Integrated Reward-Inflammation Model of First Onset of Major Depression in Adolescence

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7. Project Summary/Abstract Adolescence is an “age of risk” for the emergence of 1st onset of major depressive disorder (MD). Despite its prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to MD. Depression (Dep) is associated with a reduced sensitivity to rewards and low reward-related brain function in cortico-striatal circuitry. However, research has not yet tested whether chronically low reward responsivity (RR) or attenuated RR development during adolescence predicts 1st onset of MD. A separate literature documents elevated peripheral inflammation in Dep. Yet, research also has not examined whether chronically elevated inflammation or increases in inflammation during adolescence predicts 1st onset of MD. Further, research on inflammation and RR mostly has proceeded in parallel. Recently, however, we and others have proposed neuroimmune network models of Dep. These models draw on work indicating that peripheral inflammatory mediators (e.g., cytokines) access the brain, where they lower RR. When dysregulated, this immune-to-brain signaling can lead to chronic and worsening low RR, which is reflected in dysphoria and anhedonia. This low RR is proposed to initiate unhealthy behaviors (substance use, poor diet), as well as sleep disruption and stress generation, which further heighten inflammation. Over time, dysregulation in RR and immune signaling may synergize in a positive feedback loop, whereby dysregulation in each system exacerbates dysregulation in the other. We propose that reward-immune dysregulation is a two-hit vulnerability for the 1st onset of MD and increases in Dep symptoms (Sxs) during adolescence. Moreover, childhood and adolescent adversity and recent stressors influence both RR and inflammation, and may set the foundation for reward-immune dysregulation. This proposal is the first systematic test of these hypotheses. We will use an innovative biobehavioral high-risk design to examine bidirectional relationships between peripheral inflammation and multiple indices and domains (monetary, social) of RR and their joint prediction of 1st onset of MD and increases in Dep Sxs, particularly anhedonia. Three hundred 14-15 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with no prior MD will be selected along the entire dimension of self-reported RR, with oversampling at the low tail of the dimension in order to increase the likelihood of MD onsets. At Time 1 (T1), T3, and T5, each a year apart, Ps will complete blood draws to quantify inflammation, self-report and behavioral measures of RR, and fMRI scans of reward neural activity and functional connectivity. At T1-T5 (with T2 and T4 6 mo. between the yearly sessions), Ps also will complete diagnostic interviews, and measures of Dep Sxs, reward-relevant life events, and behaviors that increase inflammation. Adversity history will be assessed at T1 only. This proposal is an innovative integration of research on reward and inflammatory signaling in understanding 1st onset of MD in adolescence. It has the potential to facilitate novel neuroimmune and behavioral interventions to treat, and ideally prevent, MD.