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）的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反射的消失，其中先前与电击配对的音调在没有电击的情况下重复出现。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。现在人们普遍认为，灭绝是一种新的学习，就像其他形式的学习一样，通过获得，巩固和检索阶段进行。在本基金的上一个周期进行的研究表明，边缘下前额叶皮层（IL）在大鼠灭绝的巩固中起着关键作用。IL中的神经元在消退后立即表现出NMDA受体依赖性的爆发，并且这种爆发与消退记忆的强度相关。IL中与灭绝相关的爆发可能反映了灭绝巩固所需的特定输入的激活。这项资助的总体目标是了解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，我们将评估候选输入IL（从海马，基底外侧杏仁核，或内侧背丘脑）的贡献，在巩固的恐惧消退，使用训练后的药理学失活。在目标2中，我们将评估候选输入对IL神经元中与预激相关的爆发的贡献。这将通过以下方式实现：1）在单个IL神经元记录的同时，使输入失活，2）同时记录输入神经元和IL神经元，3）微刺激输入神经元以加强消退巩固。在目的3中，我们将使用全细胞膜片钳记录来评估消光对IL神经元的内在兴奋性的影响。我们将评估白细胞介素兴奋性的抑制诱导的变化的时间过程，如由注入电流诱发的尖峰的数量和爆发的趋势所证明的。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创伤经历后会患上PTSD。公共卫生相关性本研究将探索灭绝学习巩固的生理机制。了解前额叶皮层巩固恐惧消退的机制可以解释为什么少数人在创伤经历后会患上创伤后应激障碍。这些信息也可能导致新的方法来提高基于预防的治疗PTSD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.