Encoding of fear and safety discrimination in prefrontal-amygdala projections

项目总结/摘要 这项建议是一个为期四年的研究职业发展计划，重点是研究 恐惧和安全歧视的神经生理学，这与焦虑症和创伤后 应激障碍在项目开始时，候选人将被任命为 威尔康奈尔医疗中心精神病学系。该提案是对《公约》的自然延伸， 候选人之前在内侧前额叶皮层（mPFC）安全信号方面的研究和临床培训， 基底外侧杏仁核（BLA）。它概述了一个计划，为候选人实现他的目标，成为专家， 恐惧和焦虑症的电路机制，在两个维度上扩展候选人的培训， 这反映在康纳·利斯顿博士和约书亚·莱维茨博士的指导下：1.恐惧和安全的编码- 大型分布式mPFC和BLA集成中的相关信息，以及2.细胞表面受体， 前额叶输出到BLA成功的恐惧歧视，并代表有前途的药理学目标 来治疗普遍的恐惧拟议的实验和多方面的培训计划将传授 候选人具有独特的技能组合，将使他能够过渡到一个成功的独立 作为一名研究精神疾病中恐惧和焦虑的神经生理学的医生科学家。 焦虑症是最普遍的精神疾病，影响五分之一到三分之一的美国成年人 这些疾病通常是慢性的，与高疾病负担和显著的 医疗费用。虽然存在有效的治疗方法，但相当一部分患者的反应最小， 支持了开发通过不同细胞机制起作用的疗法的需要。焦虑 这些疾病彼此之间以及与其他精神疾病高度共病，突出了 研究具有跨诊断相关性的常见神经回路机制。PTSD或焦虑患者 这两种疾病都被发现表现出条件性恐惧的过度泛化，这与 mPFC和BLA的异常反应性。我的建议的目标是调查恐惧的编码， 相互连接的mPFC和BLA神经元的安全性辨别。具体而言，本提案探讨了 代谢型谷氨酸受体2（mGluR 2）在控制mPFC至BLA输出中的作用：1.定义高- mGluR 2+和mGluR 2- mPFC-BLA投射器中的维度恐惧和安全编码机制; 2. 阐明mGluR 2+和mGluR 2- mPFC之间连接的恐惧辨别学习相关变化 细胞和功能不同的下游BLA集合体; 3.剖析mGluR 2信号传导的作用 特别是mPFC-BLA突触前末梢在恐惧辨别学习中的作用。总的来说，这些实验 为mPFC-BLA回路中的恐惧和安全辨别的神经生理学提供了新的见解， 研究mGluR 2作为焦虑症和PTSD潜在治疗靶点。

Project Summary/Abstract This proposal is for a four-year research career development program, focused on the study of the neurophysiology of fear and safety discrimination, which has relevance to anxiety disorders and post-traumatic stress disorder. By the start of the project, the candidate will have been appointed an Instructor in the Department of Psychiatry at Weill Cornell Medical Center. The proposal is a natural extension of the candidate's previous research and clinical training on safety signals in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). It outlines a plan for the candidate to achieve his goal of becoming an expert in the circuit mechanisms of fear and anxiety disorders, extending the training of the candidate in two dimensions, which are reflected in the mentorship of Drs. Conor Liston and Joshua Levitz: 1. Encoding of fear and safety- related information in large, distributed mPFC and BLA ensembles and 2. Cell-surface receptors that modulate prefrontal output to the BLA for successful fear discrimination and represent promising pharmacological targets for treating generalized fear. The proposed experiments and multi-faceted training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent career as a physician-scientist studying the neurophysiology of fear and anxiety in psychiatric disorders. Anxiety disorders are the most prevalent mental disorders, affecting one-fifth to one-third of the adult US population, and the disorders are typically chronic, associated with high disease burden and significant healthcare cost. While effective treatments exist, a substantial proportion of patients are minimally responsive, underpinning the need to develop therapeutics that work through different cellular mechanisms. Anxiety disorders are highly co-morbid with each other and with other psychiatric disorders, highlighting the value of research into common neurocircuit mechanisms with trans-diagnostic relevance. Patients with PTSD or anxiety disorders have both been found to exhibit the overgeneralization of conditioned fear, which is associated with abnormal reactivity of the mPFC and BLA. The goal of my proposal is to investigate the encoding of fear and safety discrimination in interconnected mPFC and BLA neurons. Specifically, this proposal investigates the role of metabotropic glutamate receptor 2 (mGluR2) in controlling mPFC-to-BLA output by: 1. Defining high- dimensional fear and safety encoding mechanisms in mGluR2+ and mGluR2- mPFC-BLA projectors; 2. Elucidating fear discrimination learning-related changes in connectivity between mGluR2+ and mGluR2- mPFC cells and functionally-distinct downstream BLA ensembles; 3. Dissecting the role of mGluR2 signaling specifically at mPFC-BLA presynaptic terminals in fear discrimination learning. Collectively, these experiments provide novel insight into the neurophysiology of fear and safety discrimination in the mPFC-BLA circuit and investigate mGluR2 as a potential therapeutic target for anxiety disorders and PTSD.