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 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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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]
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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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Posted in 5HTT, AMPA receptor, Glutamate, GRIA3, GRIK2, tagged Antidepressant, Depression, Major depressive disorder, SSRI, Suicide on September 1, 2007 |
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Image via Wikipedia The recent paper, “Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression” finds that among 68 candidate genes, markers for 2 AMPA-type glutamate receptors (rs4825476, rs2518224: GRIA3 and GRIK2) show significant association in 120 individuals who experienced suicidal ideation in a large medication trial for major depressive disorder. Many families with loved ones suffering from depression remain wary and confused about a possible causal relationship between selective serotonin reuptake inhibitor (SSRI) antidepressants and suicide. A current FDA-mandated black box warning advises youths on the potential risks. This recent genetic study seems to provide a meaningful step forward in better understanding the mechanism of shifts in mood and cognition that occur in some individuals. But like many brain research studies though, shining a tiny ray of light on a puzzle suddenly illuminates massive complexities, previously unseen. A great deal of research shows that SSRI exposure leads to long lasting changes in AMPA receptor expression, localization and function, – but it’s unclear where a specific link between this and changes in mood and cognition will be drawn.
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