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

联合主持调查员/程序导演（最后，第一，中间）：阿南莎·谢克尔；约翰逊，菲利普·L。项目摘要/摘要：恐慌症（PD）是一种严重的焦虑症，以经常性为特征恐慌发作影响大约2-5％的人口，患有一半的PD受试者的恐惧症，并且大约三分之一的受试者导致严重的残疾。选择性5-羟色胺再摄取抑制剂（SSRI）是治疗PD的黄金标准，但对作用机理的理解很少。最近的证据已经确定Orexin下丘脑神经元是协调恐慌反应的关键调节剂之一并且恐慌患者的脑脊液确实确实具有高水平的Orexin。我们的临床前工作已经确定，在病理性恐慌模型中，奥甲蛋白在恐慌中起着至关重要的作用，但鲜为人知关于5-羟色胺在恐慌和恐惧症的背景下如何调节该系统。为了解决知识的这一差距，我们将采用传统的药理和具有新型光学和化学遗传技术的免疫组织化学技术：AIM 1）阐明角色中脑血清素能系统投影对正常的恐慌下丘脑氧气系统恐慌;目标2）该系统的破坏如何导致PD样病理；目标3）腹侧如何该血清素能系统的前额叶皮质项目也调节恐慌。我们将衡量行为和心血管恐慌/恐惧反应具有其他分子和电生理终点。拟议的项目将基于我们自己的经验数据测试一个明确的假设模型急性和慢性恐慌状态的神经元电路和机制的实验室。该提案具有创新性，因为它使用最先进的方法来研究功能 DRN和MRN中血清素能神经元亚群的特性与特定症状有关严重的焦虑症。如果这里提出的目标进一步支持我们的假设，它将强调需要开发有能力抑制恐慌和恐惧学习能力的焦虑症的成功疗法通过调节这些独特的血清素能神经元的功能子集。 PHS 398/2590（修订版09/04，重新发行4/2006）页面延续格式页面