Oxytocin receptor controls promiscuity and development in prairie voles

Reviewer #1 (Public review):

Summary:

In this remarkable study, the authors use some of their recently-developed oxytocin receptor knockout voles (Oxtr1-/- KOs) to re-examine how oxytocin might influence partner preference. They show that shorter cohabitation times lead to decreased huddling time and partner preference in the KO voles, but with longer periods preference is still established, i.e., the KO animals have a slower rate of forming preference or are less sensitive to whatever cues or experiences lead to the formation of the pair bond as measured by this assay. This helps relate the authors' recent study to the rest of the literature on oxytocin and partner preference in prairie voles. To better understand what might lead to slower partner preference, they quantified changes to the durations and frequency of huddling. In separate assays, they also found that Oxtr1-/- KOs interacted more with stranger males than wild-type females. In a partner choice assay, they found that wild-type males prefer wild-type females more than Oxtr1-/- KO females. They then performed bulk RNA-Seq profiling of nucleus accumbens of both wild-type and Oxtr1-/- KO males and females, either housed with animals of the same sex or paired with a wild-type of the opposite sex. 13 differentially expressed genes were identified, mostly due to downregulation in wild-type females. These genes were also identified in a module lost in the Oxtr1-/- voles by correlated expression profiling. They also compared results of transcriptional profiling in female and male wild-type vs Oxtr1-/- voles (independently of bonding state) and found hundreds of differentially expressed genes in nucleus accumbens, mostly in females and often with some relation to neural development and/or autism. Some of the reduction in the transcript was confirmed with in-situs, as well as compared to changes in transcription in the lateral septum and paraventricular nucleus (PVN) of the hypothalamus. Finally, they find fewer oxytocin+ and AVP+ neurons in the anterior PVN.

Strengths:

This is an important study helping to reveal the effects of oxytocin receptor knockout on behavior and gene expression. The experiments are thorough and reveal a surprising number of genetic and anatomical differences, with some sexual dimorphism as well, and the authors have more carefully examined the behavioral changes after shorter and longer periods of partner preference formation.

Weaknesses:

It is surprising that given all the genetic changes identified by the authors, the behavioral phenotypes are fairly mild. The extent of gene changes also might be under-reported given the variability in the behavior and relatively low number of animals profiled.

Reviewer #2 (Public review):

Summary:

This manuscript uses a recently published oxytocin receptor null prairie vole line to examine the effects of this mutation on pair bonding behavior and PVN gene expression. Results reveal that Oxtr sex specifically influences early courtship behavior and partner preference formation as well as suppressing promiscuity toward novel potential mates. PVN gene expression varies between Oxtr null and WT prairie voles.

Strengths:

Behavioral analyses extend beyond the typical reporting of frequency and duration. The gene expression models and analyses are well-done and convincing. The experimental designs and approaches are strong.

Weaknesses:

More details and background literature explaining the role of the Oxt system in pair bonding behaviors is necessary, particularly for the Introduction. The authors overstate several times that Oxtr expression is not necessary for partner preference formation, based on their previous findings. However, it does appear, particularly, in the short cohabitation that it is necessary. Thus, the nuanced answer may be that Oxt may accelerate partner preference formation. Improving the presentation of the statistics and figures will make the manuscript more reader-friendly.