Observational fear enhanced plasticity in dmPFC-BLA circuit as a modulator of affective behaviors

观察性恐惧增强了 dmPFC-BLA 回路作为情感行为调节器的可塑性

• 批准号: 10614980
• 负责人: Alexei Morozov
• 金额: $ 40万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614980
• 关键词: AMPA Receptors; Adverse event; Affect; Affective; Amygdaloid structure; Animals; Association Learning; Attention; Attenuated; Avoidance Learning; Behavior; Behavioral; Bilateral; Brain; Characteristics; Chronic; Data; Disease; Disinhibition; Distress; Early Intervention; Emotional disorder; Equilibrium; Etiology; Exposure to; Fright; Future; Glutamates; Goals; Hour; Knowledge; Light; Mediating; Memory; Mental Depression; Methods; Mus; Neuronal Plasticity; Neurons; Outcome; Output; Pathologic; Pathway interactions; Persons; Pharmacogenetics; Phase; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Process; Property; Psyche structure; Risk Factors; Rodent; Role; Signal Transduction; Social Concepts; Structure; Synapses; Synaptic Transmission; Testing; Training; Trauma; cell type; designer receptors exclusively activated by designer drugs; emotional behavior; experimental study; fear memory; in vivo; maladaptive behavior; pre-clinical; prevent; psychological trauma; social; social stress; trait; transmission process

Project summary Forming stronger aversive memories is a characteristic of PTSD. Meanwhile, psychological trauma is a risk factor for developing PTSD in the future, upon exposure to another adverse event. This project will use mice to investigate how observing fear in others, as a form of social distress, enhances the retention of new inhibitory avoidance (IA) memories. It serves our long- term goal to understand how neuronal plasticity contributes to emotional behaviors and to identify the means for reversing PTSD-relevant behavioral traits by artificial circuit manipulations. We have recently found that a brief exposure to a conspecific receiving electrical footshocks, the observational fear paradigm (OF), enables a stronger inhibitory avoidance (IA) learning in mice. Our preliminary data strongly implicate the pathways between the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) pathway in the enhancement. First, a pharmacogenetic disconnection of these structures during OF prevented the enhancement. Second, OF enabled facilitation of this pathway by IA training, which lasted for several hours. Third, OF generated NMDAR-only (silent) synapses, which we unsilenced by IA training. In addition, OF attenuated GABAbR-mediated depression of the feedforward GABAergic currents, evoked in BLA neurons by a 5 Hz repeated stimulation of the dmPFC inputs. We will test a hypothesis that OF enhances IA by generating silent synapses and by altering the GABAbR- dependent inhibitory balance between PV- and Sst-IN in the prefrontal-amygdala circuit, both of which enable a stronger synaptic facilitation during IA training. We will determine the necessity of dmPFC-BLA synapses at each phase of the OF-IA paradigm (Aim 1), test the causal role of the silent synapses and the transient synaptic facilitation (Aim 2), and identify the micro-circuit mechanism responsible for the abnormally high plasticity (Aim 3). The study may inform about potential targets and methods for early intervention to prevent PTSD in traumatized people.

项目摘要 形成更强烈的厌恶记忆是创伤后应激障碍的一个特征。同时，心理 创伤是未来发展PTSD的危险因素，一旦暴露于另一种不利因素， 活动这个项目将使用老鼠来研究如何观察他人的恐惧，作为一种社会形式。 痛苦，增强了新的抑制性回避（IA）记忆的保留。它服务于我们长久以来的- 学期目标是了解神经元可塑性如何影响情绪行为， 确定通过人工回路逆转PTSD相关行为特征的方法 操纵我们最近发现，短时间暴露于同种接受电 观察恐惧范式（OF）的足电击使抑制性回避（IA）更强 在老鼠身上学习 我们的初步数据强烈暗示了背内侧前额叶皮层 （dmPFC）和基底外侧杏仁核（BLA）通路的增强。一是 在OF期间，这些结构的药物遗传学断开阻止了增强。 第二，通过持续几个小时的IA培训，OF能够促进这一途径。 第三，OF只产生NMDAR（沉默）突触，我们通过IA训练使其不沉默。在 此外，OF减弱GABAbR介导的前馈GABA能电流的抑制， 通过5 Hz重复刺激dmPFC输入在BLA神经元中诱发。我们将测试 假设OF通过产生沉默突触和改变GABAbR来增强IA- 在前额叶-杏仁核回路中PV-和Sst-IN之间的依赖性抑制平衡， 这使得在IA训练期间能够实现更强的突触促进。我们将决定 的dmPFC-BLA突触在OF-IA范式的每个阶段（目的1），测试的因果作用， 沉默突触和瞬时突触易化（目标2），并确定微电路 机制负责异常高的可塑性（目的3）。该研究可以提供以下信息： 早期干预的潜在目标和方法，以防止创伤后应激障碍的人。