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: 10378676
• 负责人: VADIM BOLSHAKOV
• 金额: $ 48.63万
• 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/10378676
• 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）到杏仁核的投影，其基底外侧核（BLA），特别是 在编码恐惧记忆灭绝时，在杏仁核的上下文表示中起着重要的作用。 但是，VHPC-Amygdala投影可以控制功能的突触和网络级别机制 杏仁核和杏仁核依赖于恐惧相关的行为在很大程度上是未知的。结合使用 具有离体和体内电生理学的化学生成和光遗传学技术，病毒式追踪 向量以及行为培训和测试，我们将探讨VHPC-Amygdala预测的功能作用 有条件的恐惧和恐惧在突触和电路特异性水平上的灭绝。在AIM 1中，我们将调查如何 VHPC对杏仁核亚核中突触可塑性的机制会影响信号流中的信号流 恐惧调节和灭绝的神经回路。光构激活VHPC-Amygdala投影，我们将 从杏仁核不同细分中的神经元记录在片段中，来自控制，恐惧和恐惧 - 熄灭小鼠并测定行为训练对记录中兴奋性和抑制性驱动的影响 神经元及其突触驱动的尖峰发射输出。然后，我们将探索VHPC-Amygdala的角色 控制与恐惧相关行为的途径（AIM 2）。具体来说，我们将研究 VHPC输入到杏仁核的行为引起的突触可塑性，特别关注远程 GABA能VHPC-BLA预测（由我们确定），编码恐惧灭绝的上下文依赖性 使用化学发生工具的记忆。我们还将系统地探索是否相关 VHPC-BLA投影处的GABA能突触传播的增强可能满足突触的标准 可塑性和记忆（SPM）假设，因此可能将这些塑料突触修饰与 恐惧灭绝的上下文依赖性的编码。最后（AIM 3），我们将研究突触和神经 VHPC-Amygdala投影中的电路级机制与反复压力触发有关的恐惧更新 在恐惧中扑灭老鼠。我们假设重复应力可能会影响灭绝的机制 VHPC-BLA投影，损害上下文表示，触发突触可塑性，因此可能 导致恐惧更新。我们的研究可以确定特定的突触机制和神经预测 有可能针对涉及恐惧系统功能障碍的疾病的治疗治疗 大脑。