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

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。

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.