Distal regulatory sequences contribute to diversity in brain oxytocin receptor expression patterns and social behavior

• Published in: bioRxiv
• Main Authors: Zhang, Qi, Luis Augusto Eijy Nagai, Tsukamoto, Mina, Kandasamy, Lenin C, Inoue, Kiyoshi, Pires, Maria F, Shin, Minsoo, Nagasawa, Yutaro, Sambuu, Tsetsegee, Ogawa, Sonoko, Nakai, Kenta, Itohara, Shigeyoshi, Young, Larry J
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 09.11.2023
• Subjects: Behavior; Geographical distribution; Lability; Mammary gland; Maternal behavior; Microtus ochrogaster; Natural selection; Neural networks; Neural plasticity; Oxytocin; Phylogeny; Regulatory sequences; Rodents; Social behavior; Transcription factors; Transgenic mice
• DOI: 10.1101/2022.12.01.518660

The oxytocin receptor (OXTR) modulates social behaviors in a species-specific manner. Remarkable inter- and intraspecies variation in brain OXTR distribution are associated with diversity in social behavior. To test the causal effect of developmental variation of OXTR expression on the diversity of social behaviors, and to investigate potential genetic mechanisms underlying the phylogenetic plasticity in brain Oxtr expression, we constructed BAC transgenic mice harboring the entire prairie vole Oxtr locus with the entire surrounding intergenic regulatory elements. Eight independent volized prairie vole-Oxtr (Oxtr) mouse lines were obtained; remarkably, each line displayed a unique pattern of brain expression distinct from mice and prairie voles. Four pvOxtr lines were selected for further investigation. Despite robust differences in brain expression, Oxtr expression in mammary tissue was conserved across lines. These results and topologically associating domain (TAD) structure analysis suggest that Oxtr expression patterns in brain, but not other tissues, involve contributions of distal regulatory elements beyond our BAC construct. Moreover, volized mouse lines with different brain Oxtr expression patterns showed differences in partner preference and maternal behaviors. We speculate that transcriptional hypersensitivity to variable distal chromosomal sequences through long-distance interactions with proximal regulatory elements may contribute to evolvability of brain Oxtr expression. The evolvability of brain Oxtr expression constitutes a transcriptional mechanism to generate variability in brain OXTR which, through natural selection, can generate diversity in adaptive social behaviors while preserving critical peripheral expression. Transcriptional lability of brain OXTR expression may also contribute to variability in social phenotype in humans, including psychiatric outcomes.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We added Hi-C analysis data, and added multiple figures and tables.