Cognitive Improvement Induced by Environment Enrichment in Chronic Cerebral Hypoperfusion Rats: a Result of Upregulated Endogenous Neuroprotection?

Environment enrichment (EE) has been demonstrated to improve the cognitive impairment that is induced by chronic cerebral hypoperfusion (CCH), but the underlying mechanism has not yet been elucidated. This study aimed to investigate the role of endogenous neuroprotection in EE-induced cognitive improvement in rats with CCH. Permanent bilateral common carotid artery occlusions (2-vessel occlusions (2VOs)) were performed to induce CCH in male adult Wistar rats. Four weeks after the surgeries, the rats were exposed to enriched environments for 4 weeks (6 h/day). Subsequently, we assessed the effects of EE on cognitive function, brain histone acetylation levels, neuroprotection-related transcription factors (i.e., cAMP response element-binding protein (CREB), phospho-CREB (p-CREB), hypoxia-inducible factor 1 (HIF-1) α, and nuclear regulatory factor 2 (Nrf2)), and oxidative stress and histological changes in the brain. After 2VO, the rats exposed to the EE treatment exhibited increased acetylation of histone 4 and increased p-CREB and Nrf2 protein levels in the brain. HIF-1α levels were increased after 2VO and reduced after EE treatment. The oxidative damage, histopathological changes in the brain, and spatial learning and memory impairments induced by 2VO were subsequently restored after EE treatment. These data indicate that EE promotes the acetylation of histone 4, regulates some neuroprotection-related transcription factors, attenuates oxidative damage, and protects against the histopathological damage to the brain induced by CCH. Together, the effects of EE in CCH rats might contribute to the recovery of spatial learning and memory.