Social Stress Exacerbates Focal Cerebral Ischemia in Mice

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Abstract
Background and Purpose — The purpose of the present study was to determine whether exposure to stress or elevated corticosterone concentrations in the days preceding cerebral ischemia exacerbates ischemic injury as assessed by histological and behavioral outcomes. Methods — For 7 consecutive days, male C57/BL6 mice were exposed to social stress for 45 minutes or injected with 1 mg/kg corticosterone or vehicle. The animals exposed to social stress were injected with either 1 mg/kg mifepristone, a glucocorticoid receptor antagonist, or the vehicle 30 minutes before stress. On the seventh day, all animals were trained in a passive avoidance task. Twenty-four hours after training, the animals were subjected to 60 minutes of intraluminal middle cerebral artery occlusion (MCAO) or sham surgery. At 72 hours of reperfusion, the animals were tested for retention of the passive avoidance task, and infarction size was determined. Results — Animals subjected to chronic social stress or treated with exogenous corticosterone before MCAO exhibited larger infarcts and reduced retention of passive avoidance compared with the nonstressed MCAO control. The effects of social stress on infarct volume and passive avoidance were reversed by pretreatment with mifepristone. There was no difference between stressed and control groups in physiological parameters or reduction of laser-Doppler flow signal during MCAO or reperfusion. Conclusions — Prior exposure to social stress increases infarction volume and exacerbates cognitive deficits associated with transient cerebral ischemia. The mechanism underlying the effects of stress on stroke outcome likely involves corticosterone acting through glucocorticoid receptors to increase subsequent ischemia-induced neuronal death.