Frederik Gudmundsen: "Whole Brain Circuit Dissection - A Promising Avenue for Understanding the Pathophysiology of OCD"

Master stud. from Mikael Palner’s group at Neurobiology Research Unit

Abstract: Obsessive Compulsive Disorder (OCD) is a severe chronic neuropsychiatric disorder, with an estimated prevalence of around 3% worldwide. Despite the severity and relatively high prevalence, the understanding of the underlying mechanisms is still very limited. However, over the last decades, converging evidence point towards abnormalities within the Cortico-Striato-Thalamo-Cortical Circuit as a main contributor to the pathophysiology of OCD.
My Thesis was concerned with the CSTC circuit, and how modulation of the dopaminergic projections from Substantia Nigra pars compacta (SNc) to Dorsomedial Striatum (DMS) induce regional changes in neuronal activity within the CSTC circuit. Throughout the thesis we used Positron Emission Tomography (PET) with the tracer [18F]FDG to measure regional changes in neuronal activity within the CSTC circuit elicited by chemogenetic activation of the dopaminergic projections from SNc to DMS in rats. Furthermore, regional [18F]FDG uptake within the CSTC circuit were afterwards correlated to assess changes in functional connectivity before and after chemogenetic stimulation of the dopaminergic projections from SNc to DMS. As a control we did a unilateral 6-OHDA lesion study to evaluate the role of dopaminergic signaling in modulating neuronal activity within the CSTC circuit.
Here we found a general hypoactive state throughout the CSTC circuit after chemogenetic stimulation, with significant changes in striatal and frontocortical areas which are often associated with a hyperactive state in OCD patients. These regional changes in neuronal activity were partly reversed in the 6-OHDA lesion study, indicating that malfunctioning striatal dopamine release could be a contributor to the pathophysiology of OCD. Furthermore, changes in functional connectivity within the CSTC circuit were found between striatal-, frontocortical areas and thalamus, suggesting that chemogenetic stimulation of the dopaminergic projections from SNc to DMS disrupts striatal-cortical connectivity, which is often found to be in a hyperactive state in OCD patients. These results not only support pre-existing theories regarding the CSTC circuit as a main contributor to the pathophysiology of OCD. But also provide a promising avenue for understanding the pathophysiology of OCD, by dissecting the individual role of neuronal subpopulations through chemogenetic control and [18F]FDG PET measurement, in vivo.