Prefrontal-Amygdala Interactions in Fear Conditioning

描述(申请人提供)：关于恐惧学习的研究改变了我们对焦虑症的病因和治疗的思考方式，如创伤后应激障碍(PTSD)。我们所知道的许多东西都是从动物模型中得出的，这些动物模型将冻结作为一种恐惧反应，这类似于创伤后应激障碍患者的夸大恐惧。然而，患有创伤后应激障碍的人也表现出对与其创伤事件相关的线索的持续回避。持续的回避会干扰日常活动，减少消亡的机会，从而延长创伤后应激障碍的症状。在这笔赠款的前一个周期中的研究表明，前额叶皮质(PL)通过投射到杏仁基底外侧核(BLA)来驱动冰冻，而边缘下部前额叶皮质(IL)通过投射到杏仁核内的抑制性中间神经元来介导消亡。为了研究回避，我们开发了一种平台中介的回避任务(PA)，即大鼠通过踏上附近的平台来避免足部电击。该平台保护大鼠免受休克，但也防止大鼠获得食物，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)是表达回避所必需的。然而，PL和NAC的失活会导致大鼠恢复冰冻行为。比较操作对不同行为(冻结和回避)的影响有助于区分产生恐惧的电路和产生回避的电路。在目标1中，我们将使用药理学、单单位记录和光遗传学工具来研究调节回避的回路。在目标2中，我们将研究调节回避反应消退的神经回路。在目标3中，我们将描述与灭绝失败(持续回避)有关的神经回路。我们计划使用光遗传技术来沉默和/或激活与回避表达和灭绝有关的通路，以修复持续回避者的电路。

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.