Project Summary Loss of a loved one elevates the risk for physical and mental illness and leads to impaired daily function. For most people, the deleterious effects of loss improve with time. However, in a subset of bereaved individuals, the failure to adapt leads to pathological manifestations of loss and an extension of bereavement-associated health impairments. A lack of investigation into the neuronal and molecular processes that underlie healthy adaptation to loss has hampered our ability to ameliorate the negative consequences of loss. To address this gap in our understanding, we propose to use partner separation in monogamous prairie voles to operationally produce loss. Socially monogamous prairie voles form life-long pair bonds and exhibit distress upon partner separation. However, pairs bonds fade with time after partner separation, as evidenced by reduced bonding- related behaviors. To identify the key neural and molecular changes that underlie the adaptive processes engaged after loss of a partner, we will compare voles with intact partner bonds to those who have been separated from their partner. In Aim 1, we will comprehensively assess behavioral and transcriptional responses to partner separation over time. In Aim 2, we will ask how the molecular identity of the neurons responsive to partner interaction changes as a function of separation time. Finally, in Aim 3 we will test the hypothesis that ablation of partner-active neurons facilitates bond dissolution and enables the vole to form a new bond. Together, these experiments will provide the first insights into key neuromolecular changes that underlie adaptation to loss, thereby representing potential therapeutic targets for treating the negative aspects of grief and Prolonged Grief Disorder.