A Novel Insular/Orbital-Prelimbic Circuit That Prevents Persistent Avoidance in a Rodent Model of Compulsive Behavior.

BACKGROUND: A common symptom of obsessive-compulsive disorder is the persistent avoidance of cues incorrectly associated with negative outcomes. This maladaptation becomes increasingly evident as subjects fail to respond to extinction-based treatments such as exposure-with-response prevention therapy. While previous studies have highlighted the role of the insular-orbital cortex in fine-tuning avoidance-based decisions, little is known about the projections from this area that might modulate compulsive-like avoidance. METHODS: Here, we used anatomical tract-tracing, single-unit recording, and optogenetics to characterize the projections from the insular-orbital cortex. To model exposure-with-response prevention and persistent avoidance in rats, we used the platform-mediated avoidance task followed by extinction-with-response prevention training. RESULTS: Using tract-tracing and unit recording, we found that projections from the agranular insular/lateral orbital (AI/LO) cortex to the prefrontal cortex predominantly target the rostral portion of the prelimbic (rPL) cortex and excite rPL neurons. Photoinhibiting this projection induced persistent avoidance after extinction-with-response prevention training, an effect that was still present 1 week later. Consistent with this, photoexcitation of this projection prevented persistent avoidance in overtrained rats. This projection to rPL appears to be key for AI/LO's effects, considering that there was no effect of photoinhibiting AI/LO projections to the ventral striatum or basolateral amygdala. CONCLUSIONS: Our findings suggest that projections from the AI/LO to the rPL decreases the likelihood of avoidance behavior following extinction. In humans, this connectivity may share some homology of projections from lateral prefrontal cortices (i.e., ventrolateral prefrontal cortex, orbitofrontal cortex, and insula) to other prefrontal areas and the anterior cingulate cortex, suggesting that reduced activity in these pathways may contribute to obsessive-compulsive disorder.

Prolonged avoidance training exacerbates OCD-like behaviors in a rodent model.

Obsessive-compulsive disorder (OCD) is characterized by compulsive behaviors that often resemble avoidance of perceived danger. OCD can be treated with exposure-with-response prevention (ERP) therapy in which patients are exposed to triggers but are encouraged to refrain from compulsions, to extinguish compulsive responses. The compulsions of OCD are strengthened by many repeated exposures to triggers, but little is known about the effects of extended repetition of avoidance behaviors on extinction. Here we assessed the extent to which overtraining of active avoidance affects subsequent extinction-with-response prevention (Ext-RP) as a rodent model of ERP, in which rats are extinguished to triggers, while the avoidance option is prevented. Male rats conditioned for 8d or 20d produced similar avoidance behavior to a tone paired with a shock, however, the 20d group showed a severe impairment of extinction during Ext-RP, as well as heightened anxiety. Furthermore, the majority of overtrained (20d) rats (75%) exhibited persistent avoidance following Ext-RP. In the 8d group, only a minority of rats (37%) exhibited persistent avoidance, and this was associated with elevated activity (c-Fos) in the prelimbic cortex and nucleus accumbens. In the 20d group, the minority of non-persistent rats (25%) showed elevated activity in the insular-orbital cortex and paraventricular thalamus. Lastly, extending the duration of Ext-RP prevented the deleterious effects of overtraining on extinction and avoidance. These rodent findings suggest that repeated expression of compulsion-like behaviors biases individuals toward persistent avoidance and alters avoidance circuits, thereby reducing the effectiveness of current extinction-based therapies.