Region-specific onset of handling-induced changes in corticotropin-releasing factor and glucocorticoid receptor expression.

Kristina A Fenoglio,Tallie Z Baram,Kristen L Brunson,Sarit Avishai-Eliner,Yuncai Chen

doi:10.1210/en.2004-0111

Kristina A Fenoglio, Tallie Z Baram + Show 3 more

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https://doi.org/10.1210/en.2004-0111

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Abstract

Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2-9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45). However, the initial site(s) and time of onset of these enduring changes have remained unclear. Therefore, we used semiquantitative in situ hybridization to delineate the spatiotemporal evolution of CRF and GR expression throughout stress-regulatory brain regions in handled (compared with undisturbed) pups. Enhanced CRF mRNA expression was apparent in the amygdaloid central nucleus (ACe) of handled pups already by P6. By P9, the augmented CRF mRNA levels persisted in ACe, accompanied by increased peptide expression in the bed nucleus of the stria terminalis and reduced expression in the paraventricular nucleus. The earliest change in GR consisted of reduced expression in the ACe of handled pups on P9, a time point when hippocampal GR expression was not yet affected. Thus, altered gene expression in ACe, bed nucleus of the stria terminalis as well as paraventricular nucleus may contribute to the molecular cascade by which handling (and increased maternal care) influences the stress response long term.

Highlights

Early-life experience influences hormonal and behavioral responses to stress long term, a fact with implications for emotional health and cognitive function [1,2,3]
corticotropin-releasing factor (CRF) mRNA, but not glucocorticoid receptor (GR) mRNA, levels are altered in amygdaloid central nucleus (ACe) already by P6
The temporal onset and progression of CRF and GR mRNA expression changes were determined in rats that were handled from P2 to P5 and killed on P6

Summary

Introduction

Early-life experience influences hormonal and behavioral responses to stress long term, a fact with implications for emotional health and cognitive function [1,2,3]. The levels of corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN), where CRF release elicits ACTH and glucocorticoid secretion, are reduced in early-life handled rats This reduction of hypothalamic CRF is associated with attenuated hormonal stress responses: after restraint stress, plasma ACTH and corticosterone levels are significantly lower in early-life handled rats compared with undisturbed controls [6, 7]. Life handled rats, consistent with increased sensitivity to circulating glucocorticoids [corticosterone (CORT)] and more efficient glucocorticoid-mediated negative feedback (Ref. 8, but see Ref. 9) These changes in CRF and GR expression and function are considered to underlie the enduring attenuation of neuroendocrine stress response that follows early-life handling [7]. The aims of the current studies were: 1) to determine the stress-regulatory regions that are initially involved in handling-induced changes in CRF and GR expression; and 2) to delineate the temporal evolution of these region-specific expression changes by examining CRF and GR expression during, as well as at the completion of the daily handling paradigm

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