Mechanisms of Serotonin Modulation of Panic

共同主要研究者/项目负责人（最后、第一、中间）：Shekhar，Anantha;约翰逊，Philip L. 项目概述/摘要：惊恐障碍（PD）是一种严重的焦虑障碍，其特征是反复发作， 惊恐发作影响约2-5%的人群，其中一半PD受试者存在广场恐怖症，以及 导致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（SSRI） 是治疗PD的金标准，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恐慌反应的关键调节器之一 恐慌症患者的脑脊液中确实有高水平的食欲素。我们的临床前 在病理性惊恐模型中，食欲素在惊恐中起着关键作用，但目前还知之甚少 关于血清素如何在恐慌和恐惧症的背景下调节这个系统。 为了解决这一知识差距，我们将采用传统的药理学和 免疫组化技术与新的光和化学遗传学技术，目的：1）阐明作用 下丘脑OX系统在正常调节中的作用 恐慌;目的2）该系统的破坏如何导致PD样病理;目的3）腹内侧 前额叶皮质投射到这个神经元能系统也调节恐慌。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学终点。 该项目将测试一个明确的假设模型，主要基于我们自己的经验数据。 研究急性和慢性恐慌样状态发展的神经回路和机制的实验室。 该提案具有创新性，因为它首次使用了最先进的方法来研究功能性 DRN和MRN内的多巴胺能神经元亚群的特性与特定的症状有关， 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 我们需要开发成功的治疗焦虑症的方法，这种方法能够抑制恐慌和恐惧学习 通过调节这些不同的多巴胺能神经元的功能子集来控制神经回路。 PHS 398/2590（2004年9月修订，2006年4月重新印发）

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