Contribution of the Parabrachial CGRP-Expressing Neurons to the Pathophysiology of Panic Disorder

项目总结/摘要 惊恐障碍是一种使人衰弱的焦虑障碍，其特征是突然和反复发作的 强烈的，无法控制的焦虑和恐惧。这种精神疾病在其他与焦虑有关的疾病中是独一无二的。 因为惊恐障碍患者在发作期间不仅会出现精神症状， 他们还患有急性身体症状，包括心肺、自主神经和胃肠道症状 症状此外，这些恐慌发作是自发发生的，与先天无条件的 恐惧（即，没有通过令人厌恶的经历学到的恐惧）。为了了解是什么导致了这些 在恐慌症中，无条件的恐惧和相关的生理症状的发作， 描述先天威胁感知的神经回路。臂旁外侧核（PBN） 在脑干内调节心肺和自主神经功能，也中继多模态厌恶， 传递给杏仁核的感觉信号初步数据显示，在惊恐障碍中， 患者，如咖啡因，育亨宾或高CO2水平，强烈激活神经元在外侧区 表达特定神经肽降钙素基因相关肽（CGRP）的PBN（PBel），和 这些神经元的激活对于先天的威胁感知是必要和充分的。然而， 关于惊恐障碍发病机制中PBel CGRP表达神经元的回路机制。到 为了解决这个问题，建议的实验使用最先进的神经回路解剖工具来监测 并操纵PBel CGRP神经元以及表达CGRP的靶神经元的活性 受体的该建议的中心目标是确定PBel CGRP神经元如何响应和 编码先天的感觉威胁，以及这些神经元如何有助于独特的身体和情感 惊恐障碍的合并症为了实现这一目标，将监测PBel CGRP神经元的活性（通过 体内钙成像），因为小鼠暴露于多模式感觉威胁或致恐慌剂（目的1）。 然后使用光遗传学和化学遗传学方法操纵（抑制或激活）PBel CGRP神经元。 技术，以建立CGRP神经元活性和生理变化之间的因果关系， 先天威胁感知（目标2）。最后，下游神经元的活动（那些表达CGRP受体的神经元， 由PBe 1 CGRP神经元支配的脑区域）将被监测和操纵以建立功能性的神经元通路。 神经回路参与惊恐障碍发病机制（目的3）。拟议研究的贡献将是 意义重大，因为它将促进对惊恐障碍发病机制的回路水平的理解。研究 该计划是创新的，因为它首次调查了PBel参与恐慌症的情况 使用细胞类型特异性回路解剖工具研究发病机制。成功完成拟议的研究 因此，将提供基于神经回路的恐慌症症状的理解，这可能提供 对发展惊恐障碍治疗干预的重要见解。

Project Summary/Abstract Panic disorder is a debilitating anxiety disorder that is characterized by sudden and recurrent attacks of intense, uncontrollable anxiety and fear. This psychiatric illness is unique among other anxiety-related disorders because individuals with panic disorder not only experience mental symptoms during an attack, but they also suffer acute physical symptoms, including cardiorespiratory, autonomic, and gastrointestinal symptoms. In addition, these panic attacks occur spontaneously, and are associated with innate unconditioned fear (i.e., fear that has not been learned through an aversive experience). To understand what causes these bouts of unconditioned fear and associated physiological symptoms in panic disorder, it is critical to characterize the neural circuitry underlying innate threat perception. The lateral parabrachial nucleus (PBN) within the brainstem regulates cardiorespiratory and autonomic functions, and also relays multimodal aversive sensory signals to the amygdala. Preliminary data show that factors that induce panic attack in panic disorder patients, such as caffeine, yohimbine or high CO2 levels, robustly activate neurons in the external lateral region of the PBN (PBel) that express a particular neuropeptide, Calcitonin gene-related peptide (CGRP), and activation of these neurons is necessary and sufficient for innate threat perception. However, little is known about the circuit mechanism of the PBel CGRP-expressing neurons in panic disorder pathogenesis. To address this problem, proposed experiments use state-of-the-art neural circuit dissection tools to MONITOR and MANIPULATE the activity of PBel CGRP neurons, as well as target neurons that express the CGRP receptor. The central objective of this proposal is to determine how PBel CGRP neurons respond to and encode innate sensory threats, and how these neurons contribute to the unique physical and emotional comorbidities in panic disorder. To achieve this objective, activity of PBel CGRP neurons will be monitored (via in vivo calcium imaging) as mice are exposed to multimodal sensory threats or panicogenic agents (Aim 1). PBel CGRP neurons will then be manipulated (inhibited or activated) using optogenetic and chemogenetic techniques to establish causal relationships between CGRP neuronal activity and physiological changes during innate threat perception (Aim 2). Lastly, activity of downstream neurons (those that express CGRP receptors in brain regions innervated by PBel CGRP neurons) will be monitored and manipulated to establish functional neural circuits involved in panic disorder pathogenesis (Aim 3). Contributions of the proposed research will be significant because it will advance the circuit-level understanding of panic disorder pathogenesis. The research plan is innovative because it investigates, for the first time, involvement of the PBel in panic disorder pathogenesis using cell type-specific circuit dissection tools. Successful completion of the proposed research will therefore provide neural circuit-based understanding of panic disorder symptoms, which may provide important insights toward developing therapeutic interventions for panic disorder.