Project Summary The Research Domains Criteria (RDoC) initiative was developed by the NIMH to address growing concern about the validity of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its potential to limit research on mental illness. The overarching aim of RDoC to identify dimensions of brain structure and function that will possess greater biological validity than our current taxonomy holds great promise for rational diagnosis and treatment of mental illness. The proposed study aims to examine one of the core components of RDoC that is focused on reward circuits and behavior, namely the Positive Valence Systems domain (PVS). The PVS has been linked to diverse psychiatric disorders including schizophrenia, bipolar disorder and major depressive disorder. There is consensus that schizophrenia and bipolar disorder share substantial genetic risk and multiple overlapping phenotypic variations at the levels of corticostriatal brain circuits, cognitive functions, and behavior. Yet it remains unknown precisely which dimensions are shared, which may diverge between syndromes, and how the associated phenotypes relate to shared and non-shared genetic risk. The proposed research will examine the RDoC PVS domains in two large genetically informative cohorts comprising more than 5,000 individuals already ascertained in the Netherlands. Participants include 1,000 schizophrenia patients, 1,750 subjects with bipolar disorder, more than 1,000 first-degree relatives and almost 1,500 healthy comparison subjects. Extensive clinical and neurocognitive data is already available, which will contribute significantly to our understanding of basic brain circuitry that controls behavior in health and disease. Available genome-wide genotype and whole genome sequencing data provide a unique opportunity to examine the heritability of the PVS measures and its relationship with the etiology of psychiatric disorder. We will collect multi-level data pertaining to each of the four primary PVS component processes identified by the RDoC Workshop focused on Reward Seeking and Consummatory Behavior (Approach Motivation) through online assessments of these cognitive constructs. These will be further validated by in-laboratory measures using functional MRI in a subset of participants (n=500). Analyses will focus on the ventral striatal (VS) and ventromedial prefrontal cortex (vmPFC) responses to anticipation and receipt of reward. We will derive response profiles from the four PVS cognitive tests that possess greatest concurrent validity with respect to individual differences in neural circuit function. Results of this study will provide important new data about the relations of the PVS component processes proposed in RDoC to the primary neural circuits, and enable the results in our genetically informative samples to be evaluated in the context of research on a broad range of mental disorders and healthy individuals.