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

The dentate gyrus (DG) of the hippocampus encodes contextual information associated with fear, and cell activity in the DG is required for acquisition and extinction of contextual fear. However, the underlying molecular mechanisms are not fully understood. Here we show that mice deficient for peroxisome proliferator-activated receptor-alpha (PPAR alpha) exhibited a slower rate of contextual fear extinction. Furthermore, selective deletion of PPAR alpha in the DG attenuated, while activation of PPAR alpha in the DG by local infusion of aspirin facilitated extinction of contextual fear. The intrinsic excitability of DG granule neurons was reduced by PPAR alpha deficiency but increased by activation of PPAR alpha with aspirin. Using RNA-Seq transcriptome we found that the transcription level of neuropeptide S receptor 1 (Npsr1) was tightly correlated with PPAR alpha activation. Our results provide evidence that PPAR alpha plays an important role in regulating DG neuronal excitability and contextual fear extinction.