EP 21. Neuromodulation of the hyperdirect pathway to study flexibility as an endophenotype of obsessive compulsive disorders

Abstract

Obsessive-Compulsive Disorder (OCD) is a mental disorder featuring obsessions (intrusive ideas) and compulsions which are repetitive behaviors performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients have diminished behavioral flexibility. The pathophysiology of OCD support this hypothesis with dysfunctional cortico-basal ganglia loops including two specific structures connected together through the hyperdirect pathway: the subthalamic nucleus and the orbitofrontal cortex, both also involved in behavioral flexibility. Thus, our objective is twofold: to verify the involvement of behavioral flexibility in the compulsive behavior and to explore the neurobiological bases underlying flexibility in patients and an animal model of OCD (SAPAP3-KO). We aim at developing similar behavioral tasks in both species where we could chronically modulate neural activity using deep brain stimulation and optogenetic. Behavioral flexibility may be challenged in reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. When the association has been learned, reward contingencies are inverted. This task has been implemented easily for neuropsychological studies in human. However, the adaptation of non-spatial reversal learning task in rodents is much more laborious due to the high number of trials required for the acquisition. To overcome this issue, we developed automated behavioral cages where animals could live and be exposed continuously to the reversal learning task. Our protocol is based on 5 main successive stages of training and allow to perform multiple reversal within one session. This experimental setup has also be designed to integrate chronic neuronal stimulation device to automatically modulate neural activity in the hyperdirect pathway during relevant events of the task. We succeeded in designing a similar reversal learning task to explore the behavioral flexibility both in humans and rodents. With our automatic ecological behavioral setup for mice, we reduced very significantly the time necessary to perform visual reversal learning task compared to more classical paradigm. Moreover we obtained preliminary results which are in line with the hypothesis of an impaired behavioral flexibility in compulsive subjects. Indeed, we observed that both OCD patients and SAPAP3-KO mice showed perseverative maladaptive behaviors in our task. These preliminary results suggest that OCD conditions could be associated with a diminished behavioral flexibility. The development of a translational behavioral task is the first step of our aim to explore the neural basis of the behavioral flexibility and its link with compulsive behavior. For this purpose, our innovative designs will allow us to modulate the cortico-basal ganglia pathways both in patients (with DBS) and OCD mouse model (with optogenetic) during behavioral tasks to study their implications in compulsive behaviors.