Gene expression profile underlying neuronal survival and functional recovery by very early exposure to an enriched environment after hypoxic-ischemic brain injury

Abstract

Early rehabilitation is considered to have favorable outcomes for stroke patients. However, the optimal strategy for early rehabilitation is unclear because there is currently limited data on the effects of very early initiation of rehabilitation based on voluntary exercise (VE). Environmental enrichment (EE) is a therapeutic paradigm for laboratory animals that consists of complex combinations of physical, cognitive, and social stimuli and VE. During the hyperacute phase of ischemic stroke, upregulation of Fas/FasL-mediated apoptosis is observed. Therefore, inhibition of Fas/FasL-signaling may be a promising neuroprotective strategy. Few studies delineated the effect of EE on apoptosis in an experimental model of hyperacute stroke. The aim of the study is to determine whether hyperacute exposure to EE can regulate Fas/FasL-mediated apoptosis following hypoxic-ischemic brain injury and improve neurobehavioral function. C57Bl/6 mice were randomly assigned to either EE or standard cage (SC) within 3 hours after hypoxic-ischemic brain injury for 2 weeks. Neurobehavioral tests, transcriptome analysis, western blot, and immunohistochemistry were performed in cerebral cortex and hippocampus, and total infarct volume was calculated. Compared with SC, hyperacute exposure to EE was associated with greater improvement in anxiety, motor function, and cognition, reduced total infarct volume, and decreased neuronal death. It significantly downregulated Fas/FasL-mediated apoptosis, decreased expression of Fas, FADD, cleaved caspase-8/caspase-8, cleaved caspase-3/caspase-3, as well as Bax/Bcl-2 in both regions. Overall, the results of this study implicate very early exposure to EE/VE as a promising neuroprotective candidate for therapeutic translation after stroke by effective inhibition of extrinsic as well as intrinsic apoptotic pathways.