Sex differences in stroke‐induced cognitive impairment and the impact of Mir20a‐3p treatment in middle‐aged Sprague Dawley rats

Abstract

AbstractBackgroundStroke is a leading risk factor for dementia. Our previous studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke and reduces sensory‐motor impairment in the acute phase (Branyan et al., 2021). In this study, we used a battery of tests to assess the integrated functioning of affective and cognitive circuits after stroke in males and females, as well as the impact of mir20a‐3pMethodMiddle‐aged (acyclic) females and males were subject to ischemic stroke using endothelin‐1 in the left middle cerebral artery (MCA) region. Mir20a‐3p mimics or scrambled oligo was administered i.v. 4h and 24h after stroke with a supplementary dose at 60d. Long‐term cognitive changes were assessed by contextual fear conditioning (CFC) and the novel object recognition test (NORT).ResultBoth males and females showed significant sensory‐motor impairment due to stroke in the acute phase, which was attenuated by Mir20a‐3p treatment. In the chronic phase, cognitive function was assessed by cued and contextual fear conditioning, evaluated by percent freezing during acquisition, retrieval, and extinction of fear memory. When measured 30, 60 and 100d after stroke, retrieval of fear memory was significantly reduced over time in sham and stroke males and females. However, linear regression analysis revealed that among females, the rate of decline of fear memory was significantly accelerated in the stroke group that received scrambled oligo treatment, while the rate of decline in the Mir20a‐3p group was similar to the sham group, indicating a protective effect of this drug. Surprisingly, stroke+ scrambled treated male rats did not show an accelerated decline. We further examined declarative memory (as assessed by the Novel Object Recognition Task) and noted that there was a decline over time in both males and females.ConclusionThis study shows that cognitive impairment is selectively affected by stroke and that despite the fact that acute sensory‐motor impairment is seen to a similar extent in males and females, stroke significantly affected the retrieval of fear memory in females but not males. Moreover, treatment with Mir20a‐3p abrogated this effect of stroke.