Activation of CRH Neurons by the Neuropeptide PACAP

神经肽 PACAP 激活 CRH 神经元

• 批准号: 6694123
• 负责人: GABOR LEGRADI
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-13 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694123
• 关键词: biological signal transduction; cAMP response element binding protein; corticotropin releasing factor; genetic transcription; hypothalamic pituitary adrenal axis; in situ hybridization; laboratory rat; neural initiation; neuroendocrine system; neurons; neuropeptide receptor; neuropeptides; neurophysiology; paraventricular nucleus; protein structure function; psychological stressor

Fundamental aspects of the neuroendocrine, autonomic and behavioral responses to stress are integrated by parvocellular corticotropin releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). The main goal of the proposed experiments is to elucidate the role of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in the central activation of parvocellular CRH neurons and to integrate the PACAPergic mechanisms into specific neuroanatomical pathways subserving the stress response. Based on our preliminary data, we hypothesize that PACAP is an endogenous activator of parvocellular CRH neurons and its actions are exerted by PACAP containing innervation, with the involvement of intracellular signaling pathways that activate the transcription factor CREB by phosphorylation. Aim 1, using in vivo pharmacologic approaches with local intra-PVN microinjections, will investigate the role of PACAP in transcriptional activation of CRH neurons as well as its interactions with adrenergic mechanisms. Aim 2 will determine the significance of endogenous PACAP in the PVN for the activation of CRH neurons, following systemic and psychological stressors, using selective PACAP receptor antagonist microinjections into the PVN. Aim 3 will identify the brain region-specific contribution of PACAP innervation to CRH neurons in the PVN from neuroanatomical tract-tracing experiments combined with multiple-labeling immunofluorescence. Aim 4 will directly test the hypothesis whether PACAP neurons are activated by stress in brain regions that send innervation to the PVN. Thus, combined results from these aims will reveal the physiological role of PACAP for the central neuroendocrine effector system of the hypothalamic-pituitary-adrenal axis in acute stress. Synthesis of information from the proposed experiments may become applicable toward a better understanding of the pathophysiology of certain stress-related illnesses.

下丘脑室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）神经元整合了神经内分泌、自主神经和应激行为反应的基本方面。本实验的主要目的是阐明垂体腺苷酸环化酶激活多肽（PACAP）在parvocellular CRH神经元中枢激活中的作用，并将PACAP能机制整合到服务于应激反应的特定神经解剖学通路中。根据我们的初步数据，我们假设PACAP是细小细胞CRH神经元的内源性激活剂，其作用是由含有PACAP的神经支配发挥的，并参与通过磷酸化激活转录因子CREB的细胞内信号通路。目的1，采用局部pvn内显微注射的体内药理学方法，研究PACAP在CRH神经元转录激活中的作用及其与肾上腺素能机制的相互作用。目的2将使用选择性PACAP受体拮抗剂显微注射PVN，确定内源性PACAP在PVN中对CRH神经元激活的意义。目的3将通过神经解剖束示踪实验结合多重标记免疫荧光，确定PACAP神经支配对PVN中CRH神经元的脑区特异性贡献。Aim 4将直接验证PACAP神经元是否在向PVN发送神经支配的脑区被应激激活的假设。因此，综合这些目的的结果将揭示PACAP对下丘脑-垂体-肾上腺轴中枢神经内分泌效应系统在急性应激中的生理作用。从所提出的实验中合成的信息可能适用于更好地理解某些与压力有关的疾病的病理生理学。