Prefrontal circuit mechanisms of threat conditioning

恐惧症、恐慌症和创伤后应激障碍(PTSD)等精神疾病与 与恐惧相关的行为加剧。这在一定程度上是由于获得和表达更多的 威胁记忆，当在威胁环境中遇到无害的刺激时发生 成为防御性情绪反应的有力触发因素。研究表明，这种形式的记忆 啮齿类动物大脑的一个区域，类似于大脑中的病理性多动区域 人的内侧前额叶皮质(MPFC)。初步兴奋性神经元被认为是调节记忆的 通过向关键的大脑下游区域发送信号进行表达。然而，电路和突触机制 这些细胞的潜在记忆特异性招募仍然知之甚少。这个项目的目的是 鉴定与小鼠威胁记忆形成相关的初步突触变化，阐明其作用。 发生这些改变的神经回路，并定义特定的初步输出连接 调解与威胁相关的行为。在初步实验的基础上，这项工作将集中在稀疏种群 表达肽标记物生长抑素并表现出兴奋性突触增加的抑制性中间神经元 威胁学习之后的活动。我们的中心假设是，这些细胞经历了刺激相关的增加 学习后的活动，它们的功能是抑制含有小白蛋白的中间神经元，从而 解除兴奋性神经元放电的主要刹车。在目标1中，我们将使用脑片电生理学来 观察突触介导生长抑素中间神经元活性升高及其与神经元的相互作用 小白蛋白中间神经元。在目标2中，我们将使用光遗传学和基于钙的成像来自由行为 检测动物生长抑素和小白蛋白中间神经元在威胁记忆表达中的作用。最后，在 目的3，我们将确定介导生长抑素行为结果的特定兴奋性人群 神经元间操作以及建立这些神经元提供的下游大脑区域 突触输入。这个项目是首次尝试确定情绪学习如何改变复杂性。 抑制刺激处理以支持mPFC记忆功能，并将识别潜在的目标 减弱病理活动和相关行为。

Psychiatric conditions such as phobia, panic and post-traumatic stress disorder (PTSD) are associated with heightened fear-related behavior. This has been attributed in part to increased acquisition and expression of threat memory, which occurs when an innocuous stimulus encountered under threatening circumstances becomes a potent trigger for defensive emotional reactions. Research indicates that this form of memory engages the prelimbic cortex, a rodent brain region that is analogous to an area of pathological hyperactivity in the human medial prefrontal cortex (mPFC). Prelimbic excitatory neurons are thought to mediate memory expression by signaling to key downstream brain regions. However, the circuit and synaptic mechanisms underlying memory-specific recruitment of these cells remain poorly understood. The purpose of this project is to identify prelimbic synaptic changes associated with threat memory formation in mice, to elucidate the role of neural circuits where these modifications occur, and to define specific prelimbic output connections that mediate threat-related behaviors. Based on preliminary experiments, this work will focus sparse populations of inhibitory interneurons that express the peptide marker somatostatin and exhibit increased excitatory synaptic activity after threat learning. Our central hypothesis is that these cells undergo an increase in stimulus-related activity after learning and that they function to suppress parvalbumin-containing interneurons and thereby relieve a major brake on excitatory neuronal firing. In Aim 1, we will use brain slice electrophysiology to examine synapses mediating elevated activity of somatostatin interneurons as well as their interaction with parvalbumin interneurons. In Aim 2, we will use optogenetics and calcium-based imaging in freely behaving animals to test the role of somatostatin and parvalbumin interneurons in threat memory expression. Finally, in Aim 3, we will identify specific excitatory populations mediating behavioral outcomes of somatostatin interneuron manipulations as well as establish downstream brain regions to which these neurons provide synaptic input. This project represents the first attempt to establish how emotional learning alters complex inhibitory stimulus processing to support mPFC memory functions, and will identify potential targets for attenuating pathological activity and associated behaviors.