The effects of hippocampal miR-34c-5p on the age-related discrepancies in susceptibility to traumatic stress in the post-traumatic stress disorder mice model.

Post-traumatic stress disorder is a highly prevalent and debilitating psychiatric condition characterized by symptoms such as depression, anxiety, and persistent fear. Although traumatic stress significantly affects both adolescents and adults, its behavioral and neurobiological impacts may vary substantially across developmental stages. In this study, inescapable foot shock (IFS), a well-established model of traumatic stress that recapitulates aspects of fear memory reactivation, was used to investigate the underlying molecular mechanisms associated with age-dependent responses. Our results demonstrated that adult mice exhibited greater susceptibility to defensive, depressive, and dysphoric behaviors than adolescent mice under identical IFS conditions, as evidenced by adult mice displaying approximately twice the freezing duration compared with adolescents in the conditioned fear test. Concomitant with these behavioral abnormalities, adult mice also showed more pronounced deficits in neuroplasticity and increased neuronal injury relative to their adolescent counterparts. Mechanistically, miR-34c-5p was up-regulated in the hippocampus of adult mice compared with adolescent mice under IFS exposure. Notably, phospholipase C β1, a predicted target of miR-34c-5p and a molecular mediator of neuroplasticity, was markedly upregulated upon miR-34c-5p knockdown, accompanied by activation of the phosphatase and tensin homolog/protein kinase B/cAMP-response element binding protein signaling pathway. Taken together, this study demonstrated that miR-34c-5p might serve as a risk susceptibility factor accompanied by age alterations in the traumatic stress mice model. By modulating the phospholipase C β1/phosphatase and tensin homolog/protein kinase B/cAMP-response element binding protein signaling cascade, miR-34c-5p contributes to the observed age-related differences in affective disorders after IFS exposure. Hence, miR-34c-5p may act as a potential therapeutic target for mitigating post-traumatic stress disorder susceptibility across different developmental stages. SIGNIFICANCE STATEMENT: This study provides evidence that age-related vulnerability discrepancies were markedly presented in mice under inescapable foot shock exposure. MiR-34c-5p might serve as a susceptibility factor with age alterations in traumatic stress mice models. These findings reveal mechanisms by which miR-34c-5p/phospholipase C β1 axis may regulate age-dependent susceptibility differences in mice exposed to inescapable foot shock.