Cortico-Striatal Control over Adaptive Goal-Directed Responding Elicited by Cues Signaling Sucrose Reward or Punishment.

The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signaling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long-Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signaling reward, and to avoid pressing the same lever in the presence of another cue signaling punishment. Postacquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core, or IL-shell circuits were pharmacologically or chemogenetically inhibited while animals performed under (1) nonreinforced (extinction) conditions, where the appetitive and aversive cues were presented in alternating trials alone or as a compound stimulus; and (2) reinforced conditions, whereby cued responding was accompanied by associated outcomes. PL and IL inactivation attenuated nonreinforced and reinforced goal-directed cue responding, whereas NAc core and shell inactivation impaired nonreinforced responding for the appetitive, but not aversive cue. Furthermore, PL-core and IL-shell inhibition disinhibited nonreinforced but not reinforced cue responding. Our findings implicate the mPFC as a site of confluence of motivationally significant cues and outcomes, and in the regulation of nonreinforced cue responding via downstream NAc targets.