Abstract TP19: Sex Differences In The Impact Of Stroke On Retrieval Of Remote Fear Memory And Mir20a-3p Treatment

Abstract

Preamble: Stroke is the major cause of death and disability worldwide. In addition to the immediate disability, stroke also results in diffuse secondary damage to regions distal to the ischemic region. Here we used the contextual fear conditioning test to assess the integrated functioning of affective and cognitive circuits after stroke in males and females, as well as the impact of mir20a-3p on this long term behavior. Methodology: Middle-aged (acyclic) females and males were injected stereotaxically with endothelin-1 in the left middle cerebral artery (MCA) region to create an ischemic stroke. Mir20a-3p mimics or scrambled oligo was administered i.v. 4h and 24h after stroke. Tests of sensory motor function including adhesive tape removal (ART) were performed prior to and after stroke. Long term cognitive changes were assessed by contextual fear conditioning (CFC) and the novel object recognition test (NORT). Results: Sensory motor deficits induced by stroke were abrogated with mir20a-3p treatment in both sexes. Contextual fear conditioning was evaluated by percent freezing during acquisition, extinction and retrieval. Sex differences were noted in fear extinction even prior to stroke, with males displaying resistance to extinction. At 30 days post-stroke, % freezing was no different from the pre-stroke extinction in females, while males showed a significant decrease in freezing rates after stroke, irrespective of treatment. In females, remote fear memory retrieval was reduced in vehicle-treated stroke rats, while the mir20a-3p treated group did not differ significantly from their pre-stroke levels. In contrast, both vehicle and mir20a-3p treated males showed a significant decline in freezing in response to fear retrieval. In female vehicle treated rats, the retrieval of remote fear memory continued to be impaired even at 100d post stroke(p<0.05), but preserved in miR20a-3p treatment group, indicating a persistent cognitive impairment and treatment effect. Conclusion: While mir20a-3p treatment improved sensory motor performance in both sexes, fear related memories were better preserved in females at 30 days, suggesting that neuroprotectants may have similar effects in the short term but may diverge in a sex specific manner in the chronic phase.