Prefrontal-Amygdala Interactions in Fear Conditioning

描述(由申请人提供)：焦虑症，如创伤后应激障碍(PTSD)，其特征是对环境线索的情绪反应调节不足。一种新兴的情绪调节动物模型是巴甫洛夫恐惧条件作用的消亡，即在没有电击的情况下，重复呈现以前与电击配对的音调。恐惧消退受损被认为是导致创伤后应激障碍和其他焦虑症的原因之一。现在人们普遍认为，灭绝是一种新的学习，像其他形式的学习一样，通过获取、巩固和提取阶段进行。在这笔赠款的前一个周期中进行的研究表明，边缘下部前额叶皮质(IL)在巩固大鼠的灭绝过程中发挥着关键作用。IL中的神经元在消亡后立即表现出NMDA受体依赖性的爆发，这种爆发与消退记忆的强度有关。与灭绝相关的IL的爆发可能反映了对巩固灭绝所必需的特定输入的激活。这项资助的总体目标是了解对IL的输入如何调节IL神经元的爆发和兴奋性，从而促进灭绝的巩固。在目标1中，我们将使用训练后的药理学失活来评估IL的候选输入(来自海马体、杏仁基底外侧核或丘脑内侧)在巩固恐惧消退方面的贡献。在目标2中，我们将评估候选输入对IL神经元与灭绝相关的爆发的贡献。这将通过：1)从单个IL神经元记录时药理学地使输入失活，2)从输入神经元和IL神经元同时记录，3)微刺激输入神经元以加强消失巩固。在目标3中，我们将利用全细胞膜片钳记录来评估消光对IL神经元内源性兴奋性的影响。我们将评估消失性诱导的IL兴奋性变化的时间过程，如注入电流诱发的尖峰数目和爆裂的趋势。然后我们将确定这一过程在多大程度上依赖于NMDA受体和IL的输入。了解IL巩固灭绝的机制可以解释为什么少数人在经历创伤后会患上创伤后应激障碍。本研究将探讨消退学习巩固的生理机制。了解前额叶皮质巩固消除恐惧的机制，可以解释为什么少数人在经历创伤后会患上创伤后应激障碍。这些信息还可能导致新的方法，以提高基于灭绝的疗法治疗创伤后应激障碍的有效性。

DESCRIPTION (provided by applicant): Anxiety disorders such as post-traumatic stress disorder (PTSD) are characterized by deficient regulation of emotional responses to environmental cues. An emerging animal model of emotional regulation is extinction of Pavlovian fear conditioning, in which a tone that had been previously paired with a shock is repeatedly presented in the absence of the shock. Impaired extinction of fear is thought to contribute to PTSD and other anxiety disorders. It is now generally accepted that extinction is new learning that, like other forms of learning, proceeds through acquisition, consolidation and retrieval phases. Studies performed in the previous cycle of this grant show that the infralimbic prefrontal cortex (IL) plays a key role in the consolidation of extinction in rats. Neurons in IL exhibit NMDA receptor-dependent bursting immediately after extinction and this bursting is correlated with the strength of extinction memory. Extinction-related bursting in IL likely reflects activation of specific inputs necessary for the consolidation of extinction. The overall goal of this grant is to understand how inputs to IL modulate bursting and excitability of IL neurons, thereby facilitating consolidation of extinction. In Aim 1, we will evaluate the contribution of candidate inputs to IL (from the hippocampus, basolateral amygdala, or mediodorsal thalamus) in the consolidation of fear extinction, using post-training pharmacological inactivation. In Aim 2, we will evaluate the contribution of candidate inputs to extinction-related bursting in IL neurons. This will be done by: 1) pharmacologically inactivating inputs while recording from single IL neurons, 2) recording simultaneously from input neurons and IL neurons, 3) microstimulating input neurons to strengthen extinction consolidation. In Aim 3, we will evaluate the effect of extinction on the intrinsic excitability of IL neurons, using whole cell patch clamp recording. We will assess the timecourse of extinction-induced changes in IL excitability, as evidenced by the number of spikes evoked by injected current and the tendency to burst. We will then determine the extent to which this process depends on NMDA receptors and inputs to IL. Understanding the mechanisms by which the IL consolidates extinction could explain why a minority of individuals develop PTSD after a traumatic experience. PUBLIC HEALTH RELEVANCE This research will explore the physiological mechanisms of consolidation of extinction learning. Understanding the mechanisms by which the prefrontal cortex consolidates extinction of fear could explain why a minority of individuals develop post-traumatic stress disorder after a traumatic experience. This information could also lead to new ways to increase the effectiveness of extinction-based therapies for treatment of PTSD.