Project Summary/Abstract Mood disorders are prevalent among individuals living with HIV for which multi-dimensional, contributing factors exist. Especially, 20-50% of youth living with HIV (YWH) report depression or elevated depressive symptoms of clinical relevance. Depression or elevated depressive symptoms in YWH result in HIV include poor adherence to HIV treatment, poor viral suppression, increased morbidity and mortality as well as decreased quality of life. In spite of growing data showing the association between blood inflammatory markers and levels of depressive mood or clinical depression in HIV- and HIV+ individuals, inconsistent findings across the studies in the inflammatory marker-depression associations pose challenges in understanding mechanisms and lead to a paucity of targeted therapeutics. Given the profound modulatory effects of multiple branches of the neuroendocrine system on immune/inflammatory activities, we propose to conduct simultaneous investigations of potentially concurrent but disparate neuro-immune pathways (“NIP”) of inflammation dysregulation (IR) in predicting depressive symptoms in 45 YWH and 45 Control youth (aged 18-25 yrs), by leveraging an ongoing R01 study of brain function and cannabis use in YWH (DA047906). We will employ an ex vivo cellular model of peripheral blood monocytes by which effects of various receptor agonists in cellular IR will be assessed [1) sympatho-adrenal (SA)/adrenergic receptor (AR); 2) glucocorticoid (GC)/GC receptor (GR), and 3) dopaminergic (DA)/DR pathways] in predicting depressive symptoms (Aim 1). The neuroimaging markers of neuroinflammation from R01 [1) diffusion tensor imaging measures (e.g., fractional anisotropy), 2) structural alterations (i.e., white matter abnormality), and 3) metabolites through MR Spectroscopy (i.e., higher choline and myo-inositol, indicating diminished neuronal integrity and increased inflammation)] will be examined as a mediator (Aim 2). We will also explore differing depressive symptom domains [1) cognitive, 2) affective, and 3) somatic domains as well as 4) apathy and 5) anhedonia], as initial evidence shows symptoms specific to HIV infection such as somatic symptoms and apathy which may provide insight into delineating NIP- brain regions-symptoms network (Aim 3). Many types of the data collected in the R01 study will be shared with this R21 such as sociodemographic; clinical; psychological and behavioral; and neuroimaging data, maximizing the feasibility of this R21. Our simultaneous investigation of three NIP pathways with careful analytical plans in predicting depressive symptoms will provide an opportunity to gain mechanistic knowledge beyond plasma inflammatory marker-depression associations and to inform targeted therapeutic modalities.