Complementary yet dissociable influences of medial and lateral orbitofrontal cortex over cue-guided decisions involving reward magnitude and uncertainty.

Converging evidence suggests that orbitofrontal cortex (OFC) subregions subserve distinct roles in decision making across a variety of tasks. Cost/benefit decisions can require an organism to choose between options based on information available in the environment (externally-guided) and knowledge from experience (internally-guided). Studies in humans have implicated both medial and lateral subdivisions of OFC (mOFC, lOFC) in externally and internally guided choice, yet, rodent studies have primarily focused on OFC regulation of internally-guided decisions. To address this gap, we examined how inactivation of these OFC subregions alters cue-guided, probabilistic decision making using a "Blackjack" task. Male rats were required to choose between a certain, 1-pellet small reward and larger, 4-pellet reward delivered with varying probability, signalled trail-to-trial with explicit auditory stimuli indicating whether the odds of receiving the larger reward was good (50%) or poor (12.5%). Inactivation of the mOFC or lOFC induced generalized decreases or increases in large/risky choice, respectively, that were associated with opposite effects on loss (but not win) sensitivity and on rats' likelihood of making consecutive choices of the small/certain option. Inactivation of the adjacent anterior agranular insular cortex had no effect. Inactivation of either OFC subregion also disrupted cue-guided reward magnitude discrimination, where tones signals which action delivered a deterministic larger reward, but did not affect a simpler conditional discrimination involving choice between rewarded and unrewarded actions. Together these data highlight complementary yet heterogeneous roles for different OFC regions in using discriminative stimuli to guide action towards higher value targets.Significance Statement The orbitofrontal cortex mediates risk/reward decisions across species. This region can be partitioned into medial and lateral compartments that have distinct connectivity, yet there have been few studies directly comparing their involvement in these types of decisions. Here we show these two orbitofrontal regions play opposing roles in biasing risky choices guided by external stimuli informing about the likelihood of receiving larger, uncertain rewards, while playing complementary roles in using cues to guide action towards larger deterministic rewards. These findings broaden our understanding of how different frontal lobe regions influence these types of decisions and further highlight differences in how these systems are recruited in shaping decision biases guided by external cues vs internal representations of risk/reward contingencies.