Role of Neuropeptides in Anxiety

神经肽在焦虑中的作用

• 批准号: 8603871
• 负责人: VALENTINA SABINO
• 金额: $ 40.93万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-12 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603871
• 关键词: Accounting; Adult; Affect; American; Amino Acids; Amygdaloid structure; Animal Model; Anorexia Nervosa; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attention; Behavior; Behavioral; Boston; Brain; Brain region; Cell Nucleus; Chronic; Communities; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Disease; Exposure to; Functional disorder; Gene Deletion; Glucagon; Goals; Hypothalamic structure; Injection of therapeutic agent; Investigation; Knockout Mice; Knowledge; Lead; Literature; Mediating; Medical; Mental disorders; Microinjections; Molecular; Mood Disorders; National Institute of Mental Health; Neurobiology; Neurons; Neuropeptides; Neurosciences; Neurosecretory Systems; Neurotransmitters; PACAP38; PACAPR-1 protein; Pathogenesis; Peptides; Peripheral Nervous System; Pharmacological Treatment; Pituitary Gland; Pituitary-Adrenal System; Quality of life; Rattus; Recruitment Activity; Regulation; Research; Role; Secretin; Signal Transduction; Site; Stress; Structure of terminal stria nuclei of preoptic region; System; Testing; Therapeutic Agents; United States; Universities; Work; base; biological adaptation to stress; fascinate; insight; interdisciplinary approach; interest; member; novel; novel therapeutics; paraventricular nucleus; pituitary adenylate cyclase activating polypeptide; polypeptide; receptor; research study; response; stress disorder; stress related disorder; stressor

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.

描述（由申请人提供）：焦虑症是美国最常见的精神障碍形式，影响着近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，涉及垂体腺苷酸环化酶激活多肽（PACAP）神经肽，它是分泌素/胰高血糖素/VIP超家族的成员，是一种对神经内分泌和行为系统具有显著中枢作用的多效分子。尽管人们对这种令人着迷的多肽的兴趣呈指数级增长，但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）中的功能尚未得到阐明。这种差距的持续存在阻碍了了解PACAP在压力和焦虑障碍中的作用所带来的潜在益处。我们的初步数据表明，PACAP在调节应激行为反应中的作用，这似乎是由主要脑应激肽促肾上腺皮质激素释放因子（CRF）的受体介导的。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。本应用程序的目的是了解PACAP系统如何参与对压力的行为反应，其长期目标是为压力和焦虑障碍的管理提供新的治疗策略。本研究的中心假设是，暴露于压力后，外延杏仁核中的内源性PACAP系统被招募，PAC1受体拮抗剂发挥类似焦虑的作用。一个次级假设是，PACAP的焦虑效应是由下丘脑外CRF系统的募集介导的。这一假设将通过追求三个具体目标来检验；在特异性目的1中，我们将使用颅内微注射PACAP-38来描述对PACAP焦虑作用重要的脑部位。通过研究PAC1拮抗剂的潜在抗焦虑作用以及应激源对离散脑区PACAP和PAC1受体水平的影响，我们将在Specific Aim 2中探讨内源性脑PACAP系统在焦虑样行为中的作用。最后，Specific Aim 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。通过这种多学科的方法，所提出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，并可能最终导致治疗焦虑样障碍的新一类治疗药物。