NMDA Mediated Processes in Extinction of Conditioned Fear

这一提议解决了神经科学中的一个基本问题，即感官刺激如何获得情感意义？更具体地说，一旦刺激不再预示危险，对刺激的恐惧反应是如何消失的？对厌恶刺激的恐惧联想的获得是通过一种被称为恐惧条件反射的经典条件反射形式发生的。在听觉恐惧条件反射中，音调条件刺激（CS）与足底电击非条件刺激（US）配对，导致获得对音调的恐惧反应，如冻结和反应抑制。恐惧条件反射在很大程度上取决于杏仁核， 人们对灭绝的神经机制知之甚少，在这种机制中，未加强的音调会导致恐惧反应减少。收敛的数据表明，腹内侧前额叶皮层（vmPFC），其中项目的杏仁核，是必要的巩固灭绝学习。阻断参与突触可塑性的NMDA谷氨酸受体可防止消退的巩固。这个提议的中心假设是，灭绝学习需要前额叶杏仁核回路中NMDA介导的可塑性。本研究以大鼠为实验对象，提出了三个目的来验证这一假说：1）我们将确定NMDA受体参与恐惧消退巩固的时间过程（假设：训练后向mPFC中注入NMDA受体拮抗剂或激动剂将分别损害或促进消退记忆和神经元的消退记忆， 塑性vmPFC）。2)我们将确定mPFC中抑制诱导的基因表达的时间过程（假设：消退以NMDA依赖的方式上调mPFC中的c-Fos和CREB）。3）我们将确定用vmPFC刺激增强消退记忆是否依赖于NMDA受体（假设：刺激诱导的消退记忆的增强将分别被NMDA拮抗剂或拮抗剂损害或增强）。本研究结合药理学、生理学和分子生物学的方法来探讨恐惧消退的神经机制。灭绝学习的缺陷被认为是焦虑症的基础，如创伤后应激障碍和特定恐惧症。这项研究可能会导致新的方法来加强灭绝，这可能会增加这些疾病的预防暴露疗法。

This proposal addresses a fundamental issue in neuroscience, namely, how do sensory stimuli acquire emotional significance? More specifically, how are fearful responses to stimuli extinguished once the stimuli no longer predict danger? The acquisition of fear associations to aversive stimuli occurs through a form of classical conditioning known as fear conditioning. In auditory fear conditioning, a tone conditioned stimulus (CS) is paired with a footshock unconditioned stimulus (US), resulting in the acquisition of fear responses to the tone such as freezing and response suppression. Fear conditioning depends critically on the amygdala, but less is known about the neural mechanisms of extinction, where unreinforced tones cause fear responses to decrease. Converging data suggests that the ventral medial prefrontal cortex (vmPFC), which projects to the amygdala, is necessary for consolidation of extinction learning. Blockade of NMDA glutamate receptors, which are involved in synaptic plasticity, prevents consolidation of extinction. The central hypothesis of this proposal is that extinction learning requires NMDA-mediated plasticity in prefrontal-amygdala circuits. Using rats, we propose three Aims to test this hypothesis: 1) We will determine the time course of NMDA receptor involvement in consolidation of fear extinction (Hypothesis: Post-training infusion of NMDA antagonists or agonists into the mPFC will impair or facilitate, respectively, extinction memory and neuronal plasticity vmPFC). 2) We will determine the time course of extinction-induced gene expression in mPFC (Hypothesis: Extinction upregulates c-Fos and CREB in the mPFC in an NMDA-deperdent manner), 3) We will determine if strengthening extinction memory with vmPFC stimulation depends on NMDA receptors (Hypothesis: stimulation-induced strengthening of extinction memory will be impaired or enhanced by NMDA antagonists or antagonists, respectively). This proposal combines pharmacological, physiological and molecular approaches to probe the neural mechanisms of fear extinction. Deficits m extinction learning are thought to underlie anxiety disorders such as post-traumatic stress disorder and specific phobia. This research is likely to lead to new methods to strengthen extinction, which could augment extinction-based exposure therapies for these disorders.