Chemogenetic inactivation of the nucleus reuniens and its projections to the orbital cortex produce deficits on discrete measures of behavioral flexibility in the attentional set-shifting task.

The nucleus reuniens (RE) of the ventral midline thalamus is a critical node in the communication between the orbitomedial prefrontal cortex (OFC) and the hippocampus (HF). While RE has been shown to directly participate in memory-associated functions through its connections with the medial prefrontal cortex and HF, less is known regarding the role of RE in executive functioning. Here, we examined the involvement of RE and its projections to the orbital cortex (ORB) in attention and behavioral flexibility in male rats using the attentional set shifting task (AST). Rats expressing the hM4Di DREADD receptor in RE were implanted with indwelling cannulas in either RE or the ventromedial ORB to pharmacologically inhibit RE or its projections to the ORB with intracranial infusions of clozapine-N-oxide hydrochloride (CNO). Chemogenetic-induced suppression of RE resulted in impairments in reversal learning and set-shifting. This supports a vital role for RE in behavioral flexibility - or the ability to adapt behavior to changing reward or rule contingencies. Interestingly, CNO suppression of RE projections to the ventromedial ORB produced impairments in rule abstraction - or dissociable effects elicited with direct RE suppression. In summary, the present findings indicate that RE, mediated in part by actions on the ORB, serves a critical role in the flexible use of rules to drive goal directed behavior. The cognitive deficits of various neurological disorders with impaired communication between the HF and OFC, may be partly attributed to alterations of RE -- as an established intermediary between these cortical structures.