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: 10159754
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159754
• 关键词: AMPA Receptors; Adverse event; Affect; Affective; Amygdaloid structure; Animals; 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; 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; classical conditioning; designer receptors exclusively activated by designer drugs; emotional behavior; experimental study; fear memory; in vivo; 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 形成更强的厌恶记忆是PTSD的特征。同时，心理 创伤是未来开发PTSD的危险因素，暴露于另一种不利 事件。该项目将使用小鼠调查他人观察恐惧的一种社会形式 困扰，增强了新的抑制性回避（IA）记忆的保留。它为我们的长期服务 术语目标是了解神经元可塑性如何促进情感行为和 确定通过人造电路逆转与PTSD相关的行为特征的手段 操纵。我们最近发现，短暂暴露于同种接收电气 脚印，观察性的恐惧范式（Of），使抑制性避免更强（IA） 在老鼠中学习。 我们的初步数据强烈暗示背额前额叶皮层之间的途径 （DMPFC）和基底外侧杏仁核（BLA）途径。首先，a 在OF期间，这些结构的药物遗传学断开可防止增强。 其次，通过IA培训实现了这一途径的促进，持续了几个小时。 第三，仅产生的仅NMDAR（无声）突触，我们通过IA培训未填充。在 加上衰减的Gababr介导的喂食剂Gabaergic Courten的抑郁症， 通过5 Hz反复刺激DMPFC输入，在BLA神经元中引起了诱发。我们将测试 假设通过产生沉默的突触并改变gababr-来增强IA 依赖性抑制性平衡在前额叶 - 杏仁核电路中的PV-和SST-IN之间 这使IA培训期间的突触促进能力更强。我们将确定必要性 在OF-IA范式的每个阶段的DMPFC-BLA突触（AIM 1），测试因果关系 无声突触和瞬态突触促进（AIM 2），并识别微电路 负责异常可塑性的机制（AIM 3）。该研究可能会告知 早期干预的潜在目标和方法可防止受创伤的人中的PTSD。