PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a staggering public health challenge, manifesting in ~10% of adults in the US and contributing substantially to the global burden of disease and disability. Considering the increasing prevalence of MDD, particularly in young adulthood, it is critical to understand the pathophysiological underpinnings of MDD across a broad spectrum of function in order to identify individually-tailored preventive and therapeutic interventions. Given the intimate reciprocal link between stress and MDD, a better understanding of the mechanisms underlying stress system dysfunction in MDD may provide clinically relevant insight into such treatment strategies. The central scientific premise of this proposal is that MDD serves as a vulnerability factor that sensitizes and amplifies the functional link between daily psychosocial stress processes and acute sympathetic stress reactivity. Accordingly, determining the sympathetic neurovascular consequences of naturalistic daily psychosocial stress exposure may provide insight into the pathogenesis of MDD in stress- susceptible individuals, representing a novel biosignature of MDD. Aim 1 will examine the effect of daily psychosocial stress exposure on acute sympathetic stress reactivity in MDD. Aim 2 will determine the relation between negative affective reactivity to daily psychosocial stress exposure (i.e., increase in negative affect in response to stress) and acute sympathetic stress reactivity in MDD. Our integrative multi-pronged technical approach combines the comprehensive assessment of cumulative exposure and emotional responsiveness to naturalistic everyday psychosocial stressors (ambulatory daily diary-based approach) with the direct measurement of sympathetic reactivity (microneurography) during acute laboratory-applied emotional and cognitive stressors. Consistent with the Research Domain Criteria (RDoC) framework and to ensure the assessment of stress reactivity across a full spectrum of function, we will test adults with MDD having a broad range of symptom severity, as well as healthy non-depressed adults. Identification of the functional link between daily stressors and sympathetic reactivity in MDD is the necessary first step for future studies designed to examine novel targeted treatment and preventative strategies to induce emotional, cognitive, and physiological resilience to stress, thereby mitigating current—and reducing susceptibility toward future—psychiatric, cerebrovascular, and neurocognitive diseases.