Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters plasticity, neuromodulatory signaling, and neuronal activity in distributed networks, yet the field lacks a unifying framework for its varied consequences. Here we describe neuromodulatory and plasticity changes following aversive learning by using a learned helplessness paradigm, where ketamine restores escape behavior. Dopaminergic neuron activity in the ventral tegmental area systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamines effects are blocked by chemogenetic inhibition of dopamine signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is both regulated by aversive experience and recovered by ketamine in a dopamine-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising antidepressant.