Hesl, a Notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury

摘要

Hairy and enhancer of split 1 (Hesl), a downstream target of Notch signaling, has long been recognized as crucial in inhibiting neuronal differentiation. However, the role of Hesl following traumatic brain injury (TBI) in adult neurogenesis in the mouse dentate gyrus (DG) remains partially understood. Here, we investigate the role of Hesl in regulating neurogenesis in the DG of the adult hippocampus after TBI by up- or downregulating Hesl expression. First, adenovirus-mediated gene transfection was employed to upregulate Hesl in vivo. The mice were then subjected to TBI, and the hippocampal tissue was collected for Western blot analysis at designated times, pre- and post-injury. Moreover, the brain slices were stained for BrdU and doublecortin (DCX). We show that enhancing Hesl inhibits the proliferation and differentiation of neural precursor cells (NPCs) in the DG of the hippocampus soon after TBI. Second, downregulation of Hesl via RNA interference (RNAi) results in a significant increase in neuronal production and promotes the differentiation of NPCs into mature neurons in the DG, as assessed by BrdU and NeuN double staining. Furthermore, a Morris water maze (MWM) test clearly confirmed that the knockdown of Hesl improves the spatial learning and memory capacity of adult mice following injury. Taken together, these observations suggest that Hesl represents a negative regulator of adult neurogenesis post-TBI and that the precise space-time regulation of Hesl expression in the DG may promote the recovery of neural function following TBI.