The long-term goal of this project is to identify the afferent signalling mechanisms, cellular responses, and topography of the limbic forebrain neural circuits that help regulate homeostasis in the rat. This portion of the forebrain is critical for regulating the behavioral, autonomic and endocrine response of the animal to homeostatic disturbance. The central hypothesis is that homeostatic disturbances modify chemically-coded information contained within neurons by modulating the mRNAs that code for singly- and co-expressed neuropeptides. These cell- and stimulus-specific modifications facilitate the appropriate response by the animal, either by modulating the activity of the autonomic nervous system, neuroendocrine function, or perhaps by modifying the central pattern generators that develop and regulate goal-directed behaviors. Because of the relative simplicity of the underlying physiology and behavior along with an extensive literature, the project concentrates on investigating the organization of the circuits and mechanisms controlling fluid balance in the rat. Two experimental models are used; 1), cellular dehydration provided by salt-loading; and 2), extracellular dehydration provided by iso-osmotic volume depletion. Relating the results to important and well documented models allows the interpretation of data within a compelling and contextual framework not possible with many other currently used 'stress' models. The assay methods used-principally in situhybridization and immunocytochemistry-allows the detection of changes in mRNAs and their cognate peptides in anatomically defined regions and cell types of the rat hypothalamus and amygdala in response to these two distinct, but related stimuli. This proposal will investigate the transmitter and signal transduction mechanisms underlying modified peptide gene expression. Similarly, it addresses the possibility that the way corticosterone regulates peptide gene expression may be determined by the animals physiological status. It will begin investigating how the limbic forebrain might integrate inputs from multiple stimuli to formulate an appropriate response. Finally, the proposal will address some topographical aspects of the circuits by looking at peptide (rather that mRNA) responses, and the behavior and possible significance of peptide receptor mRNAs during the imposition of the 2 dehydration stimuli. In the long term, investigating the topography and mechanisms operating within the circuits regulating homeostasis will provide a framework for addressing many of the clinical disorders (eg. hypertension, obesity, eating disorders) currently of central importance to human health, that have perturbed homeostatic regulation at the core of their etiology.
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