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.

项目总结 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，心理上 创伤是未来发生创伤后应激障碍的危险因素，如果暴露在另一种不利的环境中 事件。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，增强对新的抑制性回避(IA)记忆的保留。它服务于我们的长期- 学期目标是了解神经元可塑性如何影响情绪行为和 识别人工回路逆转创伤后应激障碍相关行为特征的方法 操纵。我们最近发现，短暂暴露在同种物质的接收电信号中 脚电，观察性恐惧范式(OF)，实现了更强的抑制性回避(IA) 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质之间的通路 (DmPFC)和基底外侧杏仁核(BLA)通路的增强。首先，一个 在OF过程中，这些结构的药物遗传断开阻止了增强。 第二，通过持续几个小时的IA培训，使这一途径得以简化。 第三，生成的仅NMDAR(沉默)突触的数量，我们通过IA训练使其不再沉默。在……里面 此外，减弱的GABABR介导的前馈GABA能电流的抑制， 通过重复刺激dmPFC输入5赫兹，在BLA神经元中进行诱发。我们将测试一个 假说认为OF通过产生沉默的突触和改变GABABR- 前额-杏仁核环路中PV-和SST-IN之间的依赖抑制平衡 这使得在IA训练过程中有更强的突触促进作用。我们将确定是否有必要 在OF-IA范式的每个阶段(目标1)，测试dmPFC-BLA突触的因果作用 沉默突触和瞬时突触易化(目标2)，并识别微回路 导致异常高塑性的机制(目标3)。这项研究可能会提供关于 早期干预的潜在目标和方法，以预防创伤患者的创伤后应激障碍。