PROJECT SUMMARY/ABSTRACT Depressive disorders are highly prevalent, recurrent, and debilitating conditions that typically first occur in adolescence. In fact, over 40% of days lost to ill-health, disability, or premature death among mental and substance use disorders are attributable to depression. There is substantial evidence that depressed individuals experience deficits in cognitive functioning (e.g., memory, executive functioning) that persist when depression is in remission. Significantly, cognitive deficits are directly associated with functional impairment in current and remitted depression. Theory and substantial empirical evidence suggest that chronic inflammation may underlie cognitive dysfunction in depression. Chronic inflammation is associated with a known risk factor for depression (stressful life events) and predicts cognitive dysfunction in medical, elderly, and healthy adult samples. Importantly, cognitive dysfunction in depression also has been directly linked to chronic inflammation. However, it is unknown whether chronic inflammation is predictive of persistent cognitive dysfunction when high levels of depression have abated. This proposal seeks to evaluate (i) whether a history of elevated depressive symptoms in adolescents/young adults predicts worse cognitive performance for those with chronic inflammation and (ii) whether a history of elevated depressive symptoms mediates the relationship between stressful events and cognitive dysfunction for those with chronic inflammation. The proposed study will recruit 100 individuals from a pool of 226 eligible participants who are taking part in an ongoing, NIMH funded R01 longitudinal study of adolescent depression. Eligible participants have completed at least two assessments of peripheral inflammatory biomarkers and have no pertinent medical disorders (e.g. autoimmune disorder), [traumatic brain injury or current depression diagnosis]. Chronic inflammation will be defined as individuals that exceed an established cut-off of a reliable biomarker of systemic, peripheral inflammation (C-reactive protein) on two or more occasions. Depression will be operationalized using person-level trajectories of depressive symptoms. Participants will complete a two-hour assessment that includes an evaluation of generalized cognitive functioning and specific domains of cognitive functioning (e.g., episodic memory, executive functioning). Thus, in line with NIMH Strategic Objective 2.2, this study proposes evaluating the relationship between inflammation, stress, depressive symptoms, and cognitive dysfunction. This study has the potential to better characterize the etiology of depression and identify intervention targets for a feature of depression that is associated with substantial functional impairment. A training plan has been designed that consists of formal classwork, workshops, experiential learning, and mentorship, to develop the applicant's expertise in the etiology of mood disorders, psyc...