DORSAL CA3 NEURAL ACTIVITY MEDIATES WITNESSING STRESS- INDUCED RECOGNITION MEMORY DEFICITS IN ADOLESCENT MALE MICE

Abstract Background Witnessing traumatic events is a common adverse life experience in children or adolescents and is associated with several adverse effects. The role of hippocampus in adolescent witnessing stress needs to be uncovered. Aims & Objectives To establish the CWSD model in adolescent male mice and reveal the involvement of hippocampus in CWSD-induced cognitive and emotional problems. Method Cognitive and anxiety-like behaviors were assessed in adolescent male mice exposed to chronic witnessing social defeat (CWSD) stress. Immediate early gene c-fos immunostaining was used to examine the neuronal functional activity of hippocampus. Chemogenetic and pharmacological experiments were performed to investigate the causal involvement of dorsal and ventral CA3 neurons in CWSD-induced behavioral deficits. Results CWSD impaired cognitive function and increased anxiety levels in adolescent male mice and the behavioral deficits persisted into adulthood. Stressed mice had more dCA3 neurons activated during the spatial object recognition test and fewer vCA3 neurons activated during the light- dark box task. Chemogenetic activation and inhibition of dCA3 neuron activity specifically mimicked and reversed CWSD-induced recognition memory deficits, not anxiety-like behaviors. In comparison, both inhibiting and activating vCA3 neurons increased anxiety-like behaviors in adolescent mice. Chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dCA3 neurons and impaired recognition memory in CWSD mice. Discussion & Conclusion These results suggest that dorsal CA3 neural activity mediates CWSD-induced recognition memory deficits in adolescent male mice, which shed light on the pathophysiology of adolescent CWSD-induced adverse effects and provide preclinical evidence for early treatment of stress-induced cognitive deficits.