Multifaceted Contributions by Different Regions of the Orbitofrontal and Medial Prefrontal Cortex to Probabilistic Reversal Learning

Abstract

Different subregions of the prefrontal cortex (PFC) contribute to the ability to respond flexibly to changes in reward contingencies, with the medial versus orbitofrontal cortex (OFC) subregions contributing differentially to processes such as set-shifting and reversal learning. To date, the manner in which these regions may facilitate reversal learning in situations involving reward uncertainty remains relatively unexplored. We investigated the involvement of five distinct regions of the rat OFC (lateral and medial) and medial PFC (prelimbic, infralimbic, and anterior cingulate) on probabilistic reversal learning wherein "correct" versus "incorrect" responses were rewarded on 80% and 20% of trials, respectively. Contingencies were reversed repeatedly within a session. In well trained rats, inactivation of the medial or lateral OFC induced dissociable impairments in performance (indexed by fewer reversals completed) when outcomes were probabilistic, but not when they were assured. Medial OFC inactivation impaired probabilistic learning during the first discrimination, increased perseverative responding and reduced sensitivity to positive and negative feedback, suggestive of a deficit in incorporating information about previous action outcomes to guide subsequent behavior. Lateral OFC inactivation preferentially impaired performance during reversal phases. In contrast, prelimbic inactivation caused an apparent improvement in performance by increasing the number of reversals completed. This was associated with enhanced sensitivity to recently rewarded actions and reduced sensitivity to negative feedback. Infralimbic inactivation had no effect, whereas the anterior cingulate appeared to play a permissive role in this form of reversal learning. These results clarify the dissociable contributions of different regions of the frontal lobes to probabilistic learning.

Significance statement: The ability to adjust behavior in response to changes involving uncertain or probabilistic reward contingencies is an essential survival skill that is impaired in a variety of psychiatric disorders. It is well established that different forms of cognitive flexibility are mediated by anatomically distinct regions of the frontal lobes when reinforcement contingencies are assured, however, less is known about the contribution of these regions to probabilistic reinforcement learning. Here we show that different regions of the orbitofrontal and medial prefrontal cortex make distinct contributions to probabilistic reversal learning. These findings provide novel information about the complex interplay between frontal lobe regions in mediating these processes and accordingly provide insight into possible pathophysiology that underlies impairments in cognitive flexibility observed in mental illnesses.

Keywords: orbitofrontal cortex; prelimbic cortex; probabilistic; reversal learning.

Figure 1.

Histology. Left, Schematics of coronal sections showing the range of acceptable locations of infusions within the medial OFC (filled circles) and lateral OFC (open circles). Right, The range of acceptable locations of infusions within the prelimbic (filled circles), infralimbic (open circles), and anterior cingulate (filled squares) regions of the PFC. Photomicrographs of representative placements in these regions are also presented, with arrows highlighting the location of the cannulae tips.

Figure 2.

Inactivation of the medial (top row) or the lateral (bottom row) regions of the OFC differentially impairs PRL. A, Microinfusions of baclofen and muscimol (Bac/Mus) into the mOFC (n = 12) reduced the number of reversals completed per 100 successful trials. For this and all other figures, circles and dashed lines represent data from individual animals following both treatments. B, Errors to achieve criterion performance during the initial discrimination and first reversal phases after inactivation and control treatments. mOFC inactivation increased errors during the first discrimination of the session, and this effect persisted during the first reversal. C, mOFC inactivation increased perseverative errors throughout the task. D, mOFC inactivation caused a decrease in both win-stay and lose-shift behavior after both correct and incorrect choices. E, lOFC inactivation (n = 10) also reduced the number of reversals completed. F, In contrast to mOFC inactivation, lOFC inactivation did not affect error rates during the initial acquisition of the task but did tend to increase the number of errors made during the first reversal. G, lOFC inactivation did not alter perseverative tendencies. H, These treatments reduced both win-stay and lose-shift behaviors only after incorrect choices. Asterisk denotes p < 0.05.

Figure 3.

Inactivation of neither the mOFC (top row, n = 8) nor the lOFC (bottom row, n = 6) affects performance of a reversal learning task when feedback was assured. A, C, Number of reversals completed per 100 successful trials following saline or inactivation treatments within the mOFC or lOFC. B, D, Errors to achieve criterion performance were not affected by inactivation of either the mOFC (B) or the lOFC (D) during the initial discrimination and first two reversal phases of the reversal with assured outcomes task after inactivation and control treatments.

Figure 4.

Inactivation of the prelimbic PFC induced an apparent improvement in PRL performance. A, Inactivation of the prelimbic PFC (n = 14) increased the number of reversals completed per 100 trials relative to control treatments. B, Errors to achieve criterion were reduced following prelimbic PFC inactivation. C, Perseverative-type errors were not affected by these treatments. D, Win-stay tendencies were increased following both correct and incorrect choices while lose-shift behavior was decreased only following correct choices. Asterisks denote p < 0.05.

Figure 5.

Inactivation of the infralimbic PFC (top row, n = 11) or the anterior cingulate (bottom row, n = 10) did not significantly affect PRL performance. A, D, the number of reversals completed per 100 trials. B, E, The number of errors made to achieve criterion during either the initial acquisition or reversal stages of the task or (C, F) win-stay/lose-shift behavior. Note, however, the trend of reduced number of reversals completed induced by anterior cingulate inactivation.