Role of Neuropeptides in Anxiety

描述（由申请人提供）：焦虑症是美国最常见的精神障碍形式，影响近4000万美国成年人，需要更有效的药物治疗。该项目将在波士顿大学丰富的神经科学社区进行，涉及神经肽垂体腺苷酸环化酶激活多肽（PACAP），分泌素/胰高血糖素/VIP超家族的成员，以及对神经内分泌和行为系统具有显着中枢作用的多效性分子。 虽然对这种迷人的多肽的兴趣继续呈指数级增长，这种神经肽在调节应激反应中的作用及其在扩展杏仁核（应激行为表现的关键大脑部位）中的功能尚未阐明。这一差距的持续存在代表了理解PACAP在应激和焦虑障碍中的作用所带来的潜在益处的障碍。 我们的初步数据表明，PACAP的作用，在调制的行为反应的压力，这似乎是介导的主要脑应激肽，促肾上腺皮质激素释放因子（CRF）的受体。因此，我们的长期目标是阐明神经肽系统在应激相关疾病的神经生物学中的作用。本申请的目的是了解PACAP系统如何参与对压力的行为反应，长期目标是为压力和焦虑症的管理提供新的治疗策略。该提案中测试的中心假设是，暴露于压力后，扩展杏仁核中的内源性PACAP系统被招募，并且PAC 1受体拮抗剂发挥抗焦虑样作用。一个亚假设是PACAP的致焦虑作用是由下丘脑外CRF系统的募集介导的。 这一假设将通过追求三个特定的目标进行测试; PACAP的致焦虑作用的重要脑部位将在特定目标1中进行表征，使用颅内微量注射PACAP-38。内源性脑PACAP系统在焦虑样行为中的作用将在具体目标2中进行探索，通过研究PAC 1拮抗剂的潜在抗焦虑作用以及压力源对离散脑区PACAP和PAC 1受体水平的影响。最后，具体目标3将使用药理学和分子方法研究下丘脑和下丘脑外CRF在PACAP效应中的作用。 通过这种多学科方法，拟议的实验结果将为这种神经肽系统作为调节焦虑样行为的机制提供新的见解，并可能最终导致一类新的治疗药物用于治疗焦虑样疾病。 公共卫生相关性：本研究的结果，提供了关于神经肽PACAP在应激和焦虑中的作用的关键信息，将定义焦虑症的具体机制，并可能为应激相关疾病和焦虑提供新的治疗策略。

DESCRIPTION (provided by applicant): Anxiety disorders are the most common form of mental disorders in the United States, affecting nearly 40 million American adults and more efficacious pharmacological treatments are needed. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/VIP superfamily, and a pleiotropic molecule with remarkable central actions on neuroendocrine and behavioral systems. Although the interest towards this fascinating polypeptide continues to increase exponentially, the role of this neuropeptide in the modulation of stress response and its function in the extended amygdala, a key brain site for the behavioral manifestations of stress, are yet to be elucidated. Continued existence of this gap represents an obstacle to the potential benefits that can derive by understanding the role of PACAP in stress and anxiety disorders. Our preliminary data suggest a role for PACAP in the modulation of behavioral response to stress, which seems to be mediated by the receptors of the major brain stress peptide, corticotropin-releasing factor (CRF). Our long-term goal is therefore to elucidate the role of neuropeptide systems in the neurobiology of stress- related disorders. The objective of this application is to understand how the PACAP system is involved in the behavioral response to stress, with the long-term goal to provide novel therapeutic strategies for the management of stress and anxiety disorders. The central hypothesis under test in this proposal is that the endogenous PACAP system in the extended amygdala is recruited following exposure to stress and that PAC1 receptor antagonists exert an anxiolytic-like action. A sub-hypothesis is that the anxiogenic effects of PACAP are mediated by the recruitment of the extra-hypothalamic CRF system. This hypothesis will be tested by pursuing three specific aims; the brain sites important for the anxiogenic effects of PACAP will be characterized in Specific Aim 1, using intracranial microinjection of PACAP-38. The role of endogenous brain PACAP system in anxiety-like behavior will be explored in Specific Aim 2, through the investigation of the potential anxiolytic effect of a PAC1 antagonist and of the effects of stressors on PACAP and PAC1 receptor levels in discrete brain regions. Finally Specific Aim 3 will investigate the role of hypothalamic and extrahypothalamic CRF in the effects of PACAP using a pharmacological and molecular approach. The results of the proposed experiments, through this multidisciplinary approach, will provide novel insights into this neuropeptide system as a mechanism for modulating anxiety-like behavior, and may ultimately lead to the a new class of therapeutic agents for the treatment of anxiety-like disorders. PUBLIC HEALTH RELEVANCE: The results of the present studies, providing key information regarding the role of the neuropeptide PACAP in stress and anxiety, will define specific mechanisms underlying anxiety disorders, and may provide novel therapeutic strategies for stress-related disorders and anxiety.