Obsessive-Compulsive Disorder (OCD) is a mental disorder featuring obsessions (intrusive ideas) and compulsions (repetitive overt behaviors such as checking or washing, or mental actions) associated with high levels of anxiety. With a prevalence of 2-3%, OCD is among the most common anxiety disorders with most severe forms bearing a high cost for the individuals and the society, thus calling for effective treatments. Current standards have validated pharmacological (serotonin-reuptake inhibitors) and psychotherapeutical (cognitive-behavioral therapy) interventions to treat OCD, however 20-30% patients do not respond to these approaches. In patients with severe treatment resistant OCD recent clinical trials have demonstrated the clinical efficacy of deep-brain stimulation of several subcortical nuclei or fibers. In this project we focus on the subthalamic nucleus (STN), which has proved to be a very potent target by the highest level of evidence. Current knowledge derived from clinical studies is however very limited regarding the role of STN in the psychopathological processes underlying OCD and the therapeutical mechanisms triggered by high-frequency stimulation of this region. TYMON project will bring together three internationally renowned teams from France, Germany and Portugal to assess the role of STN in OCD. In particular, this three-year translational project will focus on two specific cognitive processes that, when dysfunctional, could lead to compulsive checking: (i) Uncertainty-monitoring: Deficit in accumulating sensory evidence would trigger repetitive checking behavior as an attempt to reduce uncertainty before making a choice and (ii) Inhibitory control: Failing to put an end to a sequence of checking actions would result in repetitive checking. Therefore, TYMON partners will perform experiments with mice models of OCD as well as human OCD patients in order to: (a) understand the role of STN in uncertainty-monitoring, inhibition and checking processes; (b) identify circuitry dysfunction in OCD; and (c) assess the mechanisms of deep brain stimulation that may revert compulsive checking. In addition, TYMON’s outputs will also provide the research community with the bases for new powerful tools ranging across animal models of pathology and interventions to human behavioral and electrophysiological biomarkers that may not only apply to investigate other neural pathways with the OCD brain but also foster the development of new therapeutic approaches and/or improvement of existing ones in other psychiatric conditions.

Neurodevelopmental and neurodegenerative diseases affect more than one out of a thousand people in Europe, leading to learning and motor disabilities. In order to find therapies for our aging population, a main challenge for the neuroscience field is to understand how neural circuits process information from the outside world along with inner physiological states in order to produce a versatile but reliable repertoire of behaviors. To reach this goal, there are two major research obstacles: 1) the complexity and distributed nature of the circuits involved; 2) the need for data spanning multiple scales from molecular phenotypes and activity of single cells through to circuit connectivity and population dynamics and finally the behavioral output itself. The scientific goal of the ZENITH ETN, “ZEbrafish Neuroscience Interdisciplinary Training Hub”, is to understand how neural networks mediate perception and behavior in normal and pathological conditions. Our consortium will exploit the advantages of zebrafish as a small transparent vertebrate with superb genetic accessibility and use cutting-edge technology to elucidate the interactions between molecules, cells and entire networks that ultimately generate a set of adaptive behaviors. Our training goal is to create collaborative, highly interdisciplinary young scientists who can tackle the major challenges within neuroscience research. Therefore, training in cutting-edge technologies (genetics and genome engineering, in vivo electrophysiology, whole brain calcium imaging, quantitative behavior analysis, modelling) will be combined with analytical frameworks in order to enable the next generation of researchers to perform integrated, multi-scale analyses that are necessary to elucidate the neural basis of naturalistic behaviors. The training we propose is centered on highly collaborative projects between physicists, mathematicians, biologists and applied neuroscientists that will expose ESRs to broad training with academic and industrial partners. Advanced optical methods, electrophysiology and genome-editing will be utilized to link molecules to circuits, to map connectivity between cell types across the nervous system and to build computational models of brain activity that will be experimentally tested. Overall ZENITH will help to change the way young scientists are trained in Europe and provide the conceptual, technical and analytical skills needed to take on the challenge of understanding how the beautifully complex circuits of the vertebrate brain control behavior.