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Coping and glucocorticoid receptor regulation by stress inoculation.

ABSTRACT: Intermittent exposure to mildly stressful situations provides opportunities to practice coping in the context of exposure psychotherapies and stress inoculation training. Previously, we showed that stress inoculation modeled in juvenile monkeys enhances subsequent indications of resilience. Here we examine stress inoculation effects in adult female monkeys. We found that stress inoculation prevents social separation stress induced anhedonia measured using sucrose preference tests and reduces the hypothalamic pituitary adrenal (HPA) axis stress hormone response to a novel environment. Stress inoculation also increases glucocorticoid receptor (NR3C1) gene expression in anterior cingulate cortex but not hippocampus. Increased anterior cingulate cortex NR3C1 expression induced by stress inoculation is not associated with significant changes in GR1F promoter DNA methylation. On average, low levels of promoter DNA methylation and limited GR1F expression were evident in monkey anterior cingulate cortex as observed in corticolimbic brain regions of adult humans. Taken together these findings suggest that stress inoculation in adulthood enhances behavioral and hormonal aspects of coping without significantly influencing GR1F promoter DNA methylation as a mechanism for NR3C1 transcription regulation.

SUBMITTER: Lee AG

PROVIDER: S-EPMC4165807 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Coping and glucocorticoid receptor regulation by stress inoculation.

Lee Alex G AG Buckmaster Christine L CL Yi Esther E Schatzberg Alan F AF Lyons David M DM

Psychoneuroendocrinology 20140801

Intermittent exposure to mildly stressful situations provides opportunities to practice coping in the context of exposure psychotherapies and stress inoculation training. Previously, we showed that stress inoculation modeled in juvenile monkeys enhances subsequent indications of resilience. Here we examine stress inoculation effects in adult female monkeys. We found that stress inoculation prevents social separation stress induced anhedonia measured using sucrose preference tests and reduces the ...[more]

PMID: 25127085

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Project description:BackgroundAcetylation of heat shock protein 90 (Hsp90) regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis is poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress.MethodsMice subjected to chronic social defeat stress were stratified into resilient and vulnerable subpopulations. Hypothalamic-pituitary-adrenal axis function was probed using a dexamethasone/corticotropin-releasing factor test. Measurements of Hsp90 acetylation, Hsp90-GR interactions, and GR translocation were performed in the dorsal raphe nucleus. To manipulate Hsp90 acetylation, we pharmacologically inhibited histone deacetylase 6, a known deacetylase of Hsp90, or overexpressed a point mutant that mimics the hyperacetylated state of Hsp90 at lysine K294.ResultsLower acetylated Hsp90, higher GR-Hsp90 association, and enhanced GR translocation were observed in dorsal raphe nucleus of vulnerable mice after chronic social defeat stress. Administration of ACY-738, a histone deacetylase 6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FK506 binding protein 51 versus FK506 binding protein 52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point mutant of Hsp90. In vivo, ACY-738 promoted resilience to chronic social defeat stress, and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behavioral effect of ACY-738.ConclusionsHyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant histone deacetylase 6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids.

Dataset Information

Coping and glucocorticoid receptor regulation by stress inoculation.

Publications

Coping and glucocorticoid receptor regulation by stress inoculation.

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