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Rapid phosphorylation of the CRE binding protein precedes stress-induced activation of the corticotropin releasing hormone gene in medial parvocellular hypothalamic neurons of the immature rat.


The mechanisms of the molecular and neuroendocrine responses to stress in the immature rat have been a focus of intense investigation. A principal regulator of the these responses in both mature and developing rat is the neuropeptide corticotropin releasing hormone (CRH), and levels of hypothalamic CRH mRNA are enhanced by stress. In vitro, transcription of the CRH gene is governed by binding of the phosphorylated form of cAMP responsive element binding protein (pCREB) to the promoter. Here we tested the hypothesis that rapid, stress-induced CRH transcription occurred during the first two postnatal weeks, and is associated with pCREB expression. The time-course of induction of unedited, heteronuclear CRH RNA (CRH hnRNA) was examined in hypothalamic paraventricular nucleus (PVN) of immature rats subjected to both modest and strong acute stressors using in situ hybridization; pCREB abundance was determined in individual neurons in specific PVN sub-nuclei using immunocytochemistry and unbiased quantitative analysis. CRH hnRNA signal was negligible in PVN of immature rats sacrificed under stress-free conditions, but was readily detectable within 2 min, and peaked at 15 min, in PVN of stressed animals. Enhanced pCREB immunoreactivity was evident within 2 min of stress onset, and was enhanced specifically in stress-responsive, CRH-expressing medial parvocellular neurons. These data support the notion that, already during early postnatal life, stress induces rapid CREB phosphorylation, interaction of pCREB-containing transcription complexes with the CRE element of the CRH gene promoter, and initiation of CRH hnRNA production in stress-responsive neurons of rat PVN.

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