A novel post-witness social defeat stress model induces robust dorsal hippocampal synaptic and behavioral deficits

Chronic stress disrupts brain homeostasis, contributing to cognitive and emotional dysfunction in patients with psychiatric disorders. Our recently developed post-witness social defeat stress (PWSDS) model, which combines physical and emotional stressors, reliably induces cognitive deficits and anxiety- and depression-like behaviors, accompanied by dorsal hippocampal (dHP) inflammation. Here, we investigated whether PWSDS concurrently impairs dHP neuronal plasticity. Behavioral tests confirmed PWSDS-induced spatial working and recognition memory deficits, anxiety-like and anhedonic behaviors. RNA sequencing revealed dHP transcriptomic disruptions in synaptic plasticity, neurogenesis, and apoptosis pathways, validated by synaptic ultrastructural deficits (reduced postsynaptic density protein 95, widened synaptic clefts), spine loss, and cellular alterations (reduced Ki-67⁺/DCX⁺ cells, increased TUNEL⁺ cells). Strikingly, functional neuroimaging and c-fos mapping in mouse hippocampus demonstrated selective dHP dysfunction, with suppressed BOLD activation (ALFF) and reduced density of c-fos-expressing neurons, while ventral hippocampal neural function remained intact. These findings identify PWSDS as a robust model of dHP-specific maladaptation, linking convergent synaptic, cellular, and functional disruptions to stress-induced cognitive impairment. Our work highlights the unique vulnerability of the dHP to chronic stress and provides a framework for targeting dorsoventral hippocampal subcircuits in stress-related disorders.