HES1 negatively regulates neurogenesis in the adult mouse dentate gyrus following traumatic brain injury

Abstract

Traumatic brain injury (TBI) results in the activation of neurogenesis, but it also triggers multiple cell signaling pathways that may lead to either cell damage or cell survival. In general, the repair processes following TBI are characterized by a failure to replenish the neuronal population entirely. To date, the factors that determine whether neurogenesis will be sufficient for the replacement of lost neurons following brain injury are not fully understood. Decreased activation of Hes1, a transcriptional repressor, is observed as neural differentiation proceeds, and this gene continues to play a role in the quiescence of stem cells into adulthood. Since Hes1 is negatively correlated with neurogenesis in adult rodents, the present study investigated whether this gene inhibits TBI-induced neurogenesis by use of adenovirus-mediated gene transfer to upregulate Hes1 expression in the dentate gyrus (DG) in a mouse model of TBI. Western blot analysis and immunofluorescent staining revealed increased Hes1 protein expression in the subgranular zone (SGZ) of the DG following adenovirus-Hes1 (Ad-Hes1) transfection and a decreased number of bromodeoxyuridine-positive and doublecortin-positive cells in the SGZ in the transfection group following TBI. These data indicated a negative association between the expression of Hes1 and adult neurogenesis following the induction of TBI. Furthermore, the present findings demonstrate the value of downregulating Hes1 expression following TBI to promote the initiation of endogenous neurogenesis, which may be of therapeutic value for patients with brain injuries.