Sex differences in cognitive impairment after focal ischemia in middle-aged rats and the effect of iv miR-20a-3p treatment

Abstract

Stroke is a major cause of death and disability worldwide and is also a leading cause of vascular dementia and Alzheimer's disease, with older women experiencing accelerated decline. Our previous studies show that intravenous (iv) injections of miR-20a-3p, a small noncoding RNA (miRNA) delivered after stroke improves acute stroke outcomes in middle-aged male and female rats. The present study tested whether mir-20a-3p treatment would also ameliorate stroke-induced cognitive decline in the chronic phase. Acyclic middle-aged females and age-matched male Sprague Dawley rats were subjected to middle cerebral artery occlusion using endothelin-1 or sham surgery, and treated iv with miR-20a-3p mimics or scrambled oligos at 4 hours, 24 hours, and 70 days post-stroke. Stroke resulted in a significant sensory motor deficit, while miR-20a-3p treatment reduced these deficits in both sexes. Cognitive impairment was assessed periodically for 3 months after stroke using contextual fear conditioning and the novel object recognition task. Overall, the tests of associative and episodic memory were affected by focal ischemia only in female rats, and miR-20a-3p ameliorated the rate of decline.

Keywords: Fear conditioning; Ischemic stroke; MiR-20a-3p; Sex differences; Vascular contributions to cognitive impairment and dementia (VCID).