Abstract T MP16: Impact of Circadian Clock Disruption on Infarct Volume in an Ischemic Stroke Model
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Background: At perimenopause, women show increasing incidence of ischemic stroke and poor prognosis for recovery, suggesting that declining ovarian steroid levels alter the risk for neurovascular disease. Peripheral circadian clocks throughout the body may provide integral links between cycling levels of estrogen and neuroprotective responses. Circadian rhythm disruption may be a key factor coupling risk factors (ie, diabetes, obesity) to cardiovascular pathologies. Thus, the present study used an ischemic stroke model to determine whether environmental disruption of circadian rhythms in young adult female rats modulates estrous cyclicity and induces corresponding increases stroke volume and functional deficits similar to that observed in middle-aged females. Methods: Adult (5 mo) female rats were exposed for 8wks to either a fixed or shifted (12hr advance/5d) LD 12:12 cycle and then subjected to middle cerebral artery occlusion (MCAo). Pre and post sensorimotor testing was performed to assess functional deficits. Animals were terminated at 5d post MCAo. Brains processed for histological analysis of infarct volume. Before and after experimental manipulations, estrous cyclicity was assessed via vaginal smears in parallel groups of animals. Results: Circadian activity rhythms stably entrained to the fixed LD cycle but were severely disrupted in shifted LD rats. In contrast to the regular estrous cycles (~7d) in fixed LD animals, cyclicity was abolished and persistent estrous was evident in all shifted LD rats. Total infarct volume in shifted LD rats (0.47) was significantly increased (p<0.05) relative to that observed in fixed LD controls (0.27). Sensorimotor testing revealed a similar trend in which MCAo-induced functional deficits in shifted LD animals were greater than those in fixed LD rats. Conclusion: These results suggest that the loss of estrous cyclicity in young females due to circadian disruption exacerbates stroke outcomes, supporting the hypothesis that in females, middle-age may precipitate circadian disturbances that link reproductive aging to pathological changes in neuroprotective responses to injury. Supported by AHA 14GRNT18370013 to DE
