Oxytocin receptor signaling modulates social attachment via hippocampal CA2/3 function - PROJECT SUMMARY. Social attachments play a central role in every level of human interaction, from relationships between parents and children to enduring partnerships with mates. A major barrier to understanding the neural basis of this behavior is that mice and other traditional model organisms do not exhibit complex attachments. In contrast, prairie voles (Microtus ochrogaster) form social attachments and demonstrate enduring social monogamy between mates. Such attachments result in a preference for bonded partners and the robust rejection of novel conspecifics, both of which require social memory of specific individuals. This suggests that key regions such as the hippocampus contribute to the affective and behavioral responses to a given individual. Hippocampal areas CA2 and CA3, specifically, are implicated in social memory and the display of agonistic behaviors towards novel intruders in mice. Importantly, hippocampal CA2/3 is modulated by oxytocin, a key neuroendocrine mediator of attachment behaviors. However, how CA2/3 and oxytocin receptor (OxtR) signaling therein contribute to pair bonding is unknown. This proposal will delineate the molecular, cellular, and functional mechanisms by which neuroendocrine signaling in the hippocampus contributes to social attachment in the socially monogamous prairie vole. In the mentored phase of this research plan, we will identify sex- and species- specific spatial distributions of cell types and neuroendocrine receptors in the vole hippocampus. To do this, we will conduct single-nucleus RNA sequencing of the hippocampus in combination with multiplexed error robust fluorescence in situ hybridization (MERFISH). In the independent phase, we will test the hypothesis that CA2/3 and OxtR signaling therein mediate the rejection of novel, potential mates in the prairie vole. First, we will determine the hippocampal neuroendocrine cell types activated by exposure to a partner vs. a novel stranger using MERFISH with immediate early gene imaging in bonded prairie voles. Second, we will test CA2/3 ensemble responses to social interactions with partners and strangers across pair bonding using miniscope imaging. Third, we will test whether CA2/3 activity and CA2/3 OxtR function are necessary for pair bond maintenance by a) chemogenetically inhibiting CA2/3 or b) locally delivering an OxtR antagonist prior to assays for stranger rejection in pair bonded voles. These studies will provide novel insight into the neural mechanisms governing social attachment and their modulation by oxytocin, ultimately contributing to the BRAIN Initiative priority areas of identifying cell types, monitoring neural activity, and using interventional tools to understand the neural basis of complex social cognition. This work will be conducted at the University of California, San Francisco, a premier research institution with ample research and career development resources. I will receive training in transcriptomics, bioinformatics, and professional development. For this, I have assembled a mentorship team that will provide expertise for every aspect of my training and will help me to accomplish my goal of becoming faculty at a top institution.
