Orexinergic Pathways in Central Autonomic Control

中枢自主控制中的食欲素能通路

• 批准号: 6654925
• 负责人: Willis K. Samson
• 金额: $ 38.88万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654925
• 关键词: adrenocorticotropic hormone; arginine vasopressin; autonomic nervous system; brain mapping; cardiovascular function; hormone regulation /control mechanism; hypothalamic pituitary axis; hypothalamus; laboratory rat; neuroendocrine system; neurotransmitter transport; orexin; pituitary gland; psychic activity level; sleep regulatory center; stress

DESCRIPTION (provided by applicant): The hypocretins/orexins (Hcrts/ORXs) act within brain to stimulate autonomic function and have been demonstrated to be physiologic regulators of arousal state. Neuroendocrine and metabolic effects of these peptides, some related to sleep/wakefulness and arousal state, are just now being discovered. Indeed, these peptides exert a combination of autonomic (sympathoexcitation), behavioral (arousal), and neuroendocrine (ACTH release) effects in brain that suggests important roles for them in the CNS response to stress. However, little is known of the exact sites of action of these peptides in brain, or their mechanisms of action. We have identified neurons in hypothalamus and brain stem cardiovascular centers that are excited by orexin, suggesting a cellular basis for our reported actions of the peptide on autonomic function and stress hormone (ACTH) release (vide infra). We also have identified a pituitary action of the peptides to affect CRH-induced ACTH release. We seek to elucidate: 1) the cellular events and signal transduction pathways underlying the pituitary actions of Hcrt/ORX on ACTH release, 2) the integrated autonomic (neuroendocrine and cardiovascular) actions, underlying cellular mechanisms, and specific neuronal circuitry through which Hcrt/ORX exerts physiological actions in the hypothalamic paraventricular nucleus (PVN), 3) the integrated cardiovascular actions, underlying cellular mechanisms, and specific neuronal circuitry, through which Hcrt/ORX exerts physiological actions in the nucleus tractus solitarius (NTS), and 4) the membrane properties of Hcrt/ORX producing neurons in the lateral hypothalamic/perifornical area (LH/PFA), extrinsic factors controlling their excitability, and functional connectivity with critical autonomic nuclei in other regions of the brain. We propose to identify the exact sites of action of these peptides, provide insight into the receptor specificity of their pharmacologic effects and establish model systems for the study of the physiologic relevance of the interactions of the Hcrts/ORXs with brain and pituitary systems activated during stress. Long-term goals are to identify the physiologic relevance of these peptides in the central control of autonomic function and in the neuroendocrine regulation of anterior pituitary function, and to relate those functions to the cardiovascular responses to, and consequences of, stress.

描述（由申请人提供）：脑部内部的低载染素/奥雷蛋白（HCRTS/ORXS）起作用以刺激自主功能，并已被证明是唤醒状态的生理调节剂。这些肽的神经内分泌和代谢作用与睡眠/清醒和唤醒状态有关，目前才发现。实际上，这些肽在大脑中的自主神经（交感神经），行为（唤醒）和神经内分泌（ACTH释放）的效果的结合表明了它们在中枢神经系统对压力的反应中的重要作用。但是，这些肽在大脑中的确切作用部位或其作用机理几乎没有知道。我们已经确定了由Orexin激发的下丘脑和脑干心血管中心中的神经元，这暗示了我们报道的肽对自主功能和应激激素（ACTH）释放的细胞基础（VIDE INFRA）。我们还确定了肽的垂体作用，以影响CRH诱导的ACTH释放。我们寻求阐明：1）HCRT/ORX在ACTH释放中的垂体作用背后的细胞事件和信号转导途径，2）综合自主神经（神经内分泌和心血管）的作用，基本的细胞机制，以及通过HCRT/ORX ORX锻炼的特定神经循环的生理性作用，均为牛皮化的特定性均应car脉。 3) the integrated cardiovascular actions, underlying cellular mechanisms, and specific neuronal circuitry, through which Hcrt/ORX exerts physiological actions in the nucleus tractus solitarius (NTS), and 4) the membrane properties of Hcrt/ORX producing neurons in the lateral hypothalamic/perifornical area (LH/PFA), extrinsic factors controlling their excitability,以及与大脑其他区域的关键自主神经核的功能连通性。我们建议确定这些肽的确切作用部位，提供对其药理效应受体特异性的见解，并建立模型系统，以研究HCRTS/ORX在压力期间激活的HCRTS/ORX与大脑和垂体系统相互作用的生理相关性。长期目标是确定这些肽在自主功能的中心控制以及垂体前垂体功能的神经内分泌调节中的生理相关性，并将这些功能与对压力的心血管反应和后果相关。