Disinhibition of ventral tegmental area during initial punishment learning causes enduring punishment insensitivity

Abstract Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTA DA ), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTA DA activity and GABA input across punishment learning, and test their causal contribution to behavior. VTA DA activity and GABA input phasically increased to response-elicited outcomes, with VTA DA activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABA A receptors in VTA or chemogenetically activating VTA DA neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTA DA inhibition during punishment learning.