A genetic strategy to identify neural circuits that regulate social attachment in prairie voles

/ABSTRACT We form attachments at many levels of social interactions, including with spouses, family members, friends, and other members of the community. The neurobiological mechanisms that control the formation and maintenance of social attachment remain poorly understood. This is in part because traditional genetic model systems such as mice, fish, flies, and worms do not exhibit social attachment as adults, precluding the use of powerful molecular genetic approaches to dissect mechanisms underlying this behavior. Prairie voles are small rodents that form an enduring social bond (referred to as pair bonds) between adults, and they also display other related affiliative behaviors. Pharmacologic studies in prairie voles have implicated vasopressin and oxytocin signaling through their receptors OXTR and AVPR1A in the control of social attachment, providing a potential entry-point into the neural circuits that govern this behavior. However, in our published and unpublished work, we find that neither OXTR nor AVPR1A are genetically required for pair bonding. To realize our goal to understand how the brain encodes pair bonding, we propose a genetic approach that is independent of OXTR or AVPR1A to gain a new entry-point into the neural circuits underlying this behavior. In brief, we will use the FosTRAP approach first developed in mice to achieve our goal. This approach relies on using FOS to genetically tag neurons that are activated during a specific behavior, and in mice, this has revolutionized identification and functional characterization of neural circuits underlying diverse behaviors and physiology in health and disease. For the current project, we will generate genetically modified voles that have a small molecule-inducible Cre recombinase inserted into the prairie vole Fos locus and a Cre-dependent fluorescent reporter inserted into the prairie vole Rosa locus (Specific Aim 1); in Specific Aim 2, we will validate the use of these knock-in vole strains and identify neuronal populations that are activated during pair bonding. As with the FosTRAP strategy in mice, voles bearing the modified Fos and Rosa genes will enable genetic tagging of neurons activated during a specific behavior, pair bonding in our case for this project. Taken together, our studies will enable identification and functional studies of neural pathways that govern social attachment behavior in prairie voles. Health relatedness: Social attachments are thought to be critical for our mental health and personal and professional success. Failure to form or maintain social attachments is often an early indicator of a serious mental illness such as autism spectrum disorder, depression, and schizophrenia. Our proposal seeks to develop genetic means to access the neural circuits underlying social attachment in prairie voles, which have long been considered the premier mammalian model for these complex social interactions. Our projection may therefore provide a useful model system to study social behaviors relevant to human health and mental illnesses. Project Number: 1R21MH141455-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Nirao Shah | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $457,795 | Activity Code: R21 | Study Section: Neurobiology of Motivated Behavior Study Section[NMB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11218616