Natural variation in oxytocin receptor signaling causes widespread changes in brain transcription: a link to the natural killer gene complex

• Type of Material: Article
• Authors: Arjen Boender, Emory University; Zachary Vernon Johnson, Emory University; George W. Gruenhagen, Emory University; Kengo Horie, Emory University; Brianna E. Hegarty, Georgia Institute of Technology; Jeffrey T. Streelman, Georgia Institute of Technology; Hasse Walum, Emory University; Larry Young, Emory University
• Language: English
• Date: 2023-10-27
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2023.10.26.564214
• Title of Journal or Parent Work: bioRxiv
• Start Page: 564214
• Grant/Funding Information: This project was supported by NIH grants P50MH100023 and R01MH112788 to LJY, R01GM144560 to JTS for support to BEH, GWG, ZVJ and JTS, and OD P51OD011132 to Emory National Primate Research Center.
• Keywords: Oxytocin; receptor gene; C-type lectin-like receptors
• Research Categories: Biology, Genetics; Health Sciences, Immunology; Biology, Neuroscience

Abstract

Oxytocin (OXT) is a highly conserved neuropeptide that modulates social cognition, and variation in its receptor gene (Oxtr) is associated with divergent social phenotypes. The cellular mechanisms connecting Oxtr genotype to social phenotype remain obscure. We exploit an association between Oxtr polymorphisms and striatal-specific OXTR density in prairie voles to investigate how OXTR signaling influences the brain transcriptome. We discover widespread, OXTR signaling-dependent transcriptomic changes. Interestingly, OXTR signaling robustly modulates gene expression of C-type lectin-like receptors (CTLRs) in the natural killer gene complex, a genomic region associated with immune function. CTLRs are positioned to control microglial synaptic pruning; a process important for shaping neural circuits. Similar relationships between OXTR RNA and CTLR gene expression were found in human striatum. These data suggest a potential molecular mechanism by which variation in OXTR signaling due to genetic background and/or life-long social experiences, including nurturing/neglect, may affect circuit connectivity and social behavior.