Effects of persistent cortico-striatal optogenetic stimulation on behavioral flexibility in the search for an animal model of Obsessive-Compulsive Disorder (OCD)

Abstract

Mental disorders are currently the leading cause of disability. Among them, Obsessive-Compulsive Disorder (OCD) affects about 2 to 3% of the world population. Considering OCD prevalence, its strong impact on patient and family, and the high number of refractory patients, more studies for the understanding of its pathophysiology and optimization of therapeutic approaches are required. Although OCD pathophysiology is not entirely clear, accumulating evidence points to a dysregulation of the cortico-striatum-thalamus-cortical circuit, specifically a hyperactivity of the orbitofrontal cortex (OFC) and ventromedial striatum (VMS). However, it is not known whether such hyperactivity contributes to or results from the disease process. In this sense, non-human animal studies can contribute to the identification of circuits relevant for OCD and their specific functions. Although the research on compulsive-like behaviors in animal models for the study of OCD symptoms is not recent, such search has been reassessed and expanded in recent years due to the important technological gains observed in neurosciences. Great improvement has been obtained, for example, with optogenetic techniques, which guarantee temporal and spatial specificity for the activation/inhibition of neural circuits. Thus, repeated optogenetic hyperactivation of OFC-VMS projections generates progressive and persistent increase in grooming behavior, one of the most studied behaviors in animal models of OCD. Despite this progress, a broader analysis, which would consider several OCD-like behaviors resulting from the optogenetic manipulation, is still needed. For example, a relatively unexplored aspect of OCD in animal models is the impairment of behavioral flexibility, that is, deficits in the ability to modify behavior in response to changing environmental contingencies. Flexibility depends on a cognitive control network that includes OFC; therefore, it could be a better theoretical framework to align the investigations into different species, making basic research more relevant to clinical interventions for OCD. We propose here to expand the research on animal models of OCD to a model of pathological inflexibility development. For this, using an optogenetic approach to specifically and persistently activate the OFC-VMS circuit and induce grooming behavior, the present study aims to analyze the impact of such stimulation on set-shifting task and perseverative/repetitive behaviors (marble burying, nest-shredding and compulsive checking tests) in rats. We expect that the elevation of OFC-VMS activity leads to deficits in behavioral flexibility and exacerbate compulsive-like behaviors. We believe that our findings will contribute to a new vision on how OCD can develop and provide direction for new therapeutic approaches or refinements of existing OCD therapies. This project will be developed at the Massachusetts General Hospital, an international leader in neuroscience research and a premier provider of state-of-the-art basic, translational, and clinical research.