The orbitofrontal cortex regulates outcome-based decision-making via the lateral striatum

Abstract

The orbitofrontal cortex (oPFC) sends substantial projections to the ventrolateral striatum and aspects of the nucleus accumbens that are, functionally, poorly understood. This is despite probable cortico-striatal involvement in multiple diseases such as addiction and obsessive-compulsive disorder. Here we surgically disconnected the oPFC from the ventrolateral striatum using unilateral asymmetric lesions in mice and classified instrumental decision-making strategies. Mice with symmetric lesions that spared one oPFC-striatal network served as controls. As a complementary approach, we selectively knocked down Brain-derived neurotrophic factor (Bdnf) bilaterally in the oPFC and ascertained behavioral and neurobiological consequences within the downstream striatum. oPFC-striatal disconnection and oPFC Bdnf knockdown blocked sensitivity to outcome-predictive relationships in both food-reinforced and cocaine-associated settings. Bdnf knockdown simultaneously regulated striatal BDNF expression, and striatal c-Fos predicted sensitivity to action-outcome associative contingencies. Previous evidence strongly implicates the dorsolateral striatum in stimulus-response habit formation. Our findings thus provide novel evidence for functional compartmentalisation within the lateral striatum, with the dorsal compartment subserving classical stimulus-response habit systems and a ventral compartment coordinating outcome-based decision-making via oPFC interactions. This compartmentalisation may apply to both 'natural', as in the case of food-reinforced behavior, and 'pathological', as in the case of cocaine-seeking, contexts.

Keywords: action; addiction; contingency degradation; habit; mouse; orbital.

Figure 1. oPFC BDNF and oPFC-ventrolateral striatum interactions regulate action-outcome associative conditioning

(a) Composites represent virus and lesion spreads in these experiments, with gray representing the largest spread and black the smallest. At bottom left, representative viral-mediated EGFP expression in the oPFC (green). Bottom right, excitotoxic lateral striatum lesion (red) counterstained with NeuN (green). (b) oPFC-targeted Bdnf knockdown and oPFC-ventrolateral striatum disconnection impaired instrumental response acquisition, particularly when the reinforcement schedule escalated from a fixed ratio (FR) to random interval (RI) schedule of reinforcement in the final 2 conditioning sessions. (c) Mice with oPFC-targeted Bdnf knockdown and oPFC-ventrolateral striatum disconnection were insensitive to action-outcome contingency degradation: While control groups developed a preference for the non-degraded instrumental aperture after action-outcome contingency degradation, response rates in knockdown and disconnection mice did not vary from baseline (compare to final session in b). (d) Moreover, response acquisition in an instrumental reversal task sensitive to oPFC lesions was also impaired. (e) These response patterns are shown again with the addition of responding on the previously reinforced aperture (“extinction”). As is summarized in the right panel, all mice initially respond preferentially on the previously reinforced aperture during the first session, but by the fourth reversal session, control and ipsilateral mice respond preferentially on the newly reinforced aperture, while the contralateral and Bdnf knockdown groups fail to differentiate between the reinforced and extinguished apertures. (f) Orbitofrontal cortical Bdnf knockdown reduced BDNF expression in the downstream lateral striatum and amygdala, and (g) Striatal c-Fos expression predicted response rates on the reinforced aperture at the end of instrumental training (individual mice are represented; black=control group). (h) Despite these deficiencies, both Bdnf knockdown and contralateral lesions spared sensitivity to satiety-specific outcome devaluation, which decreased response rates in all groups. (i) Our model is shown: We hypothesize that while the lateral striatum coordinates stimulus-response habits as been previously reported, the ventrolateral compartment regulates, under certain circumstances, outcome-based decision-making. Means+SEMs. *p<0.05;**p<0.001.

Figure 2. oPFC BDNF regulates cocaine-conditioned place preference

Bdnf knockdown enhanced sensitivity to cocaine-associated stimuli, as evidenced by increased place preference relative to baseline after only 2 cocaine-place pairings (“early test”). All mice ultimately acquired cocaine-conditioned place preference (“late test”), but preference failed to normalize in Bdnf-deficient mice when saline replaced cocaine (“unpaired”). Inset: preference in 5-min bins during the unpaired test. Means+SEMs. *p<0.05;**p<0.001.