Prairie voles are the romantics of the rodent world. These tiny brown furballs form long-term bonds with their mating partners, and both parents care for the young. Accordingly, prairie voles have become an important model system for studying social behavior.

Over the last few decades, pharmacological studies in prairie voles have pointed to the critical role of oxytocin in these animals’ social behaviors. In female voles, oxytocin administration hastened the development of preference for a certain partner, while drugs that blocked oxytocin activity prevented voles from forming a preference for the animal they had mated with (1,2).  New research from Devanand Manoli, a neuroscientist at the University of California, San Francisco and his team now casts doubt on whether this hormone really is as indispensable as scientists once thought.

This isn’t necessarily what Manoli set out to do when he and his team created an oxytocin receptor knockout (Oxtr-null) vole. “We did think of this as a proof of principle experiment,” he said. “Our expectation was that the genetics would mirror what the pharmacology had shown.”

The team was in for a surprise, however. The social behavior of the animals without oxytocin receptors was strikingly similar to the normal prairie voles (3). Just like normal voles, the Oxtr-null voles exhibited pair bonding; after a short period of cohabitation with another vole, they developed a bond and preferred to spend time with their partner rather than a stranger vole. Similarly, male and female Oxtr-null voles were attentive parents. The time they spent in the nests and in contact with their pups was not significantly different from normal voles.

These are absolutely critical behaviors for the survival of the species, so it makes sense that there isn't a single point of failure from a genetics perspective. 
- Devanand Manoli, University of California, San Francisco

Thus, while short-term pharmacological interference with oxytocin signaling can perturb social behaviors in prairie voles, voles whose brains have developed without oxytocin signaling for their entire lives are somehow able to overcome this deficit.

“From an evolutionary perspective, it probably makes sense,” said Manoli. “These are absolutely critical behaviors for the survival of the species, so it makes sense that there isn't a single point of failure from a genetics perspective.”

For Manoli, this raises an important question: Something is driving social behaviors in these voles, but if it’s not oxytocin, what is it?

“The short answer is ‘we don’t know yet,’” he said.

Manoli noted that the idea that social behavior is driven by more than just oxytocin seems to be supported by the ambiguous results from past clinical trials using oxytocin to treat disorders involving social behavior, including autism spectrum disorder (ASD). While some smaller trials indicated that intranasal oxytocin improved social skills in some children with ASD (4,5), a larger trial in 2021 found no significant differences between children who were treated and children who received placebos (6). Trials of oxytocin treatment for schizophrenia, which also involves difficulty with social functioning, have been similarly underwhelming; various forms of anxiety and depression have not consistently responded to oxytocin treatment, either (7,8).

“Given that we had all of this data from clinical trials, maybe our results are even less surprising,” Manoli said. “We had been trying to use oxytocin as a target for social behavior in autism and many other psychiatric illnesses, and the results were equivocal. Sometimes there were subtle changes, but it wasn't a really major difference. I think that what these results suggest is that there are multiple pathways, and once we find them, we can actually start to target them with therapeutics.”

Larry Young, a social neuroscientist at Emory University who was not involved in the study, said that while he has no qualms about the data, he believes that caution is needed when interpreting the findings. He questioned how much the Oxtr-null voles, which have developed since before birth in a different way than any other vole on the planet, can really tell researchers about the role of oxytocin in social behavior in normal voles.

Young pointed out that in the wild, the prairie voles would likely have a more nuanced and complex set of social behaviors, which are difficult to assess with the relatively simple tests that are done in the lab. So, while the study indicated that oxytocin receptors were dispensable for social behaviors assessed by these simple lab tests, Young doesn’t think this would translate to real world social behaviors.

“The brain oxytocin receptor system is so critical that it’s never been dispensed of in any mammal. So, it’s not dispensable for survival in a complex environment,” said Young.

Oxytocin isn’t this plus or minus switch, but rather something that probably has very nuanced and complex genetics and neural components. 
- Devanand Manoli, University of California, San Francisco

Young believes that the reason for the null findings in a large trial of oxytocin in children with ASD is not because oxytocin is the wrong target. Oxytocin, he said, doesn’t necessarily increase social behaviors in people with ASD; instead, it makes them more attuned to social signals, both positive and negative. For oxytocin to be effective, he believes that it needs to be paired with behavioral therapy so that positive and appropriate social learning can occur.

Nevertheless, Young said that the Oxtr-null voles could be a valuable tool for studying the role of oxytocin in brain development, especially the brain circuits that control social behavior.

Manoli, for his part, wants to continue to explore oxytocin’s complexities. “Our study suggests that the nuances of what oxytocin is doing still need to be revealed,” he said. “Oxytocin isn’t this plus or minus switch, but rather something that probably has very nuanced and complex genetics and neural components. And now, we have even more evidence to suggest that we need to look at this with higher resolution.”

References

1. Williams, J. R., Insel, T. R., Harbaugh, C. R. & Carter, C. S. Oxytocin Administered Centrally Facilitates Formation of a Partner Preference in Female Prairie Voles (Microtus ochrogaster). Journal of Neuroendocrinology  6, 247–250 (1994).
2. Insel, T. R. & Hulihan, T. J. A gender-specific mechanism for pair bonding: oxytocin and partner preference formation in monogamous voles. Behav Neurosci  109, 782–789 (1995).
3. Berendzen, K. M. et al. Oxytocin receptor is not required for social attachment in prairie voles. Neuron  0, (2023).
4. Parker, K. J. et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A  114, 8119–8124 (2017).
5. Guastella, A. J. et al. The effect of oxytocin nasal spray on social interaction in young children with autism: a randomized clinical trial. Mol Psychiatry  28, 834–842 (2023).
6. Sikich, L. et al. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. New England Journal of Medicine  385, 1462–1473 (2021).
7. Williams, D. R. & Bürkner, P.-C. Effects of intranasal oxytocin on symptoms of schizophrenia: A multivariate Bayesian meta-analysis. Psychoneuroendocrinology  75, 141–151 (2017).
8. De Cagna, F. et al. The Role of Intranasal Oxytocin in Anxiety and Depressive Disorders: A Systematic Review of Randomized Controlled Trials. Clin Psychopharmacol Neurosci  17, 1–11 (2019).