Mechanisms of Serotonin Modulation of Panic

联合首席调查员/方案主任(最后、第一、中间)：Shekhar，Anantha；Johnson，Philip L. 项目摘要/摘要：惊恐障碍(PD)是一种以反复发作为特征的严重焦虑症 恐慌症发作影响了大约2%-5%的患有广场恐惧症的人口，有一半的帕金森病患者患有恐慌症，以及 导致其中约三分之一的受试者严重残疾。选择性5-羟色胺再摄取抑制剂 是治疗帕金森病的黄金标准，但其作用机制尚不清楚。最近的证据 已经确定食欲素下丘脑神经元是协调的恐慌反应的关键调节者之一 而且，恐慌症患者的脑脊液中确实存在高水平的食欲素。我们的临床前研究 研究发现，在病理性恐慌模型中，食欲素在恐慌中起关键作用，但知之甚少。 关于5-羟色胺如何在恐慌和恐惧症的背景下调节这个系统。 为了解决这一知识差距，我们将利用传统的药理学和 免疫组织化学技术结合新的光和化学遗传学技术：目的1)阐明其作用 中脑5-羟色胺能系统向惊恐的投射--下丘脑OX系统在调节正常中的作用 恐慌；目标2)这个系统的破坏如何导致类似帕金森病的病理；以及目标3)如何腹内侧 前额叶皮质投射到这个5-羟色胺能系统也调节恐慌。我们将测量行为和 心血管恐慌/恐惧反应与额外的分子和电生理终点。 拟议的项目将测试一个明确的假设模型，该模型主要基于我们自己的经验数据 研究急性和慢性惊恐状态发展的神经回路和机制的实验室。 该提案具有创新性，因为它首次使用最先进的方法来调查功能 DRN和MRN内与特定症状相关的5-羟色胺能神经元亚群的特性 严重的焦虑症。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，这种疗法能够抑制恐慌和恐惧学习 通过调节这些不同的5-羟色胺能神经元的功能亚群。 PHS 398/2590(09/04版，2006年4月4日重新发布)页面续格式页面

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