Prefrontal-Amygdala Interactions in Fear Conditioning

描述（由申请人提供）：对恐惧学习的研究改变了我们对创伤后应激障碍（PTSD）等焦虑症的病因和治疗的看法。我们所知道的大部分都来自动物模型，将冰冻作为一种恐惧反应，类似于创伤后应激障碍患者的过度恐惧。然而，患有创伤后应激障碍的人也表现出持续回避与他们的创伤事件有关的线索。持续的逃避干扰了日常活动，减少了消失的机会，从而延长了PTSD症状。在此资助的前一个周期的研究表明，前边缘前额叶皮层（PL）通过投射到基底外侧杏仁核（BLA）来驱动冻结，而边缘下前额叶皮层（IL）通过投射到杏仁核内的抑制性中间神经元来介导灭绝。为了研究回避，我们开发了一个平台介导的回避任务（PA），大鼠通过踩到附近的平台来避免脚震。这个平台可以保护大鼠免受电击，但也可以防止大鼠获得食物，类似于临床回避。此外，大约30%的大鼠无法消除这种回避反应，即使在恐惧消失后也表现出持续的回避。初步数据表明，PL、BLA和伏隔核（NAc）是回避表达所必需的。然而，PL和NAc的失活导致大鼠恢复冻结行为。比较操纵对不同行为（冻结和回避）的影响可以帮助区分产生恐惧的回路和产生回避的回路。在目标1中，我们将使用药理学、单单元记录和光遗传学工具研究介导回避的电路。在目标2中，我们将研究介导回避反应消退的神经回路。在目标3中，我们将描述与消退失败（持续回避）有关的神经回路。我们计划使用光遗传学技术来沉默和/或激活涉及回避表达和消除的途径，以修复持久回避者的电路。

DESCRIPTION (provided by applicant): Research on fear learning has transformed the way we think about the etiology and treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Much of what we know is derived from animal models measuring freezing as a fear response, which resembles exaggerated fear in PTSD sufferers. However people suffering from PTSD also show persistent avoidance of cues associated with their traumatic event. Persistent avoidance interferes with the daily activities, and reduces the opportunity for extinction, thus prolonging PTSD symptoms. Studies in the previous cycle of this grant have shown that the prelimbic prefrontal cortex (PL) drive freezing via projections to the basolateral amygdala (BLA), whereas the infralimbic prefrontal cortex (IL) mediates extinction via projections to inhibitory interneurons within the amygdala. To study avoidance, we have developed a platform-mediated avoidance task (PA) were rats avoid footshock by stepping onto a nearby platform. The platform protects the rat from shock, but also prevents the rat's access to food, similar to clinical avoidance. Furthermore, approximately 30% of rats are unable to extinguish this avoidance response, showing persistent avoidance even after extinction of fear. Preliminary data shows that PL, BLA and the nucleus accumbens (NAc) are necessary for expression of avoidance. However, inactivation of PL and NAc causes rats to revert to freezing behavior. Comparing the effects of manipulations on different behaviors (freezing and avoidance) can help distinguish fear-generating circuits from avoidance-generating circuits. In Aim 1, we will investigate the circuits mediating avoidance using pharmacological, single-unit recording and optogenetic tools. In Aim 2, we will study the neural circuits mediating the extinction of avoidance responses. In Aim 3 we will characterize the neural circuits involved in extinction failure (persistent avoidance). We plan to use optogenetic techniques to silence and/or activate pathways involved in avoidance expression and extinction in order to repair circuits in persistent avoiders.