Neural Basis of Individual Differences in Fear Extinction

恐惧消退个体差异的神经基础

• 批准号: 10554291
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554291
• 关键词: Acetylcholine; Acetylcholinesterase; Agonist; Amygdaloid structure; Animal Model; Area; Attention; Behavioral; Brain; Cardiovascular system; Cues; Data; Electrophysiology (science); Environment; Extinction; 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; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Rat Transgene; Rattus; Receptor Activation; Receptor Inhibition; Regulation; Research; Resistance; Role; Safety; Slice; Synaptic plasticity; System; TG gene; Testing; Therapeutic; Transgenic Organisms; Treatment Effectiveness; Ultrasonics; Veterans; Woman; antagonist; basal forebrain; 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; neural circuit; neurobiological mechanism; neurotransmission; optogenetics; pharmacologic; positive allosteric modulator; precision medicine; prevent; programs; 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 虽然大多数一般人口，尤其是战斗退伍军人，但会遇到创伤事件，只有一个 相对较小的比例继续发展创伤后应激障碍（PTSD），表明存在 对创伤压力长期后果的敏感性的个体差异。 PTSD患者 在恐惧灭绝，灭绝召回和安全学习中表现出障碍，因此灭绝学习过程 构成基于暴露疗法的基础。我们已经观察到行为（冻结）的个体变化 和心血管响应在示威的恐惧记忆中的爆炸大鼠中，为模型提供了模型 研究PTSD样抗恐惧的抵抗力。我们的总体目标是定义 胆碱能系统，特别是毒蕈碱受体（MACHR），在差异调节皮质中 杏仁核电路诱发了扑灭恐惧记忆的个体差异。来自 基础前脑（BF）为前额叶（PFC） - 杏仁核电路提供了强大的输入，这对于恐惧很重要 灭绝。大鼠模型中的初步数据表明，提示恐惧灭绝的个体差异是 与胆碱能神经传递和功能的差异有关，尤其是MACHR调节 基底外侧杏仁核（BLA）。我们的假设是杏仁核中的毒蕈碱受体激活降低 从PFC到抗恐惧灭绝学习的兴奋性输入，抗性（高冷冻）表型， 因此，可以在这种抗灭绝的种群中特别增强灭绝学习 对手。所有实验均比较男性和雌性大鼠的个体差异 表型。使用多学科方法，三个目标探讨了药理学方法的能力 以增强抗灭绝表型中的灭绝学习或回忆，并提供 这些作用的神经生物学作用。 AIM 1测试MACHR的治疗潜力 对抗者，激动剂和阳性变构调节剂在转移恐惧灭绝时，重点是M1和M4 选择性化合物。我们将研究条件冰冻，超声波发声和 在灭绝学习和回忆期间的心血管反应与全身性和杏仁核 MACHR化合物的注射。 AIM 2检查乙酰胆碱的差异是否从基础上释放 前脑和/或乙酰胆碱酯酶活性介导恐惧灭绝的差异。体内微透析将 用于评估乙酰胆碱和谷氨酸外排，将使用转基因大鼠模型进行 光遗传学刺激或抑制基础前脑胆碱能输入以检查我们灭绝的影响 表型。 AIM 3检查了毒蕈碱的调节兴奋性反应和突触可塑性的调节 使用光遗传学和电生理方法在杏仁核大脑中刺激PFC输入 切片。 MACHR的药理操作将与光遗传学刺激一起使用 在bla锥体神经元中记录的同时，输入的输入至关重要。这些研究会 由于对PFC输入相关的杏仁核反应，这是由于强烈 来自基础前脑的BLA，以及来自PFC的下游，用于介导行为输出。这些 研究将为基于MACHR的药理干预措施提供证据，以增强灭绝 基于曝光疗法等基于的方法，加上毒蕈碱剂的机械概况 在男性和雌性大鼠的恐惧学习和灭绝的基础神经回路内。