Persistent threat avoidance following negative reinforcement is not associated with elevated state anxiety

Obsessive-Compulsive Disorder (OCD) is a debilitating illness consisting of obsessions and compulsions. OCD severity and treatment response are correlated with avoidant behaviors thought be performed to alleviate obsession-related anxiety. However, little is known about either the role of avoidance in the development of OCD or the interplay between anxiety states and avoidance behaviors. We have developed an instrumental negative reinforcement (i.e. active avoidance) paradigm in which mice must lever-press to avoid upcoming foot shocks. We show that mice (both sexes) can learn this task with high acquisition rates (75%) and that this behavior is largely stable when introducing uncertainty and modifying task structure. Furthermore, mice continue to perform avoidance responses on trials where lever pressing is not reinforced and increase response rates as they are maintained on this paradigm. With this paradigm, we did not find a relationship between negative reinforcement history and anxiety-related behaviors in well-established anxiety assays. Finally, we performed exploratory analyses to identify candidate regions involved in well-trained negative reinforcement using expression of the immediate early gene c-Fos. We detected correlated c-Fos expression in 1) cortico-striatal regions which regulate active avoidance in other paradigms and 2) amygdala circuits known to regulate conditioned defensive behaviors. Significance Statement Studies in patients with OCD suggest that compulsions are performed to avoid perceived threats and modulate anxiety tied to obsessions and/or compulsions. The negative reinforcement of avoidance and alleviated anxiety could therefore be a key driver of compulsive behaviors. However, there are still outstanding questions concerning the relationship between these two behaviors and the neural circuits involved in mediating negative reinforcement. We have developed an operant negative reinforcement paradigm in mice with discrete avoid and escape behaviors that can be learned without prior reward training with high throughput (75% acquisition) with responding that persists during nonreinforced trials. However, no differences were observed between negative reinforcement vs. unshocked and inescapably shocked controls, suggesting that continued negative reinforcement did not impact anxiety.