Differential effects on effort discounting induced by inactivations of the nucleus accumbens core or shell.

The authors investigated the contribution of the nucleus accumbens (NAc) core and shell to effort-based decision making using a discounting procedure. Selection of 1 lever delivered a smaller, 2-pellet reward immediately, whereas the other lever delivered a 4-pellet reward after a fixed ratio of presses (2, 5, 10, or 20) that increased over 4 blocks of 10 discrete choice trials. Subsequent testing employed an equivalent delays procedure, whereby the relative delay to reward delivery after selection of either option was equalized. In well-trained rats, inactivation of the core, but not the shell, via infusion of GABA A/B agonists muscimol/baclofen reduced preference for the high-effort option under standard conditions and also when rats were tested using an equivalent delays procedure. However, inactivation of the core did not alter preference for 4-pellet versus 2-pellet rewards when the relative costs of each option were the same (1 press). Thus, the NAc core, but not the shell, appears to be part of a neural circuit that biases choice toward larger rewards associated with a greater effort cost. Furthermore, the contributions by the NAc core to this form of decision making can be dissociated from its role in delay discounting.

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.

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.

Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning.

Different subregions of the rodent prefrontal cortex (PFC) mediate dissociable types of behavioral flexibility. For example, lesions of the medial or orbitofrontal (OFC) regions of the PFC impair extradimensional shifts and reversal learning, respectively, when novel stimuli are used during different phases of the task. In the present study, we assessed the effects of inactivation of the OFC on strategy set-shifting and reversal learning, using a maze based set-shifting task mediated by the medial PFC. Long-Evans rats were trained initially on a visual-cue discrimination to obtain food. On the subsequent day, rats had to shift to using a response strategy (e.g., always turn left). On Day 3 (reversal), rats were required to reverse the direction of their turn (e.g., always turn right). Infusions of the local anesthetic bupivacaine into the OFC did not impair initial visual discrimination learning, nor did it impair performance on the set-shift. In contrast, inactivation of the OFC did impair reversal learning; yet, these rats ceased using the previously acquired response rule as readily as controls. Instead, rats receiving OFC inactivations made a disproportionate number of erroneous arm entries towards the visual-cue, suggested that these animals reverted back to using the original visual-cue based strategy. These findings, in addition to previous data, further support the notion that the OFC and medial PFC play dissociable roles in reversal learning and set-shifting. Furthermore, the lack of effect of OFC inactivations on the set-shift indicates that this type of behavioral flexibility does not require cognitive operations related to reversal learning.

Dopaminergic and glutamatergic regulation of effort- and delay-based decision making.

Cost/benefit decisions regarding the relative effort or delay costs associated with a particular response are mediated by distributed dopaminergic and glutamatergic neural circuits. The present study assessed the contribution of dopamine and NMDA glutamate receptors in these different forms of decision making using novel effort- and delay-discounting procedures. In the effort-discounting task, rats could either emit a single response on a low-reward lever to receive two pellets, or make 2, 5, 10, or 20 responses on a high-reward (HR) lever to obtain four pellets. In the delay-discounting task, one press of the HR lever delivered four pellets after a delay (0.5-8 s). A third task (effort-discounting with equivalent delays) was similar to the effort-discounting procedure, except that the relative delay to reward delivery was equalized across response options. The dopamine receptor antagonist flupenthixol reduced choice of the HR lever under all three testing conditions, indicating that dopamine antagonism alters effort-based decision making independent of any contribution of delay. Amphetamine exerted dose-dependent, biphasic effects; a higher dose (0.5 mg/kg) increased effort discounting, whereas a lower dose (0.25 mg/kg) reduced delay discounting. The noncompetitive NMDA antagonist ketamine (5 mg/kg) increased effort and delay discounting, but did not affect choice on the effort with equivalent delays task, indicating a reduced tolerance for delayed rewards. These findings highlight the utility of these procedures in pharmacologically dissociating the neurochemical mechanisms underlying these different, yet interrelated forms of decision making. Furthermore, they suggest that dopamine and NMDA receptors make dissociable contributions to these different types of cost-benefit analyses.

Amygdala-prefrontal cortical circuitry regulates effort-based decision making.

The basolateral amygdala (BLA) and the anterior cingulate cortex (ACC) region of the prefrontal cortex form an interconnected neural circuit that may mediate certain types of decision-making processes. The present study assessed the role of this pathway in effort-based decision making using a cost-benefit T-maze task. Rats were given a choice of obtaining a high reward by climbing a 30-cm barrier in 1 arm (4 pellets; high-reward [HR] arm) or a small reward in the other arm with no barrier (2 pellets; low-reward [LR] arm). In Experiment 1, bilateral inactivation of the BLA via infusion of bupivacaine impaired decision making, reducing the preference for the HR arm. This effect was not due to spatial or motor deficits because BLA inactivation did not alter behavior when the amount of effort required to obtain either reward was equalized by placing a 2nd barrier in the LR arm. In Experiment 2, disconnection between the BLA and ACC, entailing a unilateral BLA inactivation combined with a contralateral ACC inactivation also impaired decision making. These data suggest that the serial transfer of information between the BLA and ACC guides response selection when evaluating the value of an expected outcome relative to the costs of performing a particular action.

Dissociable roles for the nucleus accumbens core and shell in regulating set shifting.

The ability to behave in a flexible manner is an executive function mediated in part by different regions of the prefrontal cortex. The present study investigated the role of two major efferents of the prefrontal cortex, the nucleus accumbens (NAc) core and shell, in behavioral flexibility using a maze-based strategy set-shifting task. During initial discrimination training, rats learned to use either an egocentric response or a visual-cue discrimination strategy to obtain food reward. During the set shift, animals had to shift from the previously acquired response or visual-cue-based strategy and learn the alternate discrimination. Inactivation of the NAc core, induced by infusion of the GABA agonists baclofen and muscimol, did not impair initial acquisition of either a response or visual-cue discrimination but severely disrupted shifting from one strategy to another. Analysis of the type of errors revealed that impairments in set shifting were not attributable to increased perseveration but to a disruption of the acquisition and maintenance of a new strategy. In contrast, inactivation of the NAc shell did not impair acquisition of either a response or a visual-cue discrimination, or shifting from one strategy to another. However, inactivation of the NAc shell before initial discrimination training improved performance during the set shift relative to control animals. These data indicate that the NAc core and shell make dissociable contributions to behavioral flexibility during set shifting. The NAc core facilitates the acquisition and maintenance of novel behavioral strategies and elimination of inappropriate response options, whereas the shell may mediate learning about irrelevant stimuli.

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.