Modulating Stress Susceptibility and Resilience: Insights from miRNA Manipulation and Neural Mechanisms in Mice

This study explored the impact of microRNAs, specifically mmu-miR-1a-3p and mmu-miR-155-5p, on stress susceptibility and resilience in mice of different strains. Previous research had established that C57BL/6J mice were stress-susceptible, while NET-KO and SWR/J mice displayed stress resilience. These strains also exhibited variations in the serum levels of mmu-miR-1a-3p and mmu-miR-155-5p. To investigate this further, we administered antagonistic sequences (Antagomirs) targeting these microRNAs to C57/BL/6J mice and their analogs (Agomirs) to NET-KO and SWR/J mice via intracerebroventricular (i.c.v) injection. The impact of this treatment was assessed using the forced swim test. The results showed that the stress-susceptible C57/BL/6J mice could be transformed into a stress-resilient phenotype through infusion of Antagomirs. Conversely, stress-resilient mice displayed altered behavior when treated with Ago-mmu-miR-1a-3p. The study also examined the expression of mmu-miR-1a-3p in various brain regions, revealing that changes in its expression in the cerebellum (CER) were associated with the stress response. In vitro experiments with the Neuro2a cell line indicated that the Antago/Ago-miR-1a-3p and Antago/Ago-miR-155-5p treatments affected mRNAs encoding genes related to cAMP and Ca2+ signaling, diacylglycerol kinases, and phosphodiesterases. The expression changes of genes such as Dgkq, Bdnf, Ntrk2, and Pde4b in the mouse cerebellum suggested a link between cerebellar function, synaptic plasticity, and the differential stress responses observed in susceptible and resilient mice. In summary, this research highlights the role of mmu-miR-1a-3p and mmu-miR-155-5p in regulating stress susceptibility and resilience in mice and suggests a connection between these microRNAs, cerebellar function, and synaptic plasticity in the context of stress response.