These experiments are designed to investigate how corticosterone feedback mechanisms and neural afferents interact to control expression of the CRH gene in neuroendocrine neurons of the paraventricular nucleus. These neurons act as neuroendocrine transducers by releasing CRH into the hypophyseal vasculature to stimulate ACTH release and initiate the stress response. The integration mechanisms they use for assessing all their neural and humoral inputs is the foundation upon which their overall function is based, both in the basal and the stressed state.
Four specific aims are designed to investigate the hypothesis that corticosterone feedback results from the interaction of the cellular effects of specific neural inputs and corticosterone. Three sets of neural inputs form the experimental basis of this study because they are critical to CRH neuronal function in the basal and stressed state, they are well defined neuroanatomically, and (because they are unilaterally distributed) are experimentally amenable. They are: 1) inputs from the circadian pacemaker in the suprachiasmatic nucleus; 2) inputs from the lamina terminalis complex that regulate CRH gene expression during dehydration; and 3) the ascending inputs from the brainstem that convey viscerosensory information to CRH neurons. In each case the effects of unilateral deafferentation on corticosterone feedback sensitivity will be determined using in situ hybridization to measure changes in the primary transcript of the CRH gene and CRH mRNA. In addition, a final experiment will use an organotypic slice culture preparation of the PVH with a view to examining the more detailed cellular aspects of corticosterone/neurotransmitters interactions using an in vitro preparation that retains many of the features of the intact animal. Collectively, these experiments are designed to provide the basis for future investigations into how the stress response is organized in terms of circuitry and neuronal function with the overall goal of explaining how both viscerosensory and cognitive stressors are elaborated by the neuroendocrine hypothalamus.
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