Escalating demand for learning during adolescence impairs social interaction by hyperactivating midbrain dopamine...

Chronic stress during adolescence is a major risk factor for adult psychiatric disorders, yet the long-term impact of learning-related aversive stress remains poorly understood. This study established an mice model of learning demand stress by escalating the fixed ratio (FR) number of escape responses to foot shocks in a negative reinforcement learning paradigm. Remarkably, mice that performed proficiently (high-susceptible, H-Su) during this aversive learning task in adolescent developed late-onset impairments in social interaction and novel object recognition in young adulthood, whereas poorly performing mice (low-susceptible, L-Su) exhibited normal behaviors. Furthermore, in vivo electrophysiology revealed a significant increase in spontaneous tonic firing of substantia nigra pars compacta (SNc) dopamine neurons selectively in H-Su mice. Whole-cell patch-clamp recordings showed increased intrinsic excitability (enhanced I_h currents and L-type calcium channel currents), reduced miniature excitatory postsynaptic current (mEPSC), and increased paired-pulse ratio in H-Su mice. Chemogenetic inhibition of SNc dopamine neurons in H-Su mice rescued social interaction deficits. In summary, our findings suggest that adolescent aversive learning stress can program late-onset SNc dopamine neuron hyperexcitability and behavioral dysfunctions in young adulthood.