BRAIN NORADRENERGIC NEURONS, PEPTIDES AND STRESS

大脑去甲肾上腺素能神经元、肽和压力

• 批准号: 6293059
• 负责人: RITA VALENTINO
• 金额: $ 24.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6293059
• 关键词: brain mapping; corticotropin releasing factor; electron microscopy; electrostimulus; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; locus coeruleus; microinjections; neurons; neuropeptides; neurotransmitters; norepinephrine; stress

DESCRIPTION (Adapted from applicant's abstract): This is a competitive renewal of a proposal that was designed to test the guiding hypothesis that the stress-related neurohormone, corticotropin-releasing hormone (CRH), serves as a neurotransmitter to activate the major brain noradrenergic nucleus, locus coeruleus (LC) during stress. Our previous studies provided anatomical and physiological evidence supporting this hypothesis. Additionally, these studies suggested certain circuits by which endogenous CRH activates the LC, and certain physiological consequences of this activation. The following AIMS extend these previous studies: Aim 1 will characterize the anatomical substrates underlying CRH regulation of the LC at an ultrastructural level using electron microscopy and dual labeling immunohistochemistry. It will be determined whether CRH terminals directly contact LC cells and/or LC dendrites that extend into the pericoerulear region, or terminals of other afferents to the LC. Sources of CRH inputs to the LC and pericoerulear region will be confirmed using electron microscopy and double labeling of terminals for CRH and anterograde tract tracers. This approach will also be used to identify other LC afferents that CRH may interact with. Aim 2 will identify specific CRH systems that regulate LC activity during different types of stress. The impact of activating identified CRH afferents to the LC or pericoeulear region on LC discharge will be characterized, and the role of neurotransmitter CRH in these effects will be determined. By combining retrograde tract tracing from the LC with immunohistochemistry for CRH and immediate early gene proteins, CRH afferents to the LC that are activated by specific stressors will be identified. Aim 3 will test the hypothesis that a consequence of LC activation by endogenous CRH during stress is suppression of cell-mediated immunity. The effects of CRH microinfusion into the LC on spleen T-lymphocyte mitogenic activity will be quantified and the role of stress-elicited CRH release in the LC in suppression of cell-mediated immunity will be determined. Taken together, these Aims examine the CRH-LC connection in stress at both an input (ultrastructural and systems level) and an output (functional) level. CRH-brain noradrenergic interactions are thought to be involved in adaptive and pathological consequences of stress. As stress is thought to be a major contributing factor to a number of psychiatric disorders, these studies will facilitate our understanding of the etiology of stress-related psychiatric disorders, their treatment and prevention.

描述(摘自申请者的摘要)：这是一份竞争性的 更新一项旨在检验指导性假设的提案 应激相关神经激素促肾上腺皮质激素释放激素(CRH)， 作为一种神经递质激活主要的大脑去甲肾上腺素能 应激时蓝斑(LC)核。我们之前的研究提供了 支持这一假设的解剖学和生理学证据。 此外，这些研究表明，内源性的某些回路 CRH激活LC，以及由此产生的某些生理后果 激活。以下目标扩展了这些先前的研究：目标1将 描述LC中CRH调节的解剖学基础 在超微结构水平上使用电子显微镜和双重标记 免疫组织化学。将确定CRH终端是否直接 接触伸入髓周的LC细胞和/或LC树突 区域，或LC的其他传入终端。CRH输入到的来源 将使用电子显微镜确认LC和脊髓周围区域 CRH和顺行束示踪剂终末的双重标记。 该方法还将用于识别CRH可能 与之互动。AIM 2将确定调节LC的特定CRH系统 在不同类型的压力下的活动。激活的影响 在LC放电中发现CRH传入LC或延髓周围区域 以及神经递质CRH在这些效应中的作用 将会被确定。通过将LC的逆行追踪与 CRH和即刻早期基因蛋白CRH的免疫组织化学研究 由特定应激源激活的LC的传入将是 确认身份。目标3将检验LC的一个后果的假设 内源性促肾上腺皮质激素释放激素在应激过程中的激活是细胞介导的抑制 豁免权。LC微量注射促肾上腺皮质激素释放激素对脾的影响 T淋巴细胞有丝分裂活性将被量化，其作用 应激诱导的促肾上腺皮质激素释放激素抑制细胞介导性免疫反应 豁免权将会确定。综上所述，这些目标检查CRH-LC 两个输入(超微结构和系统水平)的应力连接 和输出(功能)级别。CRH-脑去甲肾上腺素能相互作用是 被认为与压力的适应性和病理性后果有关。 因为压力被认为是导致许多 精神障碍，这些研究将有助于我们理解 应激相关精神障碍的病因、治疗和治疗 预防。