Chemogenetic inhibition of the anterior cingulate cortex increases safe decision-making in aged mice performing the Iowa Gambling Task.

RATIONALE: Elevated risk-taking negatively impacts numerous psychiatric populations, yet no targeted pharmacotherapies exist. Treatment development is hindered by an incomplete understanding of mechanisms underlying risk-based decision-making. The Iowa Gambling Task (IGT) is a cross-species translatable assessment providing humans and rodents four options of variably safe (advantageous) and risky (disadvantageous) probabilistic reward/punishment contingencies, enabling study of this behavior in rodents in a manner directly translatable to human populations. Mechanisms underlying the switch from risky to safe decision-making remains unclear, however. Clinical imaging studies implicate the anterior cingulate cortex (ACC) in human IGT performance, but causal relationships between ACC activity and decision-making require confirmation. OBJECTIVES: We used a chemogenetic strategy to determine the contribution of the ACC to mouse IGT performance. METHODS: The inhibitory DREADD, hM4Di (n = 10) (or mCherry control; n = 9) was virally expressed in ACC of male (n = 7) and female (n = 12) C57BL6/J mice (aged ~ 2 yrs), which received deschloroclozapine (DCZ; 0.1 mg/kg) or vehicle (within-subjects) prior to IGT assessment. Mice were also assessed in the Progressive Ratio Breakpoint Task (PRBT) and behavioral pattern monitor (BPM) to determine whether chemogenetically induced changes in effortful motivation or exploration may have impacted IGT performance. RESULTS: Consistent with our a priori hypothesis, chemogenetic ACC inhibition increased choice of safe options during the middle of the IGT session, without affecting PRBT or BPM behavior. ACC inhibition therefore facilitated learning of IGT contingencies, without affecting effortful motivation or locomotion. CONCLUSIONS: These findings support further investigation of the ACC as a therapeutic target for remediation of psychopathology-associated cognitive impairment.