Differential Contributions of Nucleus Accumbens Subregions to Cue-Guided Risk/Reward Decision Making and Implementation of Conditional Rules.

The nucleus accumbens (NAc) is a key node within corticolimbic circuitry for guiding action selection and cost/benefit decision making in situations involving reward uncertainty. Preclinical studies have typically assessed risk/reward decision making using assays where decisions are guided by internally generated representations of choice-outcome contingencies. Yet, real-life decisions are often influenced by external stimuli that inform about likelihoods of obtaining rewards. How different subregions of the NAc mediate decision making in such situations is unclear. Here, we used a novel assay colloquially termed the "Blackjack" task that models these types of situations. Male Long-Evans rats were trained to choose between one lever that always delivered a one-pellet reward and another that delivered four pellets with different probabilities [either 50% (good-odds) or 12.5% (poor-odds)], which were signaled by one of two auditory cues. Under control conditions, rats selected the large/risky option more often on good-odds versus poor-odds trials. Inactivation of the NAc core caused indiscriminate choice patterns. In contrast, NAc shell inactivation increased risky choice, more prominently on poor-odds trials. Additional experiments revealed that both subregions contribute to auditory conditional discrimination. NAc core or shell inactivation reduced Pavlovian approach elicited by an auditory CS+, yet shell inactivation also increased responding during presentation of a CS-. These data highlight distinct contributions for NAc subregions in decision making and reward seeking guided by discriminative stimuli. The core is crucial for implementation of conditional rules, whereas the shell refines reward seeking by mitigating the allure of larger, unlikely rewards and reducing expression of inappropriate or non-rewarded actions.SIGNIFICANCE STATEMENT Using external cues to guide decision making is crucial for adaptive behavior. Deficits in cue-guided behavior have been associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder and schizophrenia, which in turn has been linked to aberrant processing in the nucleus accumbens. However, many preclinical studies have often assessed risk/reward decision making in the absence of explicit cues. The current study fills that gap by using a novel task that allows for the assessment of cue-guided risk/reward decision making in rodents. Our findings identified distinct yet complementary roles for the medial versus lateral portions of this nucleus that provide a broader understanding of the differential contributions it makes to decision making and reward seeking guided by discriminative stimuli.

Noradrenergic modulation of risk/reward decision making.

RATIONALE: Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. OBJECTIVES: The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. METHODS: We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 µg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. RESULTS: In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. CONCLUSIONS: These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

Overriding phasic dopamine signals redirects action selection during risk/reward decision making.

Phasic increases and decreases in dopamine (DA) transmission encode reward prediction errors thought to facilitate reward-related learning, yet how these signals guide action selection in more complex situations requiring evaluation of different reward remains unclear. We manipulated phasic DA signals while rats performed a risk/reward decision-making task, using temporally discrete stimulation of either the lateral habenula (LHb) or rostromedial tegmental nucleus (RMTg) to suppress DA bursts (confirmed with neurophysiological studies) or the ventral tegmental area (VTA) to override phasic dips. When rats chose between small/certain and larger/risky rewards, LHb or RMTg stimulation, time-locked to delivery of one of these rewards, redirected bias toward the alternative option, whereas VTA stimulation after non rewarded choices increased risky choice. LHb stimulation prior to choices shifted bias away from more preferred options. Thus, phasic DA signals provide feedback on whether recent actions were rewarded to update decision policies and direct actions toward more desirable reward.