Abstract WMP111: MicroRNAs As A Therapeutic Target To Reduce Microglial Activation After Post-stroke Social Isolation

Abstract

Introduction: Social isolation (SI) and loneliness are linked to all-cause mortality, as well as mortality from stroke and other vascular diseases. However, the mechanisms mediating the effects of social factors on stroke recovery are unknown. We hypothesized that differential expression of miRNAs contributes to the deleterious effects of post-stroke SI. Methods: Aged (18-20 months) C57BL/6 male mice were used to examine the detrimental effects of post-stroke SI on miRNA profiles in the brain. Mice were randomly assigned to either pair housing (PH), or single housing (SI) three days after a 60-minute transient right middle cerebral artery occlusion (MCAO). At this time point (post-stroke day 3), the infarct is complete, and was equivalent between groups, avoiding potential changes seen with differing infarct sizes. Temporal miRNA profiling of the ipsilateral hemisphere was assessed at two-time points (post-stroke SI D4 and D27). Brain cells were analyzed by flow cytometry. Results: Post-stroke SI resulted in significant alterations of distinct miRNA profiles within the brain across both acute and chronic time points (n=4/grp, FDR adjusted * p <0.05). MiRNA-mRNA interactional analysis revealed miR-10a-5p and miR-10b-5p as pivotal nodes within the pool of miRNAs that interacted with the largest subset of miRNAs for post-stroke at SI D4 and D27, respectively. Downstream pathway analysis utilizing an independent repository, the KEGG pathway showed 4 days of isolation resulted in the enrichment of pathways related to microglial activation and 27 days of isolation lead to the activation of neuronal-specific pathways that regulate cognition and motivation (FDR adjusted * p <0.05). Independent validation cohorts demonstrated significant activation of microglia at post-stroke SI D4 as assessed by the median fluorescence intensity (MFI) of purinergic receptor P2Y12 (P2RY12), in CD45 int CD11b + P2RY12 + cells in the brain. MFI of P2RY12 was significantly downregulated in post-stroke SI mice at D4 (n=7-8/grp, * p <0.05) compared to PH mice. Conclusions: These results support our hypothesis that post-stroke SI exacerbates microglia activation, and results in the differential expression of microglial pathway-related miRNAs.