Mechanisms of Serotonin Modulation of Panic

血清素调节恐慌的机制

基本信息

批准号：
10548824
负责人：
WILLIAM Anthony TRUITT
金额：
$ 50.47万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-12 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548824
关键词：
Acute Address Affect Agoraphobia Animal Model Animals Anxiety Disorders Area Biological Models Carbon Dioxide Cardiovascular system Cerebrospinal Fluid Chemicals Chronic Cognitive Cognitive Therapy Data Development Diagnosis Disinhibition Dorsal Electrophysiology (science)Esthesia Experimental Models Female Fright Gene Silencing Genetic Genetic Techniques Goals Hypothalamic structure Inhalation Interneurons Knowledge Laboratories Lateral Learning Lesion Life Literature Mediating Mediator Mental Depression Mental disorders Methods Midbrain structure Modeling Molecular National Institute of Mental Health Neurons Panic Panic Attack Panic Disorder Pathologic Pathological anxiety Pathology Pathway interactions Patients Persons Pharmacological Treatment Phobias Play Population Post-Traumatic Stress Disorders Prefrontal Cortex Principal Investigator Property Psychotherapy Publishing Reaction Recurrence Research Domain Criteria Rodent Role Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Serotonin Receptor 5-HT1A Severities Strategic Planning Structure Symptoms System Techniques Testing Time Translational Research Wing Work behavior measurement brain cell comorbidity disability disabling symptom effective therapy gastrointestinal human disease hypocretin innovation male neural circuit neuromechanism news novel optogenetics pharmacologic pre-clinical receptor response side effect suicidal behavior suicidal risk

项目摘要

Co-Principal Investigators/ProgramDirectors (Last, First, Middle): Shekhar, Anantha; Johnson, Philip L. Project Summary/Abstract: Panic disorder (PD) is a severe anxiety disorder characterized by recurrent panic attacks affecting about 2-5% of the population with agoraphobia present in half of PD subjects, and results in severe disability in about a third of those subjects. Selective serotonin reuptake inhibitors (SSRI’s) are the gold standard for treating PD, but the mechanisms of action are poorly understood. Recent evidence has identified that orexin hypothalamic neurons are one of the key regulators of a coordinated panic response and that patients with panic do indeed have high levels of orexin in their cerebrospinal fluid. Our preclinical work has identified that orexin plays critical role in panic in models of pathological panic, but little is known about how serotonin regulate this system in the context of panic and phobias. In order to address this gap in knowledge, we will employ traditional pharmacological and immunohistochemical techniques with novel opto- and chemo-genetic techniques to: Aim 1) elucidate the role of midbrain serotonergic system projection to the panic-ON hypothalamic OX system in regulating normal panic; Aim 2) how disruption of this system results in PD-like pathology; and Aim 3) how ventromedial prefrontal cortical projections to this serotonergic system also regulates panic. We will measure behavioral and cardiovascular panic/fear responses with additional molecular and electrophysiological endpoints. The proposed project will test a clear hypothetical model, basedlargely on empirical data from our own laboratories for the neural circuits and mechanisms underlying development of acute and chronic panic-like states. This proposal is innovative because it uses state-of-the-art approaches to, for the 1st time, investigate the functional properties of subpopulations of serotonergic neurons withinthe DRN and MRN relevant to specific symptoms of severe anxiety disorders. If our hypotheses are further supported by the aims proposed here, it will emphasize the need to develop successful therapies for anxiety disorders that have the ability to inhibit panic and fear learning circuits by modulating these distinct functional subsets of serotonergic neurons. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

联合首席研究员/项目总监（最后、第一、中间）：Shekhar、Anantha Johnson、Philip L. 项目摘要/摘要：恐慌症（PD）是一种严重的焦虑症，其特征是反复发作惊恐发作影响了大约 2-5% 的人群，半数 PD 受试者中存在广场恐惧症，并且大约三分之一的受试者会因选择性血清素再摄取抑制剂（SSRI）而导致严重残疾。是治疗帕金森病的黄金标准，但其作用机制目前尚不清楚。已发现食欲素下丘脑神经元是协调恐慌反应的关键调节因子之一恐慌患者的脑脊液中确实存在高水平的食欲素。研究表明，食欲素在病理性恐慌模型中的恐慌中发挥着关键作用，但人们知之甚少关于血清素如何在恐慌和恐惧症的背景下调节这个系统。为了弥补这一知识差距，我们将采用传统的药理学和免疫组织化学技术与新型光遗传学和化学遗传学技术的结合：目的 1) 阐明其作用中脑血清素能系统投射到恐慌-ON下丘脑 OX 系统在调节正常恐慌；目标 2) 该系统的破坏如何导致 PD 样病理；目标 3) 腹内侧如何前额皮质对这种血清素能系统的投射也调节恐慌。心血管恐慌/恐惧反应以及额外的分子和电生理学终点。拟议的项目将测试一个清晰的假设模型，该模型主要基于我们自己的经验数据急性和慢性恐慌状态发展的神经回路和机制实验室。该提案具有创新性，因为它首次使用最先进的方法来研究功能 DRN 和 MRN 内血清素能神经元亚群的特性与特定症状相关如果我们的假设得到这里提出的目标的进一步支持，它将强调需要开发成功的治疗焦虑症的方法，能够抑制恐慌和恐惧学习通过调节这些不同的血清素能神经元功能子集来形成回路。 PHS 398/2590（修订版 09/04，重新发布 4/2006）页面延续格式页面