Oxytocin receptors are widely distributed in the prairie vole (Microtus ochrogaster) brain: Relation to social behavior, genetic polymorphisms, and the dopamine system

Abstract

Oxytocin regulates social behavior via direct modulation of neurons, regulation of neural network activity, and interaction with other neurotransmitter systems. The behavioral effects of oxytocin signaling are determined by the species‐specific distribution of brain oxytocin receptors. The socially monogamous prairie vole has been a useful model organism for elucidating the role of oxytocin in social behaviors, including pair bonding, response to social loss, and consoling. However, there has been no comprehensive mapping of oxytocin receptor‐expressing cells throughout the prairie vole brain. Here, we employed a highly sensitive in situ hybridization, RNAscope, to construct an exhaustive, brain‐wide map of oxytocin receptor mRNA‐expressing cells. We found that oxytocin receptor mRNA expression was widespread and diffused throughout the brain, with specific areas displaying a particularly robust expression. Comparing receptor binding with mRNA revealed that regions of the hippocampus and substantia nigra contained oxytocin receptor protein but lacked mRNA, indicating that oxytocin receptors can be transported to distal neuronal processes, consistent with presynaptic oxytocin receptor functions. In the nucleus accumbens, a region involved in oxytocin‐dependent social bonding, oxytocin receptor mRNA expression was detected in both the D1 and D2 dopamine receptor‐expressing subtypes of cells. Furthermore, natural genetic polymorphisms robustly influenced oxytocin receptor expression in both D1 and D2 receptor cell types in the nucleus accumbens. Collectively, our findings further elucidate the extent to which oxytocin signaling is capable of influencing brain‐wide neural activity, responses to social stimuli, and social behavior. Key points Oxytocin receptor mRNA is diffusely expressed throughout the brain, with strong expression concentrated in certain areas involved in social behavior. Oxytocin receptor mRNA expression and protein localization are misaligned in some areas, indicating that the receptor protein may be transported to distal processes. In the nucleus accumbens, oxytocin receptors are expressed on cells expressing both D1 and D2 dopamine receptor subtypes, and the majority of variation in oxytocin receptor expression between animals is attributable to polymorphisms in the oxytocin receptor gene.

Pair-bonding and social experience modulate new neurons survival in adult male and female prairie voles (Microtus ochrogaster)

“…Microtus ochrogaster (prairie voles) are monogamous rodents that develop life-long pair bonds, showing a highly social organization and displaying biparental care for their offspring. Social behaviors associated with pair bonding involve multiple neurobiological processes including those regulated by region-specific expression of oxytocin and vasopressin receptors ( Walum and Larry, 2018 ; Froemke and Young, 2021 ; Han et al, 2021 ; Inoue et al, 2022 ; Rigney et al, 2022 ) and plastic neural processes such as neurogenesis (review in Holmes, 2016 ; Bedos et al, 2018 ). Pair bonds are established after cohabitation without sex for 24 h or mating for 6 h ( Williams et al, 1992 ).…”

“…The OB and the hippocampus are essential components of the limbic system which regulates social and sexual input such as conspecific odor signaling, partner recognition, spatial information, and partner-associated memory in rodents ( Catani et al, 2013 ). The DG of the hippocampus is critical for social memory and is proposed to play a critical role in pair bonding in titi monkeys and prairie voles ( Tabbaa et al, 2016 ; Walum and Larry, 2018 ; Baxter et al, 2020 ) and expresses high amounts of oxytocin receptors ( Inoue et al, 2022 ). Furthermore, oxytocin in the anterior DG and CA2/CA3 is necessary for discrimination of social stimulus ( Raam et al, 2017 ).…”

The neural circuits of monogamous behavior

“…For example, the auditory system is disproportionately larger in prairie voles than in other rodents ( Campi et al, 2007 ). Interestingly, OTR expression has been detected in the auditory cortex ( Inoue et al, 2022 ), and complex ultrasonic vocalizations have been observed for mate calling in male voles ( Ma et al, 2014 ) suggesting a relevant role in socio-sexual behavior. Also, common marmosets reportedly rely on scent for socio-sexual communication, and female vocalizations have been observed as a pair-bond maintenance behavior ( Evans and Poole, 1983 , 1984 ).…”

“…Experiments reporting the inhibition of vole pair-bonding behavior through the pharmacological manipulation of only a single region (NAcc, VP, or LS) ( Liu et al, 2001 ; Liu and Wang, 2003 ; Lim and Young, 2004 ; Ross et al, 2009b ; Barrett et al, 2013 ; Anacker et al, 2016 ) also imply that the whole circuit needs to be intact to function appropriately. However, a recent report has shown widespread expression of OTR throughout the prairie vole brain ( Inoue et al, 2022 ), suggesting extensive but subtle OT neuromodulatory signaling that may require interaction with other neural systems to elicit changes in plasticity associated with bonding behavior. Hence, the complexity of social monogamy has led to the conclusion that no single gene, brain structure, or neurotransmitter system can be the sole modulator of the observed behaviors ( Fink et al, 2006 ).…”

Transcription and DNA methylation signatures of paternal behavior in hippocampal dentate gyrus of prairie voles

“…In addition, exposure to psychostimulant drugs, such as amphetamine, not only diminished pair bonding [26,27], but also impaired social recognition and decreased neuronal and neurochemical activation in the DG [28]. In prairie voles, DG contains receptors for oxytocin [29] a key molecule in pair bonding and parental behaviors. It was found that oxytocin receptors are subjected to DNA methylation mediated gene expression regulation [30], whose density in DG is associated with mating tactics and reproductive success in male voles [31].…”