Abstract WP233: Sex Differences In The Impact Of Focal Ischemia On Cognitive Impairment In Middle-aged Rats And The Effect Of Iv Mir20a-3p Treatment

Abstract

Introduction: Our previous studies show that the small non-coding RNA, mir20a-3p, is neuroprotective for stroke in the acute phase (Branyan et al., 2021). Here we used a battery of tests to assess the integrated functioning of affective and cognitive circuits in the chronic phase of stroke and the impact of mir20a-3p. Methods: Middle-aged (12-month-old) female and male Sprague-Dawley rats were subject to middle cerebral artery occlusion (MCAo) using endothelin-1. Mir20a-3p mimic or scrambled oligo was administered i.v. 4h, 24h, and 60d after stroke. Cognitive changes (30-100d after stroke) were assessed by contextual fear conditioning (CFC) and the novel object recognition test (NORT). Blood samples were collected at 60 and 100d to assess cytokines and short chain fatty acids. Results: MCAo impaired sensory motor performance in the acute phase, which was ameliorated by Mir20a-3p treatment. At 30, 60 and 100d after stroke, retrieval of fear memory was significantly reduced over time in sham and stroke males and females. However, the rate of decline of fear memory was significantly accelerated in the scramble treated female stroke group, but not in the scramble treated male stroke group. Similarly, declarative memory (NORT) declined in all female groups at 30 days post stroke and continued to worsen only in the stroke+ scrambled treated group. Male rats did not show any change in performance due to stroke or its treatment at comparable time points of testing. Hyperintensities in the forebrain of T2 weighted MRI images were decreased in mir20a-3p treated stroke females compared to males. Correlation analysis showed that in females at 60d post stroke, the extent of Remote Fear memory recall was highly positively correlated with the levels of the SCFA butyric acid (+0.81) and valeric acid (+0.61), as well as the pro-inflammatory cytokine IL-12p70 (+0.64), and the serine hydrolase, butyrylcholinesterase (+0.71). Conclusion: Although acute sensory-motor impairment is seen to a similar extent in males and females, stroke significantly affected cognitive function in females but not males, and this was associated with alterations in inflammatory mediators. Mir20a-3p, which is predicted to repress inflammatory analytes, abrogated stroke effects in females.