB1 receptor) to changes in behavior (getting stoned, to put it blunt-ly) by first beginning to determine what CB1 expressing cell-types are necessary. For example, ever-mellow GABA-ergic neurons are not involved in mediating the effects of cannabinoids whilst excitatory glutamatergic neurons mediate hypolocomotor effects. Similar analyses of specific (gene x circuit) interactions will build important bridges between genetics and psychiatry. Why do the mice get to have all the fun ?
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Behavioral geneticists are fond of noting that more than half of the risk for mental illness is heritable, and, fonder of the number of specific risk factors that have been identified. What is much less well known however is how these heritable factors interact with the environment to potentiate risk. Psychiatrists, on the other hand, rightly point out that children and adults who experience traumatic and social stress are also at greater risk for psychiatric illness. Indeed, brain imaging has shown a number of anatomical regions where activity declines in subjects and patients alike who experience trauma or other difficult experience. In their recent paper, “Stress-induced changes in primate prefrontal profiles of gene expression,” Karssen and colleagues take a major step towards bridging the gene-by-experience puzzle and examine how gene expression changes in response to socially stressful experience. Using a squirrel monkey model, an experimental group of males was subjected to intermittent social separation and also exposure to new roommates – conditions known to elevate cortisol levels. Using a (note the caveat here) human microarray platform and several signal analysis protocols, the investigators present several hundred genes differentially (interestingly mostly down-regulated) expressed in the frontal cortex. So – the question begs – were any of the genes identified in the Karssen study the same, or in the same pathways, as known genetic risk factors ? Yes – well sort of. The authors present several genes, including a few involved in GABA signaling, that had previously been linked via gene expression studies to mood disorders in humans. Certainly, these are attractive candidates for family- and population-based association studies.
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