Environmental enrichment enhances recovery of function but exacerbates ischemic cell death.

Prior exposure to brief 'conditioning' episodes of ischemia protects hippocampal CA1 neurons against a subsequent more severe ischemic insult. However, protected cells exhibit abnormal function and as survival times are extended this ischemic tolerance dissipates and cells begin to die. In this study, we sought to determine whether environmental enrichment could alter the above pattern of delayed cell death and functional impairment in a gerbil model of ischemic tolerance. Gerbils received either ischemic preconditioning, 5 min of ischemia without preconditioning or sham surgery. Three days after ischemia, gerbils were placed in either an enriched environment or standard laboratory housing. Open field habituation was assessed 3, 7, 10, 30 and 60 days after ischemia. Subsequently, animals were trained in two versions (win-shift and win-stay) of a T-maze task. Following behavioral testing, extracellular CA1 field potential amplitudes and CA1 cell counts were determined. Initial open field activity was significantly higher in all experimental groups compared to sham animals (P<0.001). By 60 days, enriched ischemic preconditioned and enriched ischemic gerbils were not different than shams whereas non-enriched, ischemic preconditioned and ischemic gerbils continued to have higher activity scores (P<0.05). Preconditioned and enriched ischemic animals learned the win-shift T-maze problem as quickly as shams while non-enriched ischemic gerbils were severely impaired compared with all other groups (P<0.001). Only the sham and enriched preconditioned groups readily acquired the win-stay paradigm. CA1 field potential amplitudes were lower (P<0.05) in ischemic than sham gerbils irrespective of treatment. Surprisingly, CA1 cell counts were significantly lower (P<0.01) in enriched versus non-enriched ischemic preconditioned animals. These data demonstrate that early, intensive intervention after ischemia can improve functional outcome but that this is accompanied by increased brain damage. Careful consideration needs to be given to the timing of rehabilitation after stroke and related types of brain injury.