Neural Basis of Individual Differences in Fear Extinction

恐惧消退个体差异的神经基础

• 批准号: 10082412
• 负责人: Marlene A. Wilson
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082412
• 关键词: Acetylcholine; Acetylcholinesterase; Agonist; Amygdaloid structure; Animal Model; Area; Attention; Attenuated; Behavioral; Brain; Cardiovascular system; Cues; Data; Electrophysiology (science); Environment; Extinction (Psychology); Female; Freezing; Fright; General Population; Glutamates; Goals; Impairment; Individual; Individual Differences; Injections; Intervention; Learning; Long-Evans Rats; Long-Term Potentiation; Mediating; Medical; Memory; Microdialysis; Modeling; Muscarinic Acetylcholine Receptor; Muscarinics; Neurobiology; Output; Patients; Pattern; Pharmacology; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Rattus; Receptor Activation; Regulation; Research; Resistance; Role; Safety; Slice; Synaptic plasticity; System; Testing; Therapeutic; Transgenic Organisms; Treatment Effectiveness; Ultrasonics; Veterans; Woman; basal forebrain; base; biological adaptation to stress; cholinergic; combat; combat veteran; evidence base; experience; experimental study; fear memory; hippocampal pyramidal neuron; in vivo; individual variation; innovative technologies; interdisciplinary approach; learning extinction; male; men; nerve supply; neural circuit; neurobiological mechanism; neurotransmission; optogenetics; positive allosteric modulator; precision medicine; prevent; programs; relating to nervous system; response; stress disorder; stressor; targeted agent; therapeutic evaluation; trauma exposure; traumatic event; traumatic stress; vocalization

ABSTRACT While most of the general population, and particularly combat veterans, experience traumatic events, only a relatively small proportion go on to develop post-traumatic stress disorder (PTSD), suggesting there are individual differences in susceptibility to the long-term consequences of traumatic stress. PTSD patients also show impairments in fear extinction, extinction recall, and safety learning, so extinction learning processes form the basis of exposure-based therapies. We have observed individual variation in the behavioral (freezing) and cardiovascular responses during the extinction of cued fear memories in outbred rats, providing a model to study PTSD-like resistance to fear extinction. Our overarching goal is to define the mechanistic role of cholinergic system, and specifically muscarinic receptors (mACHRs), in differentially regulating the cortico- amygdalar circuit to induce individual differences in extinguishing fear memories. Cholinergic inputs from the basal forebrain (BF) provide strong inputs to the prefrontal (PFC)-amygdalar circuit which is important for fear extinction. Preliminary data in our rat model suggests that individual differences in cued fear extinction are related to differences in cholinergic neurotransmission and function, but particularly mACHR regulation in the basolateral amygdala (BLA). Our hypothesis is that muscarinic receptor activation in the amygdala decreases excitatory inputs from the PFC to diminish fear extinction learning in the resistant (high freezing) phenotype, and thus extinction learning can be enhanced specifically in this extinction resistant population with mACHR antagonists. All experiments compare individual differences in male and female rats with distinct extinction phenotypes. Using a multidisciplinary approach, three Aims explore the ability of pharmacological approaches to enhance extinction learning or recall in the extinction resistant phenotype, and provide a mechanistic view of the neurobiological effects underlying these effects. Aim 1 tests the therapeutic potential of mACHR antagonists, agonists, and positive allosteric modulators in shifting fear extinction, with a focus on M1 and M4 selective compounds. We will examine extinction of conditioned freezing, ultrasonic vocalizations, and cardiovascular responses during extinction learning and recall with both systemic and intra-amygdalar injections of mACHR compounds. Aim 2 examines if the differential release of acetylcholine from the basal forebrain and/or acetylcholinesterase activity mediates differences in fear extinction. In vivo microdialysis will be used to assess acetylcholine and glutamate efflux, and a transgenic rat model will be used for optogenetically stimulating or inhibiting basal forebrain cholinergic inputs to examine effects in our extinction phenotypes. Aim 3 examines muscarinic modulation of excitatory responses and synaptic plasticity evoked by stimulation of PFC inputs using optogenetic and electrophysiological approaches ex vivo in amygdalar brain slices. Pharmacological manipulations of mACHRs will be used in conjunction with optogenetic stimulation of the infralimbic inputs critical for fear extinction, while recording from BLA pyramidal neurons. These studies will focus on amygdalar responses associated with PFC inputs, due to the strong cholinergic innervation to the BLA from the basal forebrain, as well as being downstream from PFC for mediating behavioral outputs. These studies will provide evidence for mACHR based pharmacological interventions that might enhance extinction- based approaches such as exposure therapy, plus provide a mechanistic profile of how muscarinic agents may be acting within the neural circuitry underlying fear learning and extinction in both male and female rats.

抽象的 虽然大多数普通民众，特别是退伍军人，都经历过创伤事件，但只有一小部分人经历过创伤事件。 相对较小的比例继续发展为创伤后应激障碍（PTSD），这表明 对创伤应激的长期后果的易感性存在个体差异。 PTSD 患者还 在恐惧消退、消退回忆和安全学习方面表现出障碍，因此消退学习过程 形成基于暴露的疗法的基础。我们观察到行为（冻结）的个体差异 和远交大鼠提示恐惧记忆消失过程中的心血管反应，提供了一个模型 研究类似创伤后应激障碍（PTSD）的对恐惧消退的抵抗力。我们的首要目标是定义 胆碱能系统，特别是毒蕈碱受体（mACHR），在差异调节皮质- 杏仁核回路诱导消除恐惧记忆的个体差异。胆碱能输入来自 基底前脑（BF）为前额叶（PFC）-杏仁核回路提供强大的输入，这对恐惧很重要 灭绝。我们的大鼠模型中的初步数据表明，提示恐惧消退的个体差异是 与胆碱能神经传递和功能的差异有关，特别是 mACHR 调节 基底外侧杏仁核（BLA）。我们的假设是杏仁核中毒蕈碱受体的激活减少 来自 PFC 的兴奋性输入可减少抵抗（高冷冻）表型中的恐惧消退学习， 因此，在具有 mACHR 的灭绝抵抗种群中，可以特别增强灭绝学习能力 对手。所有实验都比较了具有明显灭绝的雄性和雌性大鼠的个体差异 表型。使用多学科方法，三个目标探索药理学方法的能力 增强灭绝抵抗表型中的灭绝学习或回忆，并提供机械论观点 这些效应背后的神经生物学效应。目标 1 测试 mACHR 的治疗潜力 转移恐惧消退过程中的拮抗剂、激动剂和正变构调节剂，重点是 M1 和 M4 选择性化合物。我们将研究条件冷冻、超声波发声和 全身和杏仁核内消退学习和回忆过程中的心血管反应 注射mACHR化合物。目标 2 检查乙酰胆碱从基础细胞中的差异释放是否 前脑和/或乙酰胆碱酯酶活性介导恐惧消退的差异。体内微透析将 用于评估乙酰胆碱和谷氨酸流出，转基因大鼠模型将用于 光遗传学刺激或抑制基底前脑胆碱能输入以检查对我们灭绝的影响 表型。目标 3 检查毒蕈碱对兴奋反应和突触可塑性的调节 使用光遗传学和电生理学方法在杏仁核离体刺激 PFC 输入 切片。 mACHR 的药理学操作将与光遗传学刺激结合使用 从 BLA 锥体神经元记录时，边缘下输入对于恐惧消除至关重要。这些研究将 由于强烈的胆碱能神经支配，重点关注与 PFC 输入相关的杏仁核反应 BLA 来自基底前脑，位于 PFC 下游，用于调节行为输出。这些 研究将为基于 mACHR 的药物干预提供证据，这可能会增强灭绝- 基于暴露疗法等方法，并提供毒蕈碱剂如何发挥作用的机制概况 在雄性和雌性大鼠的恐惧学习和消退背后的神经回路中发挥作用。