Selective Modulation of Orbitofrontal Network Activity during Negative Occasion Setting

Discrete cues can gain powerful control over behavior to help an animal anticipate and cope with upcoming events. This is important in conditions where understanding the relationship between complex stimuli provides a means to resolving situational ambiguity. However, it is unclear how cortical circuits generate and maintain these signals that conditionally regulate behavior. To address this, we established a Pavlovian serial feature-negative conditioning paradigm, where male mice are trained on a trial in which a conditioned stimulus (CS) is presented alone and followed by reward, or a feature-negative trial in which the CS is preceded by a feature cue indicating there is no reward. Mice learn to respond with anticipatory licking to a solitary CS, but significantly suppress their responding to the same cue during feature-negative trials. We show that the feature cue forms a selective association with its paired CS, because the ability of the feature to transfer its suppressive properties to a separately rewarded cue is limited. Next, to examine the underlying neural dynamics, we conduct recordings in the orbitofrontal cortex (OFC). We find that the feature cue significantly and selectively inhibits CS-evoked activity. Finally, we find that the feature triggers a distinct OFC network state during the delay period between the feature and CS, establishing a potential link between the feature and future events. Together, our findings suggest that OFC dynamics are modulated by the feature cue and its associated conditioned stimulus in a manner consistent with an occasion setting model.SIGNIFICANCE STATEMENT The ability of patterned cues to form an inhibitory relationship with ambiguously rewarded outcomes has been appreciated since early studies on learning and memory. However, it was often assumed that these cues, despite their hierarchical nature, still made direct associative links with neural rewarding events. This model was significantly challenged, largely by the work of Holland and colleagues, who demonstrated that under certain conditions cues can inherit occasion setting properties whereby they modulate the ability of a paired cue to elicit its conditioned response. Here we provide some of the first evidence that the activity of a cortical circuit is selectively modulated by such cues, thereby providing insight into the mechanisms of higher order learning.