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

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。

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.