A single episode of restraint stress regulates central corticotrophin- releasing hormone receptor expression and binding in specific areas of the mouse brain

Abstract

The importance of restraining stress-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) system within tolerable limits requires efficient mechanisms for feedback inhibition. Recently, central corticotrophin-releasing hormone (CRH) receptor type 1 (CRHR1) has been shown to mediate HPA system feedback inhibition. To date, most of the data regarding stress-associated expression changes of CRHR1 and CRHR2 mRNA and their ligand CRH have been generated in rats. Taken considerable species differences into consideration, and with the growing importance of transgenic mice, a systematic analysis of the time course of expression changes of CRH and its two receptors in the mouse brain is needed to provide more insight into the regulation of the HPA system, both under physiological and pathophysiological conditions in this species. We analysed in detail the time course of expression changes of CRH, CRHR1 and CRHR2 mRNA after of restraint stress in mice in stress-relevant brain regions (paraventricular nucleus, hippocampus, neocortex). We could show a rapid, strong and long-lasting decrease in cortical and hippocampal CRHR1 mRNA expression after stress, whereas CRHR2 mRNA increased in the same neuroanatomical areas. In situ hybridisation analyses could be further confirmed at the protein level by CRH receptor autoradiography with changes in CRH binding that persisted even 7 days after a single episode of restraint stress. Our observation that stress has opposing effects on CRHR1 and CRHR2 neuronal systems supports the idea that regulation of the relative contribution of the two CRH receptors to brain CRH pathways may be essential in coordinating physiological responses to stress. We further hypothesise that the sustained alteration of CRH receptor expression and binding after a single episode of stress could mediate the long-term effects of stress on neuroendocrine function and emotional regulation.