Medial orbitofrontal cortical regulation of different aspects of Pavlovian and instrumental reward seeking.

RATIONALE: The medial subregion of the orbitofrontal cortex (mOFC) is thought to play an important role representing the expected outcome of a given course of action, as lesioning or inactivating this cortical region results in the adoption of choice strategies based more on observable (rather than previously learned) information. Despite this, its role in mediating basic associative learning remains to be fully clarified. OBJECTIVE: The present series of experiments examined the role of the mOFC in (1) Pavlovian conditioned approach, (2) conditioned reinforcement, (3) extinction, and (4) cue-induced reinstatement of food-seeking behavior. METHODS: Separate cohorts of rats went through Pavlovian or instrumental training. Intra-mOFC infusions of either saline or GABA agonists (to temporarily inactivate neural activity) were given prior to Pavlovian approach, conditioned reinforcement, first or second day of instrumental extinction training, or cue-induced reinstatement test days. RESULTS: mOFC inactivation increased lever-CS contacts in Pavlovian conditioned approach and (2) had no effect on conditioned reinforcement. These manipulations (3) accelerated within-session instrumental extinction during the initial extinction session, but impaired subsequent extinction learning on drug-free days. (4) mOFC inactivation induced differential effects on reinstatement that depended on baseline performance. mOFC inactivation abolished reinstatement in "Reinstater" rats (who displayed robust responding under control conditions) and robustly increased reinstatement in "Non-Reinstater" rats (who showed little reinstatement under control conditions) suggesting that individual differences in reinstatement may be supported by differences in mOFC mediated representations of expected outcomes. CONCLUSIONS: These findings have important implications for understanding how the mOFC uses stimulus-outcome and action-outcome expectancies to guide behavior, and how dysfunction within this region may contribute to pathological patterns of reward seeking.

Distinct Medial Orbitofrontal-Striatal Circuits Support Dissociable Component Processes of Risk/Reward Decision-Making.

The medial orbitofrontal cortex (mOFC) regulates a variety of cognitive functions, including refining action selection involving reward uncertainty. This region sends projections to numerous subcortical targets, including the ventral and dorsal striatum, yet how these corticostriatal circuits differentially regulate risk/reward decision-making is unknown. The present study examined the contribution of mOFC circuits linking the nucleus accumbens (NAc) and dorsomedial striatum (DMS) to risk/reward decision-making using pharmacological disconnections. Male rats were well trained on a probabilistic discounting task involving choice between small/certain or large/risky rewards, with the probability of obtaining the larger reward decreasing or increasing over a session. Disconnection of mOFC-striatal pathways was achieved using infusions of GABA agonists inactivating the mOFC in one hemisphere, combined with NAc or DMS inactivation in the contralateral or ipsilateral hemisphere. Perturbing mOFC → NAc circuits induced suboptimal, near-random patterns of choice that manifested as a flattening of the discounting curve. Animals were equally likely to stay or shift following rewarded/nonrewarded choices, suggesting this pathway mediates use of information about reward history to stabilize decision biases. In contrast, mOFC → DMS disconnection impaired adjustments in decision biases, causing opposing changes in risky choice depending on how probabilities varied over time. This was driven by alterations in lose-shift behavior, suggesting mOFC → DMS circuits track volatility in nonrewarded actions to adjust choice in accordance with changes in profitability. Thus, separate mOFC-striatal projection pathways regulate dissociable processes underlying decision-making, with mOFC → NAc circuits aiding in establishing and stabilizing tasks states and mOFC → DMS circuits facilitating transitions across states to promote flexible reward seeking.SIGNIFICANCE STATEMENT The medial orbitofrontal cortex regulates a variety of goal-directed behaviors, yet the functional circuits through which it mediates higher order decision-making functions are unclear. The present study revealed that different mOFC projection pathways facilitate diverse aspects of decision-making involving risks and rewards by engaging separate networks of neurons that interface with distinct ventral and dorsal striatal targets. These findings clarify some of the normal functions of these corticostriatal pathways and may have implications for understanding how dysfunction in these circuits relate to certain psychiatric disorders.

Medial orbitofrontal cortex dopamine D1/D2 receptors differentially modulate distinct forms of probabilistic decision-making.

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D1 and D2 receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D1 or D2 antagonists or agonists prior to task performance. mOFC D1 and D2 blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D1 blockade impaired, while D2 blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D1 blockade reduced, while D2 blockade increased preference for larger/risky rewards. Excess D1 stimulation had no effect on either task, while excessive D2 stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D1 and D2 receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.

Prefrontal Dopamine D1 and D2 Receptors Regulate Dissociable Aspects of Decision Making via Distinct Ventral Striatal and Amygdalar Circuits.

Mesocortical dopamine (DA) regulates a variety of cognitive functions via actions on D1 and/or D2 receptors. For example, risk/reward decision making is modulated differentially by these two receptors within the prefrontal cortex (PFC), with D2 receptors enabling flexible decision making and D1 receptors promoting persistence in choice biases. However, it is unclear how DA mediates opposing patterns of behavior by acting on different receptors within the same terminal region. We explored the possibility that DA may act on separate networks of PFC neurons that are modulated by D1 or D2 receptors and in turn interface with divergent downstream structures such as the basolateral amygdala (BLA) or nucleus accumbens (NAc). Decision making was assessed using a probabilistic discounting task in which well trained male rats chose between small/certain or large/risky rewards, with the odds of obtaining the larger reward changing systematically within a session. Selective disruption of D1 or D2 modulation of separate PFC output pathways was achieved using unilateral intra-PFC infusions of DA antagonists combined with contralateral inactivation of the BLA or NAc. Disrupting D2 (but not D1) modulation of PFC→BLA circuitry impaired adjustments in decision biases in response to changes in reward probabilities. In contrast, disrupting D1 modulation of PFC→NAc networks reduced risky choice, attenuating reward sensitivity and increasing sensitivity to reward omissions. These findings reveal that mesocortical DA can facilitate dissociable components of reward seeking and action selection by acting on different functional networks of PFC neurons that can be distinguished by the subcortical projection targets with which they interface.SIGNIFICANCE STATEMENT Prefrontal cortical dopamine regulates a variety of executive functions governed by the frontal lobes via actions on D1 and D2 receptors. These receptors can in some instances mediate different patterns of behavior, but the mechanisms underlying these dissociable actions are unclear. Using a selective disconnection approach, we reveal that D1 and D2 receptors can facilitate diverse aspects of decision making by acting on separate networks of prefrontal neurons that interface with distinct striatal or amygdalar targets. These findings reveal an additional level of complexity in how mesocortical DA regulates different forms of cognition via actions on different receptors, highlighting how it may act upon distinct cortical microcircuits to drive different patterns of behavior.

Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala.

RATIONALE: Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown. OBJECTIVES: We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task. METHODS: Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 µg) or D2 (eticlopride, 0.1-1 µg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 µg) and D2 (quinpirole, 1-10 µg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice. RESULTS: BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior. CONCLUSIONS: These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.