Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions.

RATIONALE: Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding. OBJECTIVE: The key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance. RESULTS: When infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine. CONCLUSIONS: These data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues.

Temporal Dynamics Underlying Prelimbic Prefrontal Cortical Regulation of Action Selection and Outcome Evaluation during Risk/Reward Decision-Making.

Risk/reward decision-making is a dynamic process that includes periods of deliberation before action selection and evaluation of the action outcomes that bias subsequent choices. Inactivation of the prelimbic (PL) cortex has revealed its integral role in updating decision biases in the face of changes in probabilistic reward contingencies, yet how phasic PL signals during different phases of the decision process influence choice remains unclear. We used temporally specific optogenetic inhibition to selectively disrupt PL activity coinciding with action selection and outcome phases to examine how these signals influence choice. Male rats expressing the inhibitory opsin eArchT within PL excitatory neurons were well trained on a probabilistic discounting task, entailing choice between small/certain versus large/risky rewards, the probability of which varied over a session (50-12.5%). During testing, brief light pulses suppressed PL activity before choice or after different outcomes. Prechoice suppression reduced bias toward more preferred/higher utility options and disrupted how recent outcomes influenced subsequent choice. Inhibition during risky losses induced a similar profile, but here, the impact of reward omissions were either amplified or diminished, relative to the context of the estimated profitability of the risky option. Inhibition during large or small reward receipt reduced risky choice when this option was more profitable, suggesting these signals can both reinforce rewarded risky choices and also act as a relative value comparator signal that augments incentive for larger rewards. These findings reveal multifaceted contributions by the PL in implementing decisions and integrating action-outcome feedback to assign context to the decision space.SIGNIFICANCE STATEMENT The PL prefrontal cortex plays an integral role in guiding risk/reward decisions, but how activity in this region during different phases of the decision process influences choice is unclear. By using temporally specific optogenetic manipulations of this activity, the present study unveiled previously uncharacterized and differential contributions by PL in implementing decision policies and how evaluation of decision outcomes shape subsequent choice. These findings provide novel insight into the dynamic processes engaged by the PL that underlie action selection in situations involving reward uncertainty that may aid in understanding the mechanism underlying normal and aberrant decision-making processes.

Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats.

Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long-Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration.

Dorsomedial striatal contributions to different forms of risk/reward decision making.

Optimal decision making involving reward uncertainty is integral to adaptive goal-directed behavior. In some instances, these decisions are guided by internal representations of reward history, whereas in other situations, external cues inform a decision maker about how likely certain actions are to yield reward. Different regions of the frontal lobe form distributed networks with striatal and amygdalar regions that facilitate different types of risk/reward decision making. The dorsal medial striatum (DMS) is one key output region of the prefrontal cortex, yet there have been few preclinical studies investigating the involvement of the DMS in different forms of risk/reward decision making. The present study addressed this issue, wherein separate groups of male rats were trained on one of two tasks where they chose between a small/certain or a large/risky reward. In a probabilistic discounting task, reward probabilities changed systematically over blocks of trials (100-6.25% or 6.25-100%), requiring rats to use internal representations of reward history to guide choice. Cue-guided decision-making was assessed with a "Blackjack" task, where different auditory cues indicated the odds associated with the large/risky option (50 or 12.5%). Inactivation of the DMS with GABA agonists impaired adjustments in choice biases during probabilistic discounting, resulting in either increases or decreases in risky choice as the probabilities associated with the large/risky reward decreased or increased over a session. In comparison, DMS inactivation increased risky choices on poor-odds trials on the Blackjack task, which was associated with a reduced impact that non-rewarded choices had on subsequent choices. DMS inactivation also impaired performance of an auditory conditional discrimination. These findings highlight a previously uncharacterized role for the DMS in facilitating flexible action selection during multiple forms of risk/reward decision making.