Acute stress induces circuit-specific alterations in mesolimbic and nigrostriatal inhibitory transmission and potentiates operant learning.

Acute stress can facilitate learning about stimuli that predict rewarding outcomes, yet whether stress similarly potentiates acquisition of reward-directed actions remains less well understood. Reward learning broadly depends on dopamine signaling within mesolimbic and nigrostriatal pathways. Dopamine transmission in the mesolimbic system is traditionally associated with cue-reward learning, whereas nigrostriatal dopamine signaling has been implicated in movement vigor and the acquisition of instrumental actions. Stress can alter dopamine transmission within these circuits and thereby influence reward learning. Previous work demonstrated that acute stress downregulates the potassium-chloride cotransporter KCC2 in ventral tegmental area GABA neurons. These stress-induced adaptations in inhibitory transmission enhance mesolimbic dopamine signaling and potentiate associative learning. Here, we show that prior exposure to acute restraint stress facilitates acquisition of operant sucrose self-administration in male and female rats. Enhanced learning was associated with increased temporal coincidence of GABA release events onto dopamine neurons and increased excitability of GABAergic inputs, alterations previously linked to enhanced dopamine signaling. These stress-induced adaptations exhibited marked circuit specificity within mesolimbic and nigrostriatal systems, selectively affecting inhibitory transmission onto dopamine neurons projecting to the nucleus accumbens lateral shell and dorsomedial striatum. Importantly, pharmacological enhancement of KCC2 function with CLP290 normalized inhibitory transmission within these pathways and attenuated stress-induced potentiation of operant learning. Together, these findings identify circuit-specific alterations in midbrain inhibitory signaling induced by acute stress that contribute to enhanced reward learning.