VTA excitatory neurons impact reward-driven behavior by modulating infralimbic cortical firing.

The functional dichotomy of anatomical regions of the medial prefrontal cortex (mPFC) has been tested with greater certainty in punishment-driven tasks, and less so in reward-oriented paradigms. In the infralimbic cortex (IL), known for behavioral suppression (STOP), tasks linked with reward or punishment are encoded through firing rate decrease or increase, respectively. Although the ventral tegmental area (VTA) is the brain region governing reward/aversion learning, the link between its excitatory neuron population and IL encoding of reward-linked behavioral expression is unclear. Here, we present evidence that IL ensembles use a population-based mechanism involving broad inhibition of principal cells at intervals when reward is presented or expected. The IL encoding mechanism was consistent across multiple sessions with randomized rewarded target sites. Most IL neurons exhibit FR suppression for reward acquisition intervals (T1), and subsequent exploration of a target without the reward (T2). Furthermore, FR suppression in putative IL ensembles persisted for intervals that followed reward-linked target events. Pairing VTA glutamate inhibition with reward acquisition events reduced the weight of reward-target association expressed as a lower affinity for previously rewarded targets. For these intervals, fewer IL neurons per mouse trial showed FR decrease and were accompanied by an increase in the percentage of units with no change in FR or elevated FR. Together, we conclude that VTA glutamate neurons are likely involved in establishing IL inhibition states that encode reward acquisition, and subsequent reward-target association when a reward is omitted.