Lateral septum activation as a central hub for reversing chronic stress-induced novelty-avoidance

Chronic stress is a major risk for mental disorders, particularly major depression, leading to behavioral impairments such as reduced novelty-seeking behavior. This study investigates the neurobiological mechanisms underlying chronic stress-induced deficits in novelty-driven exploratory behavior. Using a chronic unpredictable stress (CUS) model in mice, we observed significant reductions in novelty-seeking behavior during Y-maze and object location tasks, accompanied by decreased dorsal hippocampal activity. Chemogenetic activation of the dorsal hippocampus restored these behaviors, highlighting its critical role in novelty-seeking. In contrast, the ventral hippocampal activation failed to reverse the deficits, emphasizing a spatially specific function of the dorsal hippocampus. Further investigation revealed that activation of the ventral tegmental area (VTA) in CUS mice increased c-Fos expression in the lateral septum (LS) and alleviated CUS-induced novelty-avoidance. Furthermore, the LS received convergent projections from the dorsal hippocampal CA1 and VTA. Selective activation of LS-projecting pathways from the dorsal hippocampus and VTA drove novelty-seeking behavior in CUS mice. These findings suggest that LS activation is a pivotal node in enhancing novelty-seeking behavior impaired by chronic stress. By integrating spatial signals from the dorsal hippocampus with motivational inputs from the VTA, the LS emerges as a promising therapeutic target for interventions aimed to counteract chronic stress-induced novelty-avoidance. This study provides comprehensive insights into the neural underpinnings of exploratory behavior under chronic stress and underscores the translational potential of targeting the LS in stress-related disorders.