The Responses of Thermoregulatory Neurons to CGRP

体温调节神经元对 CGRP 的反应

• 批准号: 7012437
• 负责人: JOHN D GRIFFIN
• 金额: $ 21.45万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-23 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012437
• 关键词: body temperature regulation; brain stem; calcitonin gene related peptide; confocal scanning microscopy; electrophysiology; fluorescent dye /probe; glutamate decarboxylase; histochemistry /cytochemistry; hot flash; hyperthermia; hypothalamus; inhibitor /antagonist; laboratory rat; microcapsule; neural transmission; neuronal transport; neuropeptide receptor; preoptic areas; protein structure function; sympathetic nervous system; tissue /cell preparation; voltage /patch clamp

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.

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，称为潮热的神经系统疾病可能会频繁发生。这种体温的短暂高热变化与神经肽降钙素基因相关肽（CGRP）有关，CGRP在外周作用以增加血管舒张，在中枢作用以增加交感神经激活，包括代谢产热的增加。最近在啮齿动物中的研究表明，这些中枢介导的反应可能是CGRP依赖的下丘脑视前区和前区（PO/AH）的温度调节神经元活性变化的结果。使用分离的组织切片制备，PO/AH神经元的电生理反应和局部网络特性将被表征。最初的研究将记录这些神经元对温度和CGRP的反应的细胞外单单位活动。在CGRP拮抗剂或cAMP信号传导途径的选择性抑制剂存在下，还将测试表现出放电速率的CGRP依赖性变化的神经元的反应。随后进行全细胞记录，以表征细胞电导，这是这些体温调节神经元放电率的CGRP依赖性变化的原因。将进行额外的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，并投射到背内侧下丘脑或苍白中缝，这两个脑区域直接参与高热机制的交感神经激活，导致更大的热潴留和产热增加。我们希望我们的研究将导致CGRP对PO/AH中体温调节神经元活性的影响的表征，并提供导致这种高热反应的传出通路的信息。在临床上，这项研究可能会确定新的治疗干预的网站，在治疗这种短暂的体温过高的转变，称为潮热。