CRH/VP/GLUCOCORTICOID RECEPTOR MRNA REGULATION

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DESCRIPTION (Adapted from applicant's abstract): This application will investigate the role of input signal pattern on CRH and VP gene expression during stress in the rat. Also, to determine if alterations in glucocorticoid receptor (GR) expression within CRH neurons play a role in reduced glucocorticoid negative feedback during stress, GR mRNA and GR cell content will be measured. The hypothesis that will be tested is that altering the signal pattern of both stimulatory (NE, CRH) and inhibitory (corticosterone, GABA) input signals to the CRH neuron play a central role in the induction of VS expression within CRH neurons and maximizing CRH/VP responses (i.e., increases in gene expression and secretion) to stress. These studies will use hypothalamic neurons from neonatal rats as the in vitro model and administer pulsatile (at varying intervals and amplitudes) vs continuous stimuli within a perfusion system. This experimental approach is unique. Not only will effects of stimulatory/inhibitory factors to CRH neurons be examined in a controlled in vitro paradigm one molecule at a time, but the role played by the stimulus pattern for each molecule will also be investigated. During acute or chronic immunobilization stress, the HPA axis plays a critical role in the initiation and maintenance of physiological responses (e.g., metabolic, cardiovascular). The primary hypothalamic component of the HPA is the CRH neuron of the PVN. Of note, during stress VP expression is induced within CRH neurons and plays an important role in potentiating adrenocorticotropic hormone (ACTH) responses to CRH. Data reveal that CRH and VP are released in a pulsatile manner, stimulating similar secretory patterns of both ACTH and glycocorticoids. Stress stimulates a rise in the amplitude and/or frequency of CRH and VP pulsatile secretion, CRH and VP mRNA levels, as well as a reduction in glucocorticoid negative feedback at the PVN. Thus, stress is a unique physiological state in that the CRH/VP neuron is maximally stimulated in the presence of elevated glucocorticoid levels. In humans, alterations in HPA function are noted during aging, depression and Alzheimer's disease and is also an important modulator of the immune system. Therefore, increasing our understanding of the mechanisms that regulate the primary activation site of the system, the CRH/VP neuron, may have implications for various disease states, including AIDS and cancer.