Transcriptional lability of brain oxytocin receptor (Oxtr) generates diversity in brain OXTR distribution and social behaviors

Abstract

AbstractOxytocin 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 investigate potential genetic mechanisms underlying the phylogenetic plasticity in brainOxtrexpression and its consequences on social behavior, we constructed BAC transgenic mice harboring the entire prairie voleOxtrlocus with surrounding intergenic regulatory elements. Eight independent “volized” (pvOxtr) mouse lines were obtained; remarkably, each line displayed a unique pattern of brain expression distinct from mice and prairie voles. FourpvOxtrlines were selected for further investigation. Despite robust differences in brain expression,Oxtrexpression in mammary gland was conserved across lines, suggesting thatOxtrexpression in brain, but not mammary gland, is highly sensitive to local chromosomal landscape at integration sites. Moreover, different “volized” mouse lines showed differences in partner preference and maternal behaviors. Our results from this cross-species study suggest that species-specific variation in regulatory elements or distribution of transcription factors are not responsible for species-typical brainOxtrexpression patterns. Thus, transcriptional hypersensitivity to surrounding sequence of brainOxtrmay be a key mechanism to generate diversity in brain OXTR distribution and social behaviors. This inherent “evolvability” of brainOxtrexpression constitutes a novel transcriptional mechanism to generate variability in neuropeptide receptor distribution which, through natural selection, can generate diversity in adaptive social behaviors while preserving peripheral expression. The “volized”Oxtrmouse lines are useful for further understanding OXTR regulation and key neural circuits/networks mediating variability in social behaviors.Significance StatementUnlike the essential physiological phenomenon including feeding, sex, parturition and lactation, which are conserved across mammalian species, there is extraordinary diversity of social behaviors between and within species. Comparative studies across species suggest that variation in brain oxytocin receptor expression may mediate diversity in social behavior. Subtle variation in human oxytocin receptor sequence have been related to psychiatric phenotypes. Our studies suggest that the oxytocin receptor gene is hypersensitive to sequence variation at its molecular address which leads to variability in brain expression pattern and social behavior. This research provides new insights into the evolvability of genes producing diversity in social behaviors, which allows efficient adaptation of animals to variable environment and potentially provides insight into psychiatric outcomes related to social behavior.