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.
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