Orexinergic Pathways in Central Autonomic Control

描述（由申请人提供）：下丘脑分泌素/食欲素（Hcrts/ORXs）在大脑内刺激自主神经功能，并已被证明是觉醒状态的生理调节剂。这些多肽的神经内分泌和代谢作用，其中一些与睡眠/觉醒和觉醒状态有关，目前才刚刚被发现。事实上，这些肽在大脑中发挥自主神经（交感神经兴奋）、行为（觉醒）和神经内分泌（ACTH释放）作用的组合，表明它们在中枢神经系统对压力的反应中发挥重要作用。然而，人们对这些肽在大脑中的确切作用部位及其作用机制知之甚少。我们已经发现下丘脑和脑干心血管中心的神经元被食欲素激发，这提示了我们报道的肽对自主神经功能和应激激素（ACTH）释放的作用的细胞基础（见下文）。我们还确定了肽的垂体作用，影响crh诱导的ACTH释放。我们试图阐明：1) Hcrt/ORX对ACTH释放的垂体作用背后的细胞事件和信号转导途径；2)Hcrt/ORX在下丘脑室旁核（PVN）中发挥生理作用的综合自主神经（神经内分泌和心血管）作用、潜在的细胞机制和特定的神经回路；3)综合心血管作用、潜在的细胞机制和特定的神经回路。4)下丘脑外侧/皮层周围区（LH/PFA）产生Hcrt/ORX的神经元的膜特性，控制其兴奋性的外在因素，以及与大脑其他区域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位点，深入了解其药理作用的受体特异性，并建立模型系统，以研究应激时激活的Hcrts/ORXs与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神经功能的中枢控制和垂体前叶功能的神经内分泌调节中的生理学相关性，并将这些功能与心血管对压力的反应及其后果联系起来。

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.