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.