The Responses of Thermoregulatory Neurons to CGRP

描述（由申请人提供）：对于绝经后的女性和前列腺癌激素治疗期间的男性来说，被称为潮热的神经系统疾病可能会频繁发生。这种体温的短暂高温变化与神经肽降钙素基因相关肽（CGRP）有关，CGRP 的作用是在外周增加血管舒张，在中枢增加交感神经激活，包括增加代谢产热。最近对啮齿动物的研究表明，这些中枢介导的反应可能是下丘脑视前区和前区 (PO/AH) 温度调节神经元活性的 CGRP 依赖性变化的结果。使用分离的组织切片制剂，将表征 PO/AH 神经元的电生理反应和局部网络特性。初步研究将记录这些神经元响应温度和 CGRP 的细胞外单单位活动。表现出 CGRP 依赖性放电率变化的神经元也将在 CGRP 拮抗剂或 cAMP 信号通路选择性抑制剂存在的情况下进行反应测试。随后将进行全细胞记录，以表征细胞电导，负责这些温度调节神经元放电率的 CGRP 依赖性变化。将进行额外的逆行标记和组织化学以确定 CGRP 反应性神经元是否具有抑制性，并投射到下丘脑背内侧或苍白中缝，这两个大脑区域直接参与高温机制的交感神经激活，从而导致更大的热量保留和增加的生热作用。我们期望我们的研究能够表征 CGRP 对 PO/AH 中温度调节神经元活动的影响，并提供导致这种高热反应的传出途径的信息。在临床上，这项研究可能会确定治疗这种短暂的体温升高（称为潮热）的新治疗干预部位。

DESCRIPTION (provided by applicant): 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.