A small population of stress-responsive neurons in the hypothalamus-habenula circuit mediates development of depression-like behavior in mice

Accumulating evidence has shown that various brain functions are associated with experience-activated neuronal ensembles. However, whether such neuronal ensembles are engaged in the pathogenesis of stress-induced depression remains elusive. Utilizing activity-dependent viral strategies in mice, we identified a small population of stress-responsive neurons, primarily located in the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). These neurons serve as “starter cells” to transmit stress-related information and mediate the development of depression-like behaviors during chronic stress. Starter cells in the mLH and LHbM form dominant connections, which are selectively potentiated by chronic stress. Silencing these connections during chronic stress prevents the development of depression-like behaviors, whereas activating these connections directly elicits depression-like behaviors without stress experience. Collectively, our findings dissect a core functional unit within the LH-LHb circuit that mediates the development of depression-like behaviors in mice. [Display omitted] •Various stressors recruit mLH and LHbM neuronal subpopulations: “starter cells”•Starter cells form dominant connections in the mLH-LHb circuit•This mLH-LHbM circuit mediates the development of depression-like behaviors Utilizing an activity-dependent viral strategy, Zheng et al. identify a small population of stress-responsive neurons that they call “starter cells.” These neurons constitute a core functional unit of the hypothalamus-habenula circuit and mediate the development of depression-like behaviors in mice.