Abstract TMP111: The Detrimental Effects Of Post-stroke Social Isolation On Microglial Activation Is Mediated By MicroRNAs

Abstract

Introduction: Social Isolation (SI) is a risk factor for a wide array of psychological disorders. SI significantly enhances the incidence of developing neurological diseases, including stroke within the elderly population. Recent studies have shown microRNA (miRNA) signatures in the brain and the circulation are altered in social defeat models and under stressful environmental conditions. Although SI has shown to influence post-stroke recovery, potential targetable interventions to mitigate these inflammatory events are limited. Hypothesis: Post-stroke SI influences temporally distinct miRNA networks in the brain that regulate acute microglial activation and contribute to chronic depressive phenotypes. Methods: Aged (18-20 month) C57BL/6 male mice were subjected to 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion. Mice were randomly assigned to either continued pair housing (PH), or SI three days after a 60-minute MCAO. Mice were euthanized at post-stroke SI Day 1, 4, and 27 and ipsilateral hemispheres were collected for miRNA sequencing and downstream analysis. Behavioral tests and brain cell analysis using flow cytometry were performed using independent experimental cohorts. Results: The top 10 differentially expressed miRNAs were identified in SI vs. PH mice across three time points (FC ≥ 1.5, FDR adjusted P <0.05, n=4/group). Interactional network analysis revealed miR-466i-3p, miR-10a-5p, and miR-10b-5p as pivotal nodes that regulated the expression of the largest subset of genes involved in microglial-specific immune activation and chronic depression after stroke at SI D4 and D27, respectively. Flow cytometry analysis showed that microglia are significantly activated at post-stroke SI Day 4, as assessed by the downregulation of microglia-specific homeostatic protein purinergic receptor P2RY12 ( P <0.05, n=7-8/group) and interestingly, chronic SI induced depressive-like behaviors in aged stroke mice; consistent with our miRNA-based pathway analysis. Conclusion: This is the first comprehensive miRNA expression profiling study using NGS technique in aging, stroke, and SI. Our data revealed that SI-specific miRNAs are involved in microglial activation and chronic depression in aged mice.