Synaptic and neuronal mechanisms of fear control: the role of hippocampal-amygdalar interactions

恐惧控制的突触和神经元机制：海马-杏仁核相互作用的作用

• 批准号: 10045093
• 负责人: VADIM BOLSHAKOV
• 金额: $ 51.19万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10045093
• 关键词: Affect; Amygdaloid structure; Anxiety; Behavior; Behavioral; Biological Assay; Brain; Cell Nucleus; Chemosensitization; Conditioned Stimulus; Dependence; Development; Disease; Electrophysiology (science); Equilibrium; Exhibits; Exposure to; Extinction (Psychology); Fright; Functional disorder; Hippocampus (Brain); Human; Impairment; Lead; Light; Link; Mediating; Memory; Modeling; Modification; Mus; Negative Valence; Neurons; Output; Pathologic; Pathway interactions; Patients; Pilot Projects; Play; Post-Traumatic Stress Disorders; Process; Reporting; Research Domain Criteria; Retrieval; Role; Signal Transduction; Slice; Stimulus; Stress; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Training; Viral Vector; Whole-Cell Recordings; base; behavior change; behavioral outcome; behavioral response; brain circuitry; conditioned fear; conditioning; experience; fear memory; in vivo; neural circuit; neural network; neuromechanism; neurotransmission; optogenetics; relating to nervous system; response; targeted treatment; tool; trait; transmission process

Projections from the ventral hippocampus (vHPC) to the amygdala, its basolateral nucleus (BLA), specifically, play an essential role in context representation in the amygdala during encoding of fear memory extinction. However, synaptic and network-level mechanisms by which vHPC-amygdala projections may control the function of the amygdala and amygdala-dependent fear-related behaviors are largely unknown. Combining the use of chemogenetic and optogenetic techniques with ex vivo and in vivo electrophysiology, tract tracing with viral vectors and behavioral training and testing, we will explore the functional roles of vHPC-amygdala projections in conditioned fear and fear extinction at synaptic and circuitry-specific levels. In Aim 1 we will investigate how the mechanisms of synaptic plasticity in vHPC projections to subnuclei of the amygdala affect the signal flow in neural circuits of fear conditioning and extinction. Optogeneticaly activating vHPC-amygdala projections, we will record from neurons in different subdivisions of the amygdala in slices from control, fear-conditioned and fear- extinguished mice and assay the effects of behavioral training on both excitatory and inhibitory drive in recorded neurons and their synaptically-driven spike firing output. We will then explore the role of the vHPC-amygdala pathway in control of fear-related behaviors (Aim 2). Specifically, we will examine the contributions of behaviorally-induced synaptic plasticity at vHPC inputs to the amygdala, specifically focusing on long-range GABAergic vHPC-BLA projections (identified by us), to the encoding of context-dependency of fear extinction memory using chemogenetic tools. We will also systematically explore whether extinction-associated potentiation of GABAergic synaptic transmission at vHPC-BLA projections may satisfy criteria of synaptic plasticity and memory (SPM) hypothesis, thus possibly linking these plastic synaptic modifications to the encoding of context-dependency of fear extinction. Finally (Aim 3), we will investigate the synaptic and neural circuit-level mechanisms in vHPC-amygdala projections implicated in fear renewal triggered by repeated stress in fear extinguished mice. We hypothesize that repeated stress may affect the mechanisms of extinction- triggered synaptic plasticity in vHPC-BLA projections, impairing context representation, and, therefore, possibly resulting in fear renewal. Our studies could identify specific synaptic mechanisms and neural projections which could potentially be targeted for therapeutic treatments of disorders implicating dysfunctions of the fear system of the brain.

从腹侧海马 (vHPC) 到杏仁核及其基底外侧核 (BLA) 的投影，具体来说， 在恐惧记忆消退的编码过程中，杏仁核的上下文表征中发挥着重要作用。 然而，vHPC-杏仁核投射可以控制功能的突触和网络级机制 杏仁核和杏仁核依赖的恐惧相关行为在很大程度上是未知的。结合使用 化学遗传学和光遗传学技术与离体和体内电生理学、病毒追踪 向量和行为训练和测试，我们将探索 vHPC-杏仁核预测的功能作用 在突触和电路特定水平上的条件性恐惧和恐惧消退。在目标 1 中，我们将研究如何 vHPC 投射到杏仁核亚核的突触可塑性机制影响信号流 恐惧调节和消退的神经回路。光遗传学激活 vHPC-杏仁核投射，我们将 记录来自控制组、恐惧条件组和恐惧组的杏仁核不同分区的神经元的切片 消灭小鼠并分析行为训练对记录的兴奋性和抑制性驱动的影响 神经元及其突触驱动的尖峰放电输出。然后我们将探讨 vHPC-杏仁核的作用 控制恐惧相关行为的途径（目标 2）。具体来说，我们将审查以下人员的贡献： 行为诱导的 vHPC 输入杏仁核的突触可塑性，特别关注长程 GABAergic vHPC-BLA 投影（由我们识别），编码恐惧消退的情境依赖性 使用化学遗传学工具进行记忆。我们还将系统地探讨灭绝是否与 vHPC-BLA 投射处 GABA 能突触传递的增强可能满足突触标准 可塑性和记忆（SPM）假说，因此可能将这些可塑性突触修饰与 恐惧消退的情境依赖性的编码。最后（目标 3），我们将研究突触和神经 vHPC-杏仁核预测中的电路级机制与重复压力引发的恐惧更新有关 老鼠因恐惧而灭亡。我们假设重复的压力可能会影响灭绝机制—— 触发 vHPC-BLA 投射中的突触可塑性，损害上下文表征，因此可能 导致恐惧重新出现。我们的研究可以确定特定的突触机制和神经投射 可能成为治疗涉及恐惧系统功能障碍的疾病的目标 大脑的。