Prefrontal Amygdala Interactions in Fear Conditioning

描述（由申请人提供）：该提案解决了情绪研究中的一个基本问题，即恐惧消退的神经回路是什么？恐惧消退是指在无条件刺激（US）的情况下，条件刺激（CS）重复出现时，恐惧反应的减少。自巴甫洛夫以来，我们已经知道灭绝并没有消除CS-US关联，而是一种新的学习。虽然恐惧条件反射的神经回路已经被很好地理解，但对恐惧消退的神经回路知之甚少，这被认为是创伤后应激障碍（PTSD）和其他焦虑症的损害。利用大鼠的听觉恐惧条件反射，我们将研究恐惧消退的神经回路。杏仁核对于条件性恐惧的获得和表达至关重要，而与杏仁核紧密相连的内侧前额叶皮层（mPFC）则与消退学习的巩固和表达有关。这一提议的中心假设是，前额叶-杏仁核系统介导了恐惧消退的获得、巩固和表达。具体目标1将检查前额叶杏仁核系统在恐惧消退的获取阶段，使用损伤技术和行为大鼠的单单位记录（假设：杏仁核的基底核负责恐惧消退的短期记忆，如损伤缺陷和基底神经元的亚群所示，在消退期间增加它们的音调反应）。具体目标2将在恐惧消退的巩固阶段检查前额叶杏仁核系统，使用药理学失活、蛋白质合成和NMDA受体的局部抑制以及行为大鼠的单单位记录（假设：消退触发随后的NMDA激活和蛋白质合成，导致前额叶紧张反应增加和长期消退记忆）。具体目标3将在麻醉大鼠中使用电刺激和单单位记录来检查恐惧消退的表达阶段中的前额叶-杏仁核系统（假设：消退后前额叶神经元的活动增加通过抑制杏仁核中枢神经元对条件性音调的反应来减少冻结）。对恐惧消退的电路和药理学的详细了解可以改善目前基于创伤后应激障碍和恐惧症的治疗方法，这些方法依赖于消退学习。

DESCRIPTION (provided by applicant): This proposal addresses a fundamental issue in emotion research, namely, what are the neural circuits of fear extinction? Fear extinction is the decrease in fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US). Since Pavlov, we have known that extinction does not erase the CS-US association but is new learning. While the neural circuits of fear conditioning are well understood, little is known about the neural circuits of fear extinction, which are thought to be compromised in post-traumatic stress disorder (PTSD) and other anxiety disorders. Using auditory fear conditioning in rats, we will investigate the neural circuits of fear extinction. While the amygdala is critical for acquisition and expression of conditioned fear, the medial prefrontal cortex (mPFC), which is reciprocally connected with the amygdala, has been implicated in the consolidation and expression of extinction learning. The central hypothesis of this proposal is that the prefrontal - amygdala system mediates the acquisition, consolidation, and expression of fear extinction. Specific Aim 1 will examine the prefrontal-amygdala system in the acquisition phase of fear extinction, using lesion techniques and single-unit recording in behaving rats (hypothesis: the basal nucleus of the amygdala is responsible for short-term memory for fear extinction, as indicated by lesion deficits and a sub-population of basal neurons that increase their tone responses during extinction). Specific Aim 2 will examine the prefrontal-amygdala system in the consolidation phase of fear extinction, using pharmacological inactivation, local inhibition of protein synthesis and NMDA receptors, and single-unit recording in behaving rats (hypothesis: extinction triggers subsequent NMDA activation and protein synthesis resulting in increased prefrontal tone responses and long-term extinction memory). Specific Aim 3 will examine the prefrontal-amygdala system in the expression phase of fear extinction, using electrical stimulation, and single-unit recording in anesthetized rats (hypothesis: increased activity of prefrontal neurons after extinction reduces freezing by inhibiting the response of amygdala central neurons to conditioned tones). A detailed knowledge of the circuits and pharmacology of fear extinction could improve current exposure-based treatments for PTSD and phobias, which rely on extinction learning.