Prefrontal-Amygdala Interactions in Fear Conditioning

描述（由申请人提供）：焦虑障碍，如创伤后应激障碍（PTSD），其特征是缺乏对环境线索的情绪反应调节。一种新兴的动物情绪调节模式是巴甫洛夫恐惧条件反射的消失，即在没有电击的情况下，之前与电击配对的音调会反复出现。恐惧消退受损被认为是造成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，消退是一种新的学习，像其他形式的学习一样，经历了习得、巩固和检索阶段。在此资助的前一个周期中进行的研究表明，边缘下前额叶皮层（IL）在大鼠的灭绝巩固中起着关键作用。IL神经元在消失后立即表现出NMDA受体依赖性的破裂，这种破裂与消失记忆的强度有关。IL中与灭绝相关的爆发可能反映了灭绝巩固所必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神经元的破裂和兴奋性，从而促进灭绝的巩固。在目的1中，我们将利用训练后的药理学失活来评估IL的候选输入（来自海马体、杏仁核基底外侧或丘脑中背侧）在恐惧消退巩固中的作用。在目标2中，我们将评估候选输入对IL神经元中与灭绝相关的爆发的贡献。这将通过以下方法来实现：1)在记录单个IL神经元的同时用药物灭活输入；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Aim 3中，我们将使用全细胞膜片钳记录来评估消失对IL神经元内在兴奋性的影响。我们将评估消失引起的IL兴奋性变化的时间过程，这可以通过注射电流引起的尖峰数量和爆发趋势来证明。然后，我们将确定这一过程在多大程度上取决于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个体在创伤经历后患上PTSD。本研究将探讨消退学习巩固的生理机制。了解前额皮质巩固恐惧消失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。这一信息也可能导致新的方法来提高基于灭绝的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.