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Posts Tagged ‘Stress’

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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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Zebra Zen
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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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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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Saimiri sciureus.
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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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