For women after menopause and men during hormone therapy in the treatment of prostate cancer, the neurologic disorder known as a hot flash can become a frequent occurrence. This transient hyperthermic shift in body temperature has been linked to the neuropeptide calcitonin gene-related peptide (CGRP), which acts peripherally to increase vasodilation and centrally to increase sympathetic activation, including an increase in metabolic heat production. Recent studies in rodents have demonstrated that these centrally mediated responses may be the result of CGRP dependent changes in the activity of thermoregulatory neurons in the preoptic and anterior regions of the hypothalamus (PO/AH). Using an isolated tissue slice preparation, the electrophysiologic responses and local network properties of PO/AH neurons will be characterized. Initial studies will record the extracellular single-unit activity of these neurons in response to temperature and CGRP. Neurons that demonstrate CGRP dependent changes in firing rate will also be tested for responses in the presence of CGRP antagonists or selective inhibitors of the cAMP signaling pathway. This will be followed by whole-cell recordings to characterize the cellular conductance(s), responsible for CGRP dependent changes in the firing rates of these thermoregulatory neurons. Additional retrograde labeling and histochemistry will be done to determine if CGRP responsive neurons are inhibitory, and project to either the dorsomedial hypothalamus or the raphe pallidus, two regions of the brain directly involved with the sympathetic activation of hyperthermic mechanisms, leading to greater heat retention and increased thermogenesis. We expect that our studies will lead to the characterization of the effects of CGRP on the activity of thermoregulatory neurons in the PO/AH and provide information on the efferent pathways which lead to this hyperthermic response. Clinically, this research may identify new sites of therapeutic intervention in the treatment of this transient hyperthermic shift in body temperature, known as a hot flash. ? ?
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