Peroxisome proliferator-activated receptor-α activation by aspirin facilitates contextual fear extinction and modulates intrinsic excitability of dentate gyrus neurons

Abstract

AbstractPost-traumatic stress disorder (PTSD) is characterized by the incapability to extinguish learned fear. The persistent expression of fear and the impairment in fear extinction are often caused by the loss of contextual modulation of fear memories. The dentate gyrus (DG) of the hippocampus encodes contextual information associated with fear, and its activity is required for contextual fear acquisition and extinction. However, the molecular mechanisms underlying the DG-modulation on contextual fear are not well understood. Here we report that Peroxisome Proliferator-Activated Receptor-α (PPARα) in the DG is critical for maintaining the intrinsic excitability of DG granule neurons and is required for the extinction of contextual fear. Moreover, activation of PPARα by aspirin exerted a bi-phase modulation on DG granule neurons excitability and facilitated contextual fear extinction. Furthermore, using RNA-Seq transcriptome, we further identified Npsr1 as the downstream molecule mediating effects of PPARα on modulating DG function. Our findings revealed the direct evidence linking PPARα activation with DG neuronal excitability and contextual fear extinction and provide the biological basis of aspirin to assist extinction-based exposure therapies for PTSD.