Adolescent stress recruits a latent amygdala-dopamine circuit to drive punishment-resistant reward-seeking

Abstract

Adolescent stress is a lifelong risk factor for addiction, but the underlying neural circuit changes remain unknown. Here, we show that chronic unpredictable stress in adolescent mice causes a prominent increase in punishment-resistant reward-seeking - behavior tightly linked to the diagnostic criteria for addiction - establishing a model for mechanistic investigation. Using this model, we find a "gain-of-function" in reward processing wherein persistent hyperexcitability in a subset of central amygdala (CeA) neurons projecting to the substantia nigra pars lateralis (SNL) disinhibits dopamine release in the tail of the striatum (TS), newly recruiting TS to participate in punishment-resistant reward-seeking. Normalizing circuit-specific CeA hyperexcitability or optogenetically counteracting excessive TS dopamine release prevented the increase in punishment resistance. These results identify a novel circuit mediator for the lifelong effects of adolescent stress on a core feature of addictive disorders, opening a new avenue for interventions targeted to at-risk populations with specific formative experiences.