Archive for the ‘Glucocorticoid receptor’ Category

Turn and Cry
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It is commonly known that some of us handle stress better than others.  Some can calmly accept the dire economic news of an impending layoff while others may fret incessantly day-in-and-out and endure many a sleepless night.  Why ?  What are some of the brain systems that mediate the effects of accute and chronic stress ? What genetic and environmental differences might influence the development of these systems ?

In an ongoing set of experiments, Professor Michael Meaney’s laboratory has focused on the role of the glucocorticoid receptor (GR) and its role as a feedback modulator in the so-called hypothalamic-pituitary-adrenal (HPA) axis.  A number of experiments have shown that upregulation of the GR is somewhat beneficial insofar as it dampens the deleterious rise of circulating corticosteroids during stress.  Therefore, any mechanism that downregulates or blocks the expression of GR may make it harder for a person to cope with the typical physiologic responses (increases in corticosteroids) to stressful experiences (news of a layoff).

What Professor Meaney’s lab has shown so convincingly over the past several years is that individual differences in the reactivity of the HPA system are heavily influenced by maternal and early life experience.  That is, offspring (often rat or mouse pups) who have attentive mothers who keep them warm and well groomed, have more responsive HPA systems that more readily dampen the deleterious rise of corticosteroids in response to steroids.  In some cases, the level of maternal care is enough to modify the level of CpG methylation in the promoter region of the glucocorticoid receptor.  This type of “epigenetic” form of gene regulation is a way in which the promoter region can be altered in a long-term manner given a particular early-life experience.  Unfortunately, this type of epigenetic mark, can lead to life-long difficulty in managing stress.

Their recent paper, “Epigenetic regulation of the glucocorticoid receptor in human brain associates with child abuse” [doi 10.1038/nn.2270]  explores the extent of CpG methylation in post-mortem tissue (hippocampus) from 24 individuals who tragically passed away in completion of suicide.  The research team compared the levels of methylation (via bisulfite mapping) in the GR promoter region and found that there was significantly more methylation in (n=12) individuals who had a recorded history of childhood abuse (sexual contact, severe physical abuse and/or severe neglect) as compared to (n=12) individuals with no history of abuse (their CpG levels were not distinguishable from control tissue).  Thus (as confirmed by qRT-PCR) it seems as if epigenetic marks were visible in the genomes of hippocampal cell nuclei – which may have very well been written during early childhood trauma – and may have exacerbated the difficulties these individuals may have had in coping with psychosocial stress.

Further studies conducted by the team evaluate the possibility that the sites of abuse-induced-CpG methylation have the effect of blocking the binding of the EGR1 transcription factor which provides an additional mechanistic part in a larger complex of proteins that transduce the effects of experience into long-lasting behavioral predispositions.

For more on the exciting rise of epigenetics and its role in nature-meets-nuture and cognitive development click here.

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