Encoding of fear and safety discrimination in prefrontal-amygdala projections

前额杏仁核投射中恐惧和安全歧视的编码

• 批准号: 10936865
• 负责人: Joseph Matthew Stujenske
• 金额: $ 15.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10936865
• 关键词: Encoding; fear; safety; discrimination; prefrontal

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.

项目概要/摘要 该提案是一项为期四年的研究职业发展计划，重点研究 恐惧和安全歧视的神经生理学，与焦虑症和创伤后相关 应激障碍。在项目开始时，候选人将被任命为讲师 威尔康奈尔医学中心精神病学部。该提案是该提案的自然延伸 候选人之前关于内侧前额皮质 (mPFC) 安全信号的研究和临床培训，以及 基底外侧杏仁核（BLA）。它概述了候选人实现成为某领域专家的目标的计划 恐惧和焦虑症的循环机制，在两个维度上扩展候选人的训练， 这反映在博士的指导中。 Conor Liston 和 Joshua Levitz：1. 恐惧和安全的编码—— 大型分布式 mPFC 和 BLA 整体中的相关信息以及 2. 调节的细胞表面受体 BLA 的前额输出可成功区分恐惧，并代表有希望的药理学目标 用于治疗普遍的恐惧。所提出的实验和多方面的培训计划将传授 具有独特技能组合的候选人，这将使他能够转变为成功的独立人士 作为一名医师科学家，研究精神疾病中恐惧和焦虑的神经生理学。 焦虑症是最普遍的精神障碍，影响着五分之一到三分之一的美国成年人 人群，并且这些疾病通常是慢性的，与高疾病负担和显着相关 医疗保健费用。虽然存在有效的治疗方法，但相当一部分患者的反应微乎其微， 支持开发通过不同细胞机制发挥作用的疗法的需要。焦虑 这些疾病彼此之间以及与其他精神疾病高度共存，突出了 研究具有跨诊断相关性的常见神经回路机制。患有 PTSD 或焦虑症的患者 研究发现，这两种疾病都表现出条件性恐惧的过度概括，这与 mPFC 和 BLA 的异常反应性。我提案的目标是调查恐惧和恐惧的编码 相互连接的 mPFC 和 BLA 神经元的安全歧视。具体来说，该提案调查了以下角色： 代谢型谷氨酸受体 2 (mGluR2) 通过以下方式控制 mPFC 至 BLA 输出： 1. 定义高 mGluR2+ 和 mGluR2- mPFC-BLA 投影仪中的维度恐惧和安全编码机制； 2. 阐明 mGluR2+ 和 mGluR2- mPFC 之间与恐惧歧视学习相关的连接变化 细胞和功能不同的下游 BLA 整体； 3. 剖析 mGluR2 信号传导的作用 特别是在恐惧歧视学习中的 mPFC-BLA 突触前末梢。总的来说，这些实验 为 mPFC-BLA 回路中恐惧和安全歧视的神经生理学提供新的见解 研究 mGluR2 作为焦虑症和 PTSD 的潜在治疗靶点。