CaMKII Neurons in the Dentate Gyrus Are Involved in Regulating Cognitive Impairment in Mice Induced by Stress Caused...

Post-stress cognitive impairment (PSCI) is defined as a persistent neuropsychiatric condition characterized by deficits in memory consolidation, executive functioning, and environmental interaction following exposure to violent stress. Despite its high incidence, PSCI remains underdiagnosed and lacks effective therapeutic strategies, posing a substantial societal burden and highlighting a critical gap in neuropsychiatric research. A major constraint in mechanistic studies is the persistent reliance on conventional paradigms, notably the Y-maze and novel object recognition test. Their limited sensitivity and poor translational relevance to human cognitive dysfunction, compounded by slow methodological innovation, significantly impede progress. Furthermore, the specific brain regions or neuronal populations contributing to PSCI pathogenesis are insufficiently explored. To address this, we assessed post-stress cognitive impairment in mice using a triple approach: Skinner box assays, traditional behavioral paradigms, and integrated 3D ethological analysis. This multi-method framework provides novel insights for refining animal models and advancing mechanistic understanding. Using c-Fos-based whole-brain screening, we identified the dentate gyrus (DG) as a key region involved in PSCI. Stress caused by violence markedly increased activity in DG CaMKII-expressing neurons. Chemogenetic inhibition of these neurons effectively alleviated stress-induced mild cognitive impairment phenotypes. In summary, by applying novel behavioral assessment tools, this study demonstrates that DG CaMKII neurons play a critical role in regulating post-stress cognitive impairment.