Parallel ventral hippocampus-lateral septum pathways differentially regulate approach-avoidance conflict.

The ability to resolve an approach-avoidance conflict is critical to adaptive behavior. The ventral CA3 (vCA3) and CA1 (vCA1) subfields of the ventral hippocampus (vHPC) have been shown to facilitate avoidance and approach behavior, respectively, in the face of motivational conflict, but the neural circuits by which this subfield-specific regulation is implemented is unknown. We demonstrate that two distinct pathways from these subfields to lateral septum (LS) contribute to this divergent control. In Long-Evans rats, chemogenetic inhibition of the vCA3- LS caudodorsal (cd) pathway potentiated approach towards a learned conflict-eliciting stimulus, while inhibition of the vCA1-LS rostroventral (rv) pathway potentiated approach non-specifically. Additionally, vCA3-LScd inhibited animals were less hesitant to explore food during environmental uncertainty, while the vCA1- LSrv inhibited animals took longer to initiate food exploration. These findings suggest that the vHPC influences multiple behavioral systems via differential projections to the LS, which in turn send inhibitory projections to motivational centres of the brain.

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.SIGNIFICANCE STATEMENT The ability to discriminate and respond appropriately to environmental cues that signal availability of reward or punishment is essential for survival. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been implicated in adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, less is known about the role they play in orchestrating adaptive responses to natural reward and punishment cues within the same behavioral task. Here, using a novel discriminative cue responding task combined with pharmacological or chemogenetic inhibition of mPFC, NAc and mPFC-NAc circuits, we report that mPFC is critically involved in responding to changing cued response-outcomes, both when the responses are reinforced, and nonreinforced. Furthermore, the mPFC coordinates nonreinforced discriminative cue responding by suppressing inappropriate responding via downstream NAc targets.