Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset.

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset. [Display omitted] • LH is the most physiologically relevant input onto LHb in response to stress • LH fires with a unique pattern under stress that drives LHb burst • Repeated EPSP-burst pairings at LH-LHb pathway induce LTP • Emotional status can be incepted in naive mice by LH-LHb synaptic potentiation Zheng et al. reveal a circuit mechanism for processing chronic stress. Potentiating hypothalamus-to-habenula pathway leads to lasting changes of emotional status. This study makes a significant stride toward the elucidation of the neural circuit mechanisms underlying chronic-stress-induced depression and sheds light on early interventions before depression onset. [ABSTRACT FROM AUTHOR]