NMDA Mediated Processes in Extinction of Conditioned Fear

这一建议解决了神经科学中的一个基本问题，即感觉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，对刺激的恐惧反应如何消失？获得与厌恶刺激相关的恐惧是通过一种被称为恐惧条件反射的经典条件反射来实现的。在听觉恐惧条件反射中，音调条件刺激(CS)与足电击非条件刺激(US)配对，导致获得对音调的恐惧反应，如冻结和反应抑制。恐惧条件作用在很大程度上依赖于杏仁核，但 人们对灭绝的神经机制知之甚少，在这种机制下，没有加强的音调会导致恐惧反应减少。汇聚的数据表明，投射到杏仁核的腹侧内侧前额叶皮质(VmPFC)对于巩固消亡学习是必要的。阻断参与突触可塑性的NMDA谷氨酸受体，可以防止灭绝的巩固。这一提议的中心假设是，消亡学习需要前额叶-杏仁核回路中NMDA介导的可塑性。利用大鼠，我们提出了三个目的来验证这一假说：1)我们将确定nmda受体参与巩固恐惧消退的时间进程(假设：训练后将nmda拮抗剂或激动剂注入mPFC将分别损害或促进消亡记忆和神经元 塑性vmPFC)。2)我们将确定消退诱导的mPFC基因表达的时程(假设：消退以NMDA依赖的方式上调mPFC中的c-Fos和CREB)；3)我们将确定刺激vmPFC增强消退记忆是否依赖于NMDA受体(假设：NMDA拮抗剂或拮抗剂将分别削弱或增强刺激诱导的消退记忆的增强)。这一建议结合了药理学、生理学和分子生物学的方法来探索恐惧消退的神经机制。学习障碍被认为是诸如创伤后应激障碍和特定恐惧症等焦虑症的根源。这项研究可能会导致新的方法来加强灭绝，这可能会增加基于灭绝的暴露疗法来治疗这些疾病。

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.