The Responses of Thermoregulatory Neurons to CGRP

描述(申请人提供)：对于绝经后的女性和在前列腺癌治疗中接受激素治疗的男性来说，被称为潮热的神经疾病可能会频繁发生。这种体温的短暂高热变化与神经肽降钙素基因相关肽(CGRP)有关，CGRP在外周作用于增强血管扩张，在中枢作用于增强交感神经激活，包括增加代谢热产生。最近对啮齿动物的研究表明，这些中枢调节反应可能是CGRP依赖改变视前区和下丘脑前区(PO/AH)温度调节神经元活性的结果。使用分离的组织切片制备法，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对温度和降钙素基因相关肽的反应的细胞外单位活动。在CGRP拮抗剂或cAMP信号通路选择性抑制剂存在的情况下，也将对表现出CGRP依赖的放电率变化的神经元进行反应测试。随后将进行全细胞记录，以确定细胞电导的特征(S)，该电导负责这些温度调节神经元放电速率中CGRP依赖的变化。另外还将进行逆行标记和组织化学，以确定CGRP反应神经元是否具有抑制性，并投射到下丘脑背内侧或中缝苍白核，这两个区域直接参与交感神经激活高热机制，导致更大的热量保持和更多的产热。我们期望我们的研究将有助于确定CGRP对PO/AH中温度调节神经元活动的影响，并为导致这种高温反应的传出通路提供信息。在临床上，这项研究可能会确定治疗干预的新部位，以治疗这种被称为潮热的短暂体温过高。

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.