Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

Separate prefrontal-subcortical circuits mediate different components of risk-based decision making.

Choosing between smaller, assured rewards or larger, uncertain ones requires reconciliation of competing biases toward more certain or riskier options. We used disconnection and neuroanatomical techniques to reveal that separate, yet interconnected, neural pathways linking the medial prefrontal cortex (PFC), the basolateral amygdala (BLA), and nucleus accumbens (NAc) contribute to these different decision biases in rats. Disrupting communication between the BLA and NAc revealed that this subcortical circuit biases choice toward larger, uncertain rewards on a probabilistic discounting task. In contrast, disconnections between the BLA and PFC increased choice of the Large/Risky option. PFC-NAc disconnections did not affect choice but did increase choice latencies and trial omissions. Neuroanatomical studies confirmed that projection pathways carrying axons from BLA-to-PFC transverse a distinctly different route relative to PFC-to-BLA pathways (via the ventrolateral amydalofugal pathway and ventromedial internal capsule, respectively). We exploited these dissociable axonal pathways to selectively disrupt bottom-up and top-down communication between the BLA and PFC. Subsequent disconnection studies revealed that disruption of top-down (but not bottom-up) information transfer between the medial PFC and BLA increased choice of the larger, riskier option, suggesting that this circuit facilitates tracking of actions and outcomes to temper urges for riskier rewards as they become less profitable. These findings provide novel insight into the dynamic competition between these cortical/subcortical circuits that shape our decision biases and underlie conflicting urges when evaluating options that vary in terms of potential risks and rewards.

Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making.

Choices between certain and uncertain rewards of different magnitudes have been proposed to be mediated by both the frontal lobes and the mesocorticolimbic dopamine (DA) system. In rats, systemic manipulations of DA activity or inactivation of the medial prefrontal cortex (PFC) disrupt decision making about risks and rewards. However, it is unclear how PFC DA transmission contributes to these processes. We addressed this issue by examining the effects of pharmacological manipulations of D(1) and D(2) receptors in the medial (prelimbic) PFC on choice between small, certain and large, yet probabilistic rewards. Rats were trained on a probabilistic discounting task where one lever delivered one pellet with 100% probability, and the other delivered four pellets, but the probability of receiving reward decreased across blocks of trials (100, 50, 25, 12.5%). D(1) blockade (SCH23390) in the medial PFC decreased preference for the large/risky option. In contrast, D(2) blockade (eticlopride) reduced probabilistic discounting and increased risky choice. The D(1) agonist SKF81297 caused a slight, nonsignificant increase in preference for the large/risky lever. However, D(2) receptor stimulation (quinpirole) induced a true impairment in decision making, flattening the discounting curve and biasing choice away from or toward the risky option when it was more or less advantageous, respectively. These findings suggest that PFC D(1) and D(2) receptors make dissociable, yet complementary, contributions to risk/reward judgments. By striking a fine balance between D(1)/D(2) receptor activity, DA may help refine these judgments, promoting either exploitation of current favorable circumstances or exploration of more profitable ones when conditions change.

Differential effects of dopaminergic manipulations on risky choice.

RATIONALE: Evaluation of risks and rewards associated with different options is facilitated by components of the mesocorticolimbic dopamine (DA) system. Augmenting or reducing DA activity increases or decreases preference for larger, uncertain rewards when reward probabilities decrease within a session. However, manipulations of DA activity may differentially alter risky choice when shifts in the relative value of probabilistic rewards are greater or lesser than those experienced previously. OBJECTIVES: We investigated the effects of amphetamine and the DA antagonist flupenthixol on risk discounting, whereby we altered the manner in which reward probabilities changed. METHODS: Rats chose between a "Small/Certain" (one pellet) and a "Large/Risky" lever that delivered four pellets in a probabilistic manner that changed during a session. Separate groups of rats were trained with a descending (100%, 50%, 25%, 12.5%), ascending (12.5-100%) or mixed (100%, 12.5%, 25%, 50%) order of probabilities associated with the large/risky option. RESULTS: Flupenthixol consistently decreased preference for the large/risky option. In contrast, amphetamine increased preference for the large/risky lever when the probabilities decreased over a session, but reduced preference in the ascending condition. CONCLUSIONS: Reductions in normal DA tone consistently biases choice away larger, probabilistic rewards. In contrast, increases in DA release may disrupt adjustments in behavior in response to changes in the relative value of certain versus uncertain rewards. These findings further clarify the role of DA in mediating risk/reward judgments and how perturbations in DA signaling may interfere with the ability to adjust decision making in response to changes in reward contingencies.

Prefrontal cortical contribution to risk-based decision making.

Damage to various regions of the prefrontal cortex (PFC) impairs decision making involving evaluations about risks and rewards. However, the specific contributions that different PFC subregions make to risk-based decision making are unclear. We investigated the effects of reversible inactivation of 4 subregions of the rat PFC (prelimbic medial PFC, orbitofrontal cortex [OFC], anterior cingulate, and insular cortex) on probabilistic (or risk) discounting. Rats were well trained to choose between either a "Small/Certain" lever that always delivered 1 food pellet, or another, "Large/Risky" lever, which delivered 4 pellets, but the probability of receiving reward decreased across 4 trial blocks (100%, 50%, 25%, and 12.5%). Infusions of gama-aminobutyric acid agonists muscimol/baclofen into the medial PFC increased risky choice. However, similar medial PFC inactivations decreased risky choice when the Large/Risky reward probability increased over a session. OFC inactivation increased response latencies in the latter trial blocks without affecting choice. Anterior cingulate or insular inactivations were without effect. The effects of prelimbic inactivations were not attributable to disruptions in response flexibility or judgments about the relative value of probabilistic rewards. Thus, the prelimbic, but not other PFC regions, plays a critical role in risk discounting, integrating information about changing reward probabilities to update value representations that facilitate efficient decision making.

Fundamental contribution by the basolateral amygdala to different forms of decision making.

Impairments in decision making about risks and rewards have been observed in patients with amygdala damage. Similarly, lesions of the basolateral amygdala (BLA) in rodents disrupts cost/benefit decision making, reducing preference for larger rewards obtainable after a delay or considerable physical effort. We assessed the effects of inactivation of the BLA on risk- and effort-based decision making, using discounting tasks conducted in an operant chamber. Separate groups of rats were trained on either a risk- or effort-discounting task, consisting of four blocks of 10 free-choice trials. Selection of one lever always delivered a smaller reward (one or two pellets), whereas responding on the other delivered a larger, four pellet reward. For risk discounting, the probability of receiving the larger reward decreased across trial blocks (100-12.5%), whereas on the effort task, the larger reward was delivered after a ratio of presses that increased across blocks (2-20). Infusions of GABA agonists baclofen/muscimol into the BLA disrupted risk discounting, inducing a risk-averse pattern of choice, and increased response latencies and trial omissions, most prominently during trial blocks that provided the greatest uncertainty about the most beneficial course of action. Similar inactivations also increased effort discounting, reducing the preference for larger yet more costly rewards, even when the relative delays to reward delivery were equalized across response options. These findings point to a fundamental role for the BLA in different forms of cost/benefit decision making, facilitating an organism's ability to overcome a variety of costs (work, uncertainty, delays) to promote actions that may yield larger rewards.

Dopaminergic modulation of risk-based decision making.

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about delay or effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated the effects of systemic manipulations of DA transmission on risky choice using a probabilistic discounting task. Over discrete trials, rats chose between two levers; a press on the 'small/certain' lever always delivered one reward pellet, whereas a press on the other, 'large/risky' lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100, 50, 25, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D(1) (SCH23390) or D(2) (eticlopride) receptor antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D(1) (SKF81297) or D(2) (bromocriptine) receptors also increased risky choice. In contrast, activation of D(3) receptors with PD128,907 reduced choice of the large/risky lever. Likewise, D(3) antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D(4) receptors did not reliably alter behavior. These findings indicate that DA has a critical role in mediating risk-based decision making, with increased activation of D(1) and D(2) receptors biasing choice toward larger, probabilistic rewards, whereas D(3) receptors appear to exert opposing effects on this form of decision making.

Cortico-limbic-striatal circuits subserving different forms of cost-benefit decision making.

Research on the neural basis that underlies decision making in humans has revealed that these processes are mediated by distributed neural networks that incorporate different regions of the frontal lobes, the amygdala, the ventral striatum, and the dopamine system. In the present article, we review recent studies in rodents investigating the contribution of these systems to different forms of cost-benefit decision making and focus on evaluations related to delays, effort, or risks associated with certain rewards. Anatomically distinct regions of the medial and orbital prefrontal cortex make dissociable contributions to different forms of decision making, although lesions of these regions can induce variable effects, depending on the type of tasks used to assess these functions. The basolateral amygdala and the nucleus accumbens play a more fundamental role in these evaluations, helping an organism overcome different costs to obtain better rewards. Dopamine activity biases behavior toward more costly yet larger rewards, although abnormal increases in dopamine transmission can exert opposing actions on different types of decision making. The fact that similar neural circuits are recruited to solve these types of problems in both humans and animals suggests that animal models of decision making will prove useful in elucidating the mechanisms mediating these processes.