Encoding of fear and safety discrimination in prefrontal-amygdala projections

项目摘要/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，与焦虑症和创伤后相关 应激障碍。到项目开始时，应聘者将被任命为 威尔康奈尔医学中心精神病学系。这项提议是对 候选人先前对内侧前额叶皮质(MPFC)和大脑皮质的安全信号的研究和临床训练 杏仁基底外侧核(BLA)。它勾勒出了候选人实现成为专家的目标的计划 恐惧和焦虑障碍的回路机制，从两个维度延长了候选人的训练时间， 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.对恐惧和安全的编码- 大而分散的mPFC和BLA集合中的相关信息和2.调节细胞表面受体 前额叶输出到BLA用于成功的恐惧歧视和代表有希望的药理学靶点 治疗广泛性恐惧。拟议的实验和多方面的培训计划将使 拥有独特技能组合的候选人，这将使他成为一名成功的独立候选人 作为一名内科科学家，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 人群中，这些疾病通常是慢性的，与高疾病负担和显著的 医疗保健成本。虽然存在有效的治疗方法，但相当大比例的患者反应轻微， 支持了开发通过不同细胞机制发挥作用的疗法的必要性。焦虑感 精神障碍彼此之间以及与其他精神障碍高度并存，突出了 研究具有跨诊断相关性的常见神经回路机制。患有创伤后应激障碍或焦虑的患者 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反应性异常。我的建议的目标是研究恐惧和 相互连接的mPFC和BLA神经元的安全辨别。具体地说，这份提案调查了 代谢型谷氨酸受体2(MGluR2)在控制mPFC-to-BLA输出中的作用：1.定义高- MGluR2和mGluR2-mPFC-BLA投影仪的维度恐惧和安全编码机制； MGluR2和mGluR2-mPFC之间连接能力的学习相关变化 细胞和功能不同的下游BLA集成；3.剖析mGluR2信号转导的作用 尤其是在恐惧辨别学习中的mPFC-BLA突触前终末。总的来说，这些实验 对mPFC-BLA回路中恐惧和安全辨别的神经生理学提供新的见解和 研究mGluR2作为治疗焦虑症和创伤后应激障碍的潜在靶点。

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.