Prefrontal Mechanisms in Retention of Fear Extinction

描述（由申请人提供）：恐惧消退是指条件刺激（CS）在没有厌恶的非条件刺激（US）的情况下反复出现时，条件恐惧反应的减少。灭绝并没有消除最初的CS-US联系，而是形成了一种新的记忆。因此，经过消退训练后，消退记忆的回忆成为与条件反射记忆竞争和抑制条件反射记忆的关键，从而控制不适当的恐惧。在大鼠中，内侧前额叶皮层（PFC）的边缘下区（IL, area 25）在消失记忆的保留和表达中起着关键作用；最近还涉及到其他PFC区域。在人类中，虽然越来越多的证据表明，消退回路可能在创伤后应激障碍（PTSD）中受损，但对健康或疾病中恐惧消退保留的中介解剖知之甚少。本应用的总体目的是在大鼠和人的前额叶中描绘出介导恐惧消退记忆的同源区域，然后在PTSD患者中测试这些前额叶区域的功能完整性。在Aim 1中，大鼠实验将使用药物失活、单单元记录和脑微刺激来检查特定前额叶区域在恐惧消退回忆中的作用。在目标2中，我们将使用功能性核磁共振成像和健康人类受试者绘制与恐惧消退回忆有关的PFC区域。在目标3中，我们将测试PTSD受试者与创伤暴露正常对照者在恐惧消退回忆期间的PFC功能障碍。这个翻译系列的实验有望推进关于跨物种灭绝，保留和回忆的神经机制的知识。在人类中，这些知识可能对阐明焦虑障碍的病理生理学和发展改进的基于灭绝的治疗至关重要。

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.