Prefrontal Mechanisms in Retention of Fear Extinction

描述（由申请人提供）：恐惧消退是条件恐惧反应的减少，通常发生在条件刺激（CS）在不存在厌恶性非条件刺激（US）的情况下重复出现时。 灭绝并没有抹去最初的CS-US关联，而是形成了一个新的记忆。因此，在消退训练后，消退记忆的回忆变得至关重要，可以与条件记忆竞争并抑制条件记忆，从而控制不适当的恐惧。在大鼠中，内侧前额叶皮质（PFC）的边缘下区（IL，25区）已被证明在保留和表达的消光记忆中发挥关键作用;最近，其他PFC区域也有牵连。在人类中，虽然汇聚的证据表明，灭绝电路可能在创伤后应激障碍（PTSD）中受到损害，但对健康或疾病中恐惧灭绝保留的介导解剖学知之甚少。本申请的总体目标是描绘大鼠和人类中介导恐惧消退回忆的同源前额叶区域，然后测试PTSD患者中这些前额叶区域的功能完整性。在目标1中，大鼠实验将使用药理学失活、单单位记录和脑微刺激来检查特定的前额叶区域在恐惧消退回忆中的作用。在目标2中，我们将使用功能性MRI和健康人类受试者绘制涉及恐惧消退回忆的PFC区域。在目标3中，我们将测试PTSD受试者与创伤暴露的正常对照者在恐惧消退回忆过程中的PFC功能障碍。这一系列的实验有望推进关于物种灭绝、保留和回忆的神经机制的知识。在人类中，这些知识可能是阐明焦虑症的病理生理学和开发改进的预防性治疗的关键。

DESCRIPTION (provided by applicant): Fear extinction is the decrease of conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS-US association, but rather forms a new memory. Thus, after extinction training, the recall of extinction memory becomes critical to compete with and inhibit the conditioning memory, thereby controlling inappropriate fear. In rats, the infralimbic region (IL, area 25) of the medial prefrontal cortex (PFC) has been shown to play a critical role in the retention and expression of extinction memory; recently additional PFC areas have also been implicated. In humans, while converging evidence suggests that extinction circuitry may be compromised in post-traumatic stress disorder (PTSD), little is known about the mediating anatomy of fear extinction retention in health or disease. The overall aim of this application is to delineate the homologous prefrontal areas in rats and humans that mediate fear extinction recall, and then test the functional integrity of these prefrontal areas in PTSD patients. In Aim 1 rat experiments will examine the role of specified prefrontal areas in fear extinction recall, using pharmacological inactivation, single-unit recording, and brain microstimulation. In Aim 2 we will map PFC areas involved in fear extinction recall using functional MRI and healthy human subjects. In Aim 3 we will test for PFC dysfunction during fear extinction recall in subjects with PTSD vs. trauma-exposed normal controls. This translational series of experiments promises to advance knowledge regarding the neural mechanisms underlying extinction retention and recall across species. In humans, such knowledge may be critical for elucidating the pathophysiology of anxiety disorders and developing improved extinction-based treatments.