PROJECT SUMMARY/ABSTRACT The death of a loved one is monumentally painful, impacting 8 million in the US annually, and is a significant cause of psychiatric and medical morbidity, including psychiatric sequelae such as depression, anxiety, substance abuse, and complicated grief. Research exploring the association between social loss and brain function are sparse, and diagnostic criteria for the emerging disorders are based on symptom clusters rather than neural or genetic abnormalities, hindering pursuits of new therapeutic targets. This highlights the need for proper animal models for social loss to mirror the behavioral symptomology to explore the neurobiological mechanisms. Recently, we have developed an animal model of social loss using the socially monogamous prairie vole (Microtus ochrogaster), which manifest similar behavioral symptomology and disruption to normal mesolimbic reward pathway that occurs in social loss in humans. Our long-term goals are to dissect the neurocircuitry of social loss (including the mesolimbic reward and corticolimbic pain pathways), define genetic biomarkers of individual vulnerability and resiliency to social loss, and develop therapeutic intervention of neural and behavioral symptoms that appear persistent. Our theoretical neurocircuit of social loss centers in the limbic system, which receives dopamine (DA) signaling from the ventral tegmental area (VTA) and augments motivational state and emotional valence. Our specific aims will test the following hypotheses: (AIM 1) Loss of specific relationship types can propagate persistent change to the functional and structural connectivity of mesolimbic circuits; (AIM 2) Behavioral symptoms of long-term social loss are based on disruption to DA neurotransmission and can be alleviated with photostimulation and chemical innervations along select mesolimbic pathways; (AIM 3) Changes to the expression and activity of specific DA receptors in mesolimbic regions are coupled to fluctuating motivational states during loss and seeking of partner-associated cues. This contribution is significant since it will establish that several pathways targeted by photostimulation and pharmacological approaches have the potential to regulate behavioral symptomology of social loss through mesolimbic activity. The proposed research is innovative as it is the first systematic evaluation of neuromodulation of the mesolimbic system during partner loss in an animal model. Insight into the neuromodulation of social loss is impactful as it may expand diagnostic criteria for the emerging mental health disorders beyond symptom clusters and identifies neurochemical substrates for new therapeutic targets.