Micro RNA 181c-5p: A promising target for post-stroke recovery in socially isolated mice

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 x 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 RT 2 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.

Long-Term Impact of Social Isolation and Molecular Underpinnings

“…This also partially rescued locomotor effects and ameliorated anxiety. Molecularly, the re-establishment of miR-181c levels reduced glial activation in isolated mice (Antony et al, 2020), a remarkable finding as glia activation after stroke has been related to increased inflammation and poorer prognosis (Xu et al, 2020). This data suggest that social isolation could compromise neuroinflammatory responses in the brain after stroke.…”

“…Interestingly, the level of miR-29a was also altered in other tissues such as the oral cavity (Yang et al, 2013), suggesting systemic responses to social isolation. miR-181c expression was also downregulated in the brain of isolated mice after stroke (Verma et al, 2018;Antony et al, 2020) while the levels of miR-181a are affected in blood of adult humans with a history of childhood trauma (Mavrikaki et al, 2019), suggesting that miR-181 family members could be a common target of stress responses in mammals.…”

“…Non-coding RNAs such as miRNAs and lncRNAs are major regulators of gene expression across the animal kingdom (Jonas and Izaurralde, 2015;Engreitz et al, 2016;Kim et al, 2016;Li and Fu, 2019). Although different lines of evidence suggest that ncRNAs are transcriptionally altered in the brain of rodents after social isolation, direct and functional evidence on their contribution to behavioral and physiological consequences of prolonged social isolation is still sparse (Verma et al, 2018;Antony et al, 2020;Chang et al, 2020). However miRNAs and lncRNAs were proven to modulate social behaviors which are also altered as the result of prolonged social isolation (Haramati et al, 2011;Dias et al, 2014;Issler et al, 2014;Jin et al, 2016;Zhu et al, 2017;Cheng et al, 2018;Lackinger et al, 2019;Labonté et al, 2020;Ma et al, 2020).…”

“…While it is clear that miRNAs are transcriptionally dysregulated by social isolation and some of them directly modulate behaviors characteristic of chronically isolated animals, manipulating specific miRNAs in vivo has recently emerged as a promising therapeutic approach to ameliorate the negative effects of social isolation on behavior and physiology (Verma et al, 2018;Antony et al, 2020;Chang et al, 2020). For example, inhibition of miR-206 in the hippocampus of socially isolated mice or intranasal administration of an antagonist of miR-206 eliminates stress-provoked attacks via BDNF upregulation (Chang et al, 2020).…”

“…For example, inhibition of miR-206 in the hippocampus of socially isolated mice or intranasal administration of an antagonist of miR-206 eliminates stress-provoked attacks via BDNF upregulation (Chang et al, 2020). Also, social isolation can negatively influence stroke recovery in humans and rodents and this has been associated with the dysregulation of miRNAs, such as miR-181c and miR-141, in a mouse model of stroke (Verma et al, 2018;Antony et al, 2020). Mice that were socially isolated post-stroke showed a gradual decrease in the levels of miR-181c in the ipsilateral cortex as compared with group-housed mice also subjected to stroke.…”