Article

Dissociable regulation of instrumental action within mouse prefrontal cortex

Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06508, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 10/2010; 32(10):1726-34. DOI: 10.1111/j.1460-9568.2010.07438.x
Source: PubMed

ABSTRACT

Evaluation of the behavioral 'costs', such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal-directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal-directed and choice behavior, but this region's functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cue-related response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety-specific outcome devaluation or non-reinforcement (i.e. extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal-directed action when reinforcement requires the acquisition of novel response contingencies.

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    • "Response rates on the active aperture were analyzed by 2-factor (lesion x session) ANOVA with repeated measures. Response acquisition in this task is impaired by bilateral oPFC lesions targeting the lateral compartment, as here (Gourley et al., 2010). "
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    ABSTRACT: Background: Distinguishing between actions that are more likely or less likely to be rewarded is a critical aspect of goal-directed decision making. However, neuroanatomic and molecular mechanisms are not fully understood. Methods: We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacologic rescue, and designer receptors exclusively activated by designer drugs (DREADDs) to determine the anatomic and functional connectivity between the orbitofrontal cortex (OFC) and the amygdala in mice. In particular, we knocked down brain-derived neurotrophic factor (Bdnf) bilaterally in the OFC or generated an OFC-amygdala "disconnection" by pairing unilateral OFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task in which mice selected actions based on the likelihood that they would be reinforced. Additionally, we assessed the effects of DREADD-mediated OFC inhibition on the consolidation of action-outcome conditioning. Results: As in other species, the OFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral OFC and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala impede goal-directed response selection, implicating BDNF-expressing OFC projection neurons in selecting actions based on their consequences. The tyrosine receptor kinase B agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the OFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision making. Finally, DREADD-mediated OFC inhibition weakens new action-outcome memory. Conclusions: Activity-dependent and BDNF-dependent neuroplasticity within the OFC coordinate outcome-based decision making through interactions with the amygdala. These interactions brake reward-seeking habits, a putative factor in multiple psychopathologies.
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    • "For example, neuroimaging studies in humans have demonstrated decreases in activity in this region during the selection of a devalued relative to a valued action (Valentin, Dickinson & O'Doherty, 2007) or during performance of a high relative to a low instrumental contingency (Tanaka, Balleine & O'Doherty, 2008). Additionally, mice with bilateral mOFC lesions show greater instrumental perseveration during reversal learning (Gourley et al., 2010). Therefore , the limited research available suggests that this region of the cortex may also play an important role in some aspects of instrumental conditioning, however more research is needed to identify the specific involvement of the mOFC in goal-directed learning, and how it interacts with dorsal and ventral circuitry to modulate acquisition or performance. "
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    ABSTRACT: Considerable evidence suggests that distinct neural processes mediate the acquisition and performance of goal-directed instrumental actions. Whereas a cortical-dorsomedial striatal circuit appears critical for the acquisition of goal-directed actions, a cortical-ventral striatal circuit appears to mediate instrumental performance, particularly the motivational control of performance. Here we review evidence that these distinct mechanisms of learning and performance constitute two distinct 'streams' controlling instrumental conditioning. From this perspective, the regulation of the interaction between these 'streams' becomes a matter of considerable importance. We describe evidence that the basolateral amygdala, which is heavily interconnected with both the dorsal and ventral subregions of the striatum, coordinates this interaction providing input to the final common path to action as a critical component of the limbic-motor interface.
    Full-text · Dataset · Feb 2014
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    • "For example, neuroimaging studies in humans have demonstrated decreases in activity in this region during the selection of a devalued relative to a valued action (Valentin, Dickinson & O'Doherty, 2007) or during performance of a high relative to a low instrumental contingency (Tanaka, Balleine & O'Doherty, 2008). Additionally, mice with bilateral mOFC lesions show greater instrumental perseveration during reversal learning (Gourley et al., 2010). Therefore , the limited research available suggests that this region of the cortex may also play an important role in some aspects of instrumental conditioning, however more research is needed to identify the specific involvement of the mOFC in goal-directed learning, and how it interacts with dorsal and ventral circuitry to modulate acquisition or performance. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Considerable evidence suggests that distinct neural processes mediate the acquisition and performance of goal-directed instrumental actions. Whereas a cortical-dorsomedial striatal circuit appears critical for the acquisition of goal-directed actions, a cortical-ventral striatal circuit appears to mediate instrumental performance, particularly the motivational control of performance. Here we review evidence that these distinct mechanisms of learning and performance constitute two distinct 'streams' controlling instrumental conditioning. From this perspective, the regulation of the interaction between these 'streams' becomes a matter of considerable importance. We describe evidence that the basolateral amygdala, which is heavily interconnected with both the dorsal and ventral subregions of the striatum, coordinates this interaction providing input to the final common path to action as a critical component of the limbic-motor interface.
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