Posted in CRHR1, Uncategorized, tagged Add new tag, Depression, Development, Emotion, Genetics, Hypothalamic–pituitary–adrenal axis, Major depressive disorder, Mental disorder, Mental health, Single-nucleotide polymorphism, Stress on April 6, 2010|
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According to the authors of “Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension” [PMID: 19736354], theirs is “the first instance of Genes x Environment research that stress has been ascertained by more than 1 study using the same instrument“. The gene they speak of is the Corticotropin-releasing hormone receptor 1 (CRHR1) gene (SNPs rs7209436, rs110402, rs242924 which can form a so-called T-A-T haplotype which has been associated with protection from early life stress (as ascertained using the Childhood Trauma Questionnaire CTQ)).
The research team examined several populations of adults and, like many other studies, found that early life stress was associated with symptoms of depressive illness but, like only 1 previous study, found that the more T-A-T haplotypes a person has (0,1,or 2) the less likely they were to suffer these symptoms.
Indeed, the CRHR1 gene is an important player in a complex network of hormonal signals that regulate the way the body (specifically the hypothalamic pituitary adrenal axis) transduces the effects of stress. So it seems quite reasonable to see that individual differences in ones ability to cope with stress might correlate with genotype here. The replication seems like a major step forward in the ongoing paradigm shift from “genes as independent risk factors” to “genetic risk factors being dependent on certain environmental forces”. The authors suggest that a the protective T-A-T haplotype might play a role in the consolidation of emotional memories and that CRHR1 T-A-T carriers might have a somewhat less-efficient emotional memory consolidation (sort of preventing disturbing memories from making it into long-term storage in the first place?) – which is a very intriguing and testable hypothesis.
On a more speculative note … consider the way in which the stress responsivity of a developing child is tied to its mother’s own stress responsivity. Mom’s own secretion of CRH from the placenta is known to regulate gestational duration and thus the size, heartiness and stress responsiveness of her newborn. The genetic variations are just passed along from generation to generation and provide some protection here and there in an intertwined cycle of life.
The flowers think they gave birth to seeds,
The shoots, they gave birth to the flowers,
And the plants, they gave birth to the shoots,
So do the seeds they gave birth to plants.
You think you gave birth to the child.
None thinks they are only entrances
For the life force that passes through.
A life is not born, it passes through.
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Posted in 5HTT, tagged Book Reviews, Depression, Disorders, economics, Emotion, Genetics, Health care, Major depressive disorder, Mental health on March 26, 2010|
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Just a pointer to a great book – The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder by Allan V. Horwitz and Jerome C. Wakefield. Its an in-depth treatment on the many reasons and contexts in which we – quite naturally – feel sad and depressed and the way in which diagnostic criteria can distort the gray area between normal sadness and a psychiatric disorder. I really enjoyed the developmental perspective on the natural advantages of negative emotions in childhood (a signal to attract caregivers) as well as the detailed evolution of the DSM diagnostic criteria. The main gist of the book is that much of what psychiatrists treat as emotional disorders are more likely just the natural responses to the normal ups and downs of life – not disorders at all. A case for American consumers as pill-popping suckers to medical-pharma-marketing overreach (here’s a related post on this overreach notion pointing to the work of David Healy).
Reading the book makes me feel liberated from the medical labels that are all too readily slapped on healthy people. There is much that is healthy about sadness and many reasons and contexts in which its quite natural. From now on, instead of trying to escape from, or rid myself of sadness, I will embrace it and let myself feel it and work through it. Who knows, maybe this is a good first step in a healthy coping process.
If depressed emotional states are more a part of the normal range of emotions (rather than separate disordered states) then does this allow us to make predictions about the underlying genetic bases for these states? Perhaps not. However, on page 172, the authors apply their critical view to the highly cited Caspi et al., article (showing that 5HTT genotype interacts with life stress in the presentation of depressive illness – critiqued here). They note that the incidence of depression at 17% in the sample is much too high – most certainly capturing a lot of normal sadness. Hence, the prevalent short allele in the 5HTT promoter might be better thought of as a factor that underlies how healthy people respond to social stress – rather than as a drug target or risk factor for psychiatric illness.
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pointer to symptommedia.org – fantastic video resource of specific symptoms of mental illness.
“The intention of these clips are to be used in the classroom setting as visual compliments to the written description of symptoms for psychological phenomena found in the DSM handbook.”
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In Robert Sapolsky’s book, “Why Zebras Don’t Get Ulcers“, he details a biological feedback system wherein psychological stress leads to the release of glucocorticoids that have beneficial effects in the near-term but negative effects (e.g. ulcers, depression, etc.) in the long-term. The key to getting the near-term benefits and avoiding the long-term costs – is to be able to turn OFF the flow of glucocorticoids. This is normally dependent on circuitry involving the frontal cortex and hippocampus, that allow individuals to reset their expectations and acknowledge that everything is OK again. Here’s the catch (i.e. mother nature’s ironic sense of humor). These very glucocorticoids can initiate a kind of reorganization or ‘shrinkage’ to the hippocampus – and this can disable, or undermine the ability of the hippocampus to turn OFF the flow of glucocorticoids. Yes, that’s right, the very switch that turns OFF glucocorticoid flow is disabled by exposure to glucocorticoids! Can you imagine what happens when that switch (hippocampus) get progressively more disabled? Your ability to turn OFF glucocorticoids gets progressively worse and the negative effects of stress become more and more difficult to cope with.
Sounds depressing. Indeed it is, and there are many findings of reduced hippocampal volume in various depressive illnesses. The complex problem at hand, then, is how to reverse the runaway-train-like (depression leads to glucocorticoids which leads to smaller hippocampus which leads to more depression) effects of stress and depression?
One new avenue of research has been focused on the ability of the hippocampus to normally produce new cells – neurogenesis – throughout life. Might such cells be useful in reversing hippocampal remodeling (shrinkage)? If so, what molecules or genes might be targeted to drive this process in a treatment setting?
The recent paper by Joffe and colleagues, “Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness” [doi: 10.1002/hbm.20592] offers some key insights. They examined 467 healthy participants of the Brain Resource International Database (a personalized medicine company with a focus on brain health) using personality tests, structural brain imaging and genotyping for an A-to-G variation (valine-to-methionine) polymorphism in the BDNF gene. They report that lower volume of the hippocampus was associated with higher scores of neuroticism (worriers) – but, this negative relationship was not found in all people – just those who carry the A- or methionine-allele. Thus, those individuals who carry the G/G (valine/valine) genotype of BDNF may be somewhat more protected from the negative (hippocampal remodeling) effects of psychological stress. Interestingly, the BDNF gene seems to play a role in brain repair! So perhaps this neuro-biochemical pathway can be explored to further therapeutic benefit. Exciting!!
By the way, the reason zebras don’t get ulcers, is because their life revolves around a lot of short term stressors (mainly hungry lions) where the glucocorticoid-stress system works wonderfully to keep them alive. Its only homo sapiens who has enough long-term memory to sit around in front of the TV and incessantly fret about the mortgage, the neighbors, the 401K etc., who have the capacity to bring down all the negative, toxic effects of chronic glucocorticoids exposure upon themselves. My 23andMe profile shows that I am a G/G valine/valine … does this mean I’m free to worry more? Now I’m worried. More on BDNF here.
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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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Commuting to work is a total drag. Commuting to work in New York City is not just a total drag, but THE definitive commuting nightmare. Still, when one ponders the masses of people (more than 2 million each day) who tread in, out and around Manhattan, its pretty remarkable that one can get in to work and home again.
Consider then, the human brain, with 100 billion neuons and 1,000 trillion synapses – all of which need constant tender loving care and maintenance to keep firing along. In some cases, the commute to these synapses can be quite long – even for a molecule (eg. if a motor neuron were as wide as my car, the commute from the nucleus to the presynaptic membrane would be about 10 miles, which is about how long I must travel to get to work). Is the brain better able to transport cargo from home (the nucleus where lots of the basic materials are produced) to work (synaptic membranes which carry out information transfer) ?
I certainly hope so. But, like my own commute, it seems the human brain can have commuting nightmares of its own. One of the main transport vehicles in the brain is a molecule called Kinesin which literally walks (see the movie below) along microtubule tracks and delivers its cargo in little molecular satchels called protein transport vessicles. One of the components of these transport vessicles, a protein known as piccolo, is expressed in presynaptic zones and may be important for recycling presynaptic vessicles – as well as mental health.
Indeed, what might happen if the normal process of vessicle transport and synaptic maintenance were disrupted in the brain – a commuting debacle of sorts ? Well, Sullivan and colleagues [doi: 10.1038/mp.2008.125] report that a genome-wide association study of major depressive disorder yields piccolo (PCLO) as one of its major findings. The single nucleotide polymorphism rs2522833, which encodes a serine to alanine substitution near the calcium binding region (amino acid #4814) of PCLO was one of the most significant findings in the original study and a follow-up of a different case/control population study on major depressive disorder. The change from alanine to serine is notable, since the addition of N-acetylglucosamine to serine residues is a common mechanism for regulating intracellular traffic.
My 23andMe profile shows an AA for this site, which is the serine/serine form of PCLO (the form which can be modified by GlcNA -yay!) rather than the alanine/alanine form. This (A) allele is indicated as the major allele by the authors although the AA genotype is less common among individuals of European and Asian ethnicity, but quite common in sub-Saharan Africa. The authors don’t reveal which allele is associated with an increased risk of depression, but I already know the answer – I’ll never recover from the depression of my own commuting nightmare.
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Image via Wikipedia Recent meta-analytical research, “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy” (N Engl J Med 2008;358:252-60) reveals that while 94% of published antidepressant drug trials show positive findings, only 51% of all such (published and unpublished) trials show positive effects (with a range of effect sizes from 11-69%). This is probably not surprising to patients and physicians (investors? … well, maybe) who often search in vain, using trail and error, for a medication that can provide relief from major depression, one the the top disease burdens world-wide. Many have suggested that pharmacogenetics may provide a key to understanding the tremendous variability in medication response. For example, variations in the ABCB1, ATP-binding cassette sub-family B member 1, gene seem to predict who may show a response to certain antidepressants (citalopram, paroxetine, amitriptyline, and venlafaxine) medications, that are shuttled across the blood-brain-barrier endothelial membrane by ABCB1. In a pharmacogenetic medication trial involving 443 inpatients with depression who were treated at the Max Planck Institute of Psychiatry, the SNPs 2032583, rs2235015, rs2032583 and rs2235015 predict significantly different time course of response to treatment over 6 weeks. The paper, “Polymorphisms in the Drug Transporter Gene ABCB1 Predict Antidepressant Treatment Response in Depression” (doi: 10.1016/j.neuron.2007.11.017) is an example of pure and applied science at is best. The results pose a vexing dilemma for “really big” pharma however since the market size of genetic responders is obviously much smaller than market at large. Nevertheless, it seems inexorable change is underway.
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