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Micro RNA 181c-5p: A promising target for post-stroke recovery in socially isolated mice
Maria Antony1, Victoria Scranton2, Pranay Srivastava2
1Department of Neuroscience, UConn Health, Farmington, CT 06032, USA; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06268, USA.
Abstract:
Dysregulation of microRNAs (miRNAs) has been tied to several neurological disorders, including ischemic stroke. It has also been established that social environments can modulate miRNA profiles. We have previously shown that post-stroke social isolation (SI) is linked to poor stroke outcomes and that miR-181c-5p emerged as one of few lead miRNAs that was downregulated in both stroke and SI. Therefore, in this study we examined the potential role of miR-181c-5p mimic in reversing the detrimental effects of post-stroke SI. Two to three-month-old C57BL/6 male mice were pair-housed (PH) for at least two weeks. After two weeks, mice underwent stroke survival surgery using middle cerebral artery occlusion (MCAO) and were randomly assigned to one of two housing conditions: stroke isolation (ST-ISO) or stroke pair-housing with a healthy partner (ST-PH). ST-ISO mice were randomized to receive either miR-181c-5p mimic or a scrambled RNA (7 mg/kg i.v./day×drug) control at 24 h and 48 h after stroke. The effects of miR-181c-5p mimic treatment were evaluated at 1, 3, and 7 days after stroke at histological, behavioral, and biochemical levels. Target genes of miR-181c-5p were then analyzed by qPCR using an RT2 Profiler qPCR Array of pre-coated miR-181c gene targets. Temporal profile expression data suggested that miR-181c-5p was significantly downregulated (p < 0.05 vs ST-PH) up to 7 days after post-stroke SI. MiR-181c-5p mimic treatment significantly increased miR-181c-5p expression in brain tissue and showed partial swift recovery in sensorimotor deficit. Target gene analysis identified downregulation of several calcium signaling-related genes, e.g., Cpne2 and Gria 1 & 2 after miR-181c-5p mimic treatment. In summary, present data suggests that miR-181c-5p is a potential target for post-stroke SI. Data also suggests that genes related to calcium and glutamate signaling might be involved in the beneficial effect of the miR-181c-5p mimic.
Insights
Social isolation after stroke worsens outcomes, but miR-181c-5p mimic treatment shows promise. This study found that restoring miR-181c-5p levels improved sensorimotor deficits and identified potential calcium and glutamate signaling pathways involved in recovery.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNA (miRNA) dysregulation is linked to neurological disorders like ischemic stroke.
- Social environments can influence miRNA expression, and post-stroke social isolation (SI) negatively impacts stroke outcomes.
- miR-181c-5p was previously identified as downregulated in both stroke and SI conditions.
Purpose of the Study:
- To investigate the therapeutic potential of a miR-181c-5p mimic in mitigating the adverse effects of post-stroke social isolation.
- To analyze the impact of miR-181c-5p mimic treatment on histological, behavioral, and biochemical markers post-stroke.
- To identify target genes regulated by miR-181c-5p in the context of post-stroke SI.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in mice, followed by assignment to stroke isolation (ST-ISO) or stroke pair-housing (ST-PH) conditions.
- Administration of miR-181c-5p mimic or a scrambled RNA control to ST-ISO mice at 24 and 48 hours post-stroke.
- Evaluation of stroke outcomes at 1, 3, and 7 days, including behavioral tests, histological analysis, and qPCR for target gene expression.
Main Results:
- miR-181c-5p expression remained significantly downregulated in ST-ISO mice up to 7 days post-stroke compared to ST-PH mice.
- Treatment with miR-181c-5p mimic increased miR-181c-5p levels in brain tissue and led to partial, rapid recovery of sensorimotor deficits.
- Target gene analysis revealed downregulation of calcium signaling-related genes, such as Cpne2 and Gria1/2, following miR-181c-5p mimic treatment.
Conclusions:
- miR-181c-5p represents a potential therapeutic target for addressing the negative consequences of post-stroke social isolation.
- The beneficial effects of miR-181c-5p mimic treatment may involve modulation of calcium and glutamate signaling pathways.
