DESCRIPTION (provided by applicant): Human beings have a fundamental "need to belong." We are powerfully motivated to seek out, engage in, and maintain strong interpersonal attachments. Developing and maintaining close relationships, however, is not an easy task for many people with mental illnesses. Disturbances in social motivation are particularly debilitating, costly, and poorly understood in people with psychosis-related psychopathology (PRP). The RDoC affiliation construct provides a foundation for conceptualizing and unpacking the mechanisms of these disturbances in social motivation. Our scientific goal is to carve the RDoC affiliation construct into two separate sub-processes. Specifically, we will examine how the social approach and avoidance motivation systems of the brain relate to social disability across individuals with PRP and are impacted in their unaffected siblings. This project is grounded in a translational social neuroscience model of affiliation that includes two distinct neural sub-systems: (1) the social approach motivation system is sensitive to social safety signals and promotes social engagement and attachment (primarily involving the striatum, ventromedial frontal cortex, and hypothalamus); (2) the social avoidance motivation system is sensitive to social threat signals and promotes avoidance of rejection and discord (primarily involving the insula, anterior cingulate, and amygdala). These systems are modulated by select neuropeptides/transmitters, chiefly oxytocin (OXT), vasopressin (AVP), dopamine, and opioids. Data from our lab and others indicate that problems in affiliation can stem from disturbances in both of these systems across PRP. We predict that social approach and avoidance make independent contributions, though separable neurobehavioral mechanisms, to impaired social functioning in psychosis. In addition, we will evaluate these systems in unaffected siblings to determine whether they reflect vulnerability factors for social disability and psychosis (unconfounded by medication and chronicity). A diverse sample of 80 outpatients with a history of clinically significant psychotic symptoms, 80 of their unaffected siblings, and 40 healthy individuals from the community will complete established measures at four RDoC units of analysis: circuits (two social reward/punishment fMRI tasks), physiology (N170 responses to approving/ threatening faces), behavior (social reward/punishment learning task), and self-report (need for belonging, fear of rejection scales), as well as social functioning assessments. An exploratory aim will examine whether OXT/AVP molecule and receptor gene polymorphisms relate to individual differences across the four units of analysis. Our primary hypotheses test (1) the validity of the social approach and avoidance motivation constructs across multiple units of analyses and their predictive validity for explaining real world social functioning, and (2) whethe unaffected siblings show impairments in social approach/ avoidance that demonstrate significant within-family correlations. A mechanistic understanding of neural processes that lead to problems in social affiliation is essential for developing new recovery-oriented and preventative treatments.

PUBLIC HEALTH RELEVANCE: Although impaired social motivation is highly disabling across psychosis-related psychopathologies, the mechanisms of social disability are poorly understood. In 80 individuals with a history of clinically significant psychotic symptoms, 80 of their unaffectd siblings, and a community sample of 40 healthy individuals, this project examines whether disturbances in two key components of the RDoC affiliation construct, the social approach and avoidance systems of the brain, assessed across multiple units of observation, contribute to the social disability associated with psychosis. A mechanistic understanding of neurobehavioral processes that lead to problems in social affiliation can directly facilitate the development of ne recovery-oriented and preventative treatments.