You Can’t Spell ‘Love’ Without ‘Vole’

Posted by Jacqueline Mosko on February 14, 2023 in Animals, Behavioral Neuroscience, Valentine's Week | Leave a comment

In February, you may find that you have got love on the brain. With Valentine’s Day around the corner, you may be curious about the role the brain plays in forming loving connections with others. When it comes to humans, it is safe to say that relationships are complicated and nuanced. However, for certain members of the animal kingdom, neuroscientists have begun parsing out messengers in the brain that contribute to forming monogamous bonds.

Humans are social creatures, as are many of the animals we study as model organisms: mice, rats, even fruit flies. However, these animals typically have multiple mates throughout their lives, and do not form exclusive attachments with their reproductive partners. On the contrary, there are some animals which are monogamous. In biology, monogamy is typically defined as selective mating, sharing a nest, and co-parenting¹. This phenomenon is not common in the animal kingdom – only about 3-5% of mammals exhibit long-term monogamy². Even so, many may be familiar with an example from pop culture; anyone who has watched the sitcom Friends may recall hearing that “lobsters mate for life”. As much as it saddens me to be the bearer of bad news, lobsters are not actually monogamous creatures³. Instead, allow me to introduce the prairie vole, a monogamous animal that forms a close “pair bond” with its partner. These creatures have a dedicated reproductive mate with whom they rear and protect their offspring.

Remarkably, prairie voles’ pair bonds were initially studied after a happenstance observation. When scientists trapping wild voles for general research repeatedly found two voles in their trap – a bonded pair – instead of a lone vole, and they wanted to understand why it kept happening⁴! Monogamous prairie voles provide neuroscientists with a fascinating opportunity to decipher the way different experiences or psychiatric conditions affect complex social behaviors. These studies may shed light on the neural mechanisms underlying human social behaviors, as well as uncovering the basis of mating patterns in animals with a monogamous social structure⁵. Neuroscientists have explored these topics by first asking the important question of what in prairie voles’ evolution and brain chemistry has led to these behaviors, distinguishing them from other rodents and reinforcing their bonds?

Love on the Prairie

Prairie voles (Microtus ochrogaster) are a rodent indigenous to central North America, residing in regions with dry, grassy plains upon which they graze and forage^6,7,8 (Fig 1A). They have been studied in social neuroscience for many decades, though they are not as common a model organism as other species of mice and other rodents such as rats – the genetic toolkit scientists have developed to assess specific genes in mice and rats ensures that they are still crucial to many research fields. Where prairie voles can really shine is in behavioral and ethological (having to do with natural processes and behaviors) neuroscience. Prairie voles’ monogamous pair bonds, and the presence of co-parenting behavior, diverges from most rodents’ behavior. For instance, in mice and rats typically studied in laboratory settings, the male does not participate in the offspring rearing process. Even more genetically similar to the prairie vole is the meadow vole, a close relative who does not form pair bonds or coparent⁹. Voles’ co-parenting structure allows females to forage for food while males guard the pups, in addition to the males’ contributions to food resources. This is an advantageous practice for prey animals in the wild¹.

To determine what brain activity may be driving these behaviors, researchers conducted a simple partner preference assay. A vole was placed into a three-chambered arena with two voles of the opposite sex were located on either side: their pair bonded partner and a novel vole (Fig 1B). Remarkably, voles spend significantly more time with their partner compared to the novel vole. At that, voles even showed increased aggression towards novel opposite-sex voles, indicative of rejection as a potential mate¹⁰. Again, this juxtaposes typical rodent behavior; wild-type lab mice display a preference for novel mice compared to familiar mice in this type of assay¹¹.

To determine what may be reinforcing pair bond attachments in voles’ brains, neuroendocrinologists began to assess the role of numerous chemical messengers in this behavior. Some of these messengers are known as hormones and neuropeptides. Hormones act in the bloodstream and carry important functional messages to different tissues and organs. Neuropeptides function like hormones, but act in the brain. They are created and used exclusively by neurons, taken up by specialized receptors throughout the brain.  Analysis of which hormones and neuropeptides may be playing a role in pair bonding behavior in the prairie vole led to the discovery of the important roles of vasopressin and oxytocin. In male prairie voles, it has been demonstrated that vasopressin is crucial for pair bonding behavior. Blocking vasopressin receptors in specific areas of the brain relevant to social interaction was sufficient to prevent males from showing a preference for their partners over a novel vole in the partner preference assay¹². In female voles, blocking oxytocin receptors in relevant brain regions was similarly sufficient to prevent them from showing a preference for their partners over a novel vole¹². Thus, these neuropeptides’ roles in pair bonding are sexually dimorphic (that is to say, different mechanisms for male and female voles). In this article, we will focus on oxytocin.

Oxytocin is a chemical messenger that is colloquially nicknamed “the love hormone”¹³. This nickname is due to its known importance in social and intimate interactions in humans and animals. The release of the hormone oxytocin is stimulated during childbirth, and is known to promote lactation. Increased systemic oxytocin levels are also associated with prosocial behaviors and positive sexual stimulation¹⁴. Oxytocin has even been shown to increase trust in humans who were treated with intranasal oxytocin spray prior to tasks prompting them to rely on¹⁵ and confide in strangers¹⁶. Knowing oxytocin is important for pair bonding, however, does not completely answer the question of why it is so crucial for pair bonding in prairie voles specifically. After all, all mammals have oxytocin in their systems! Interestingly, when comparing the expression of the oxytocin receptor in monogamous prairie voles to voles who are non-monogamous, it has been shown that there is a significant change in receptor expression. Specifically, it has been found that monogamous prairie voles have a higher density of oxytocin receptors across several brain regions (meaning they have a higher affinity for bonding the neuropeptide) that are linked to mating behavior¹⁷. This underscores the importance not only of oxytocin, but its receptor’s expression, in genesis of pair bonding behavior.

Overall, the literature is at a consensus that neuropeptide function, specifically of oxytocin and vasopressin, plays an important role in pair bond formation and maintenance in prairie voles. In a shocking twist, a new study was recently published that challenges these notions.

No Oxytocin Receptor, No Problem?

Just this month, a new study published in Cell has questioned the importance of oxytocin in pair bond formation and parenting behavior in the prairie vole (Figure 2). To explore this topic, experimenters used a gene editing technique called CRISPR to engineer genetically modified prairie voles who expressed non-working forms of the oxytocin receptor. Three mutations tested in this study all led to a “complete lack” of oxytocin binding to the mutated receptor. Essentially, these specially bred voles completely lacked oxytocin signaling. Since it is widely known to play such a crucial role in pair bonding and preference for a vole’s partner, one may hypothesize that these voles would lack normal behaviors and fail to form pair bonds. However, this is not what researchers observed. After housing male and female voles together for 7 days, a length of time previously proven to be sufficient for pair bonding, they conducted two versions of the previously discussed partner preference assay. During both tests, to experimenters’ surprise, both male and female voles devoid of oxytocin signaling still demonstrated a significant preference for their partner, indicating that they had formed a pair bond. Additionally, the experimental animals still demonstrated co-parenting behaviors. The only differences detected were found to be linked to nursing in mother voles – voles completely lacking oxytocin receptor expression were unable to nurse their pups to the same degree as wild-type voles, but their pups still survived to weaning age (notably, at a reduced weight)¹⁰. Interestingly, mice lacking oxytocin receptor show a complete lack of milk letdown and thus cannot rear pups successfully. This difference shed additional light on the subtly different roles of oxytocin across rodent species.

In Conclusion…

The scientists who conducted this study discussed their intention to one day target the loss of oxytocin receptor function to specific regions of the brain, to pin down which areas are necessary for the behaviors they tested. It is important to note that while their findings do not agree with the previous literature, previous findings still contribute to our understanding of the role oxytocin is playing in the processes of pair bonding and parenting. The authors note that in past studies, it is possible that the compounds used to activate oxytocin receptors may also have activated other receptors crucial for pair-bond formation (essentially, a lack of specificity leading to the improper conclusion). During studies where oxytocin receptors were blocked, they similarly hypothesize that oxytocin’s binding to additional receptors may have been inhibited as well. Altogether, the circuit underlying the formation of pair bonds is much less cut and dry than we once thought it was, and this research is an excellent step towards uncovering the extent of oxytocin’s role in pair bonding.

Though neuroscience tries its best to uncover the mysteries of love, it seems they will persist. Even so, every new discovery is an important puzzle piece in what will one day shape up to be a full picture of the interactions in voles’ brains that lead to observed behaviors. With a newfound, deeper understanding of oxytocin’s role in the formation of monogamous pair bonds, the field is moving closer than ever to better understanding this unique social phenomenon.

Citations

¹Wachter, K. W., Bulatao, R. A., & Young, L. (2003). The Neural Basis of Pair Bonding in a Monogamous Species: A Model for Understanding the Biological Basis of Human Behavior. In Offspring: Human fertility behavior in biodemographic perspective (pp. 91–103). essay, National Academies Press.

²Kleiman, D. G. (1977). Monogamy in Mammals. The Quarterly Review of Biology, 52(1), 39–69. http://www.jstor.org/stable/2824293

³Mahi, I. (2022, December 6). Do lobsters mate for life? secrets of lobsters mating. Ocean Fauna. Retrieved February 13, 2023, from https://oceanfauna.com/do-lobsters-mate-for-life/#:~:text=In%20one%20line%2C%20lobsters%20don,multiple%20partners%20over%20their%20lifetime.

⁴Getz, L.L., Carter, C.S., and Gavish, L. (1981). The mating system of the prairie vole, Microtus ochrogaster: field and laboratory evidence for pair- bonding. Behav. Ecol. Sociobiol. 8, 189–194. https://doi.org/10.1007/BF00299829.10.

⁵McGraw, L. A., & Young, L. J. (2010). The prairie vole: An emerging model organism for understanding the social brain. Trends in Neurosciences, 33(2), 103–109. https://doi.org/10.1016/j.tins.2009.11.006

⁶Hiura, L. C., & Donaldson, Z. R. (2022). Prairie vole pair bonding and plasticity of the Social Brain. Trends in Neurosciences. https://doi.org/10.1016/j.tins.2022.10.009

⁷Carter, C. S., & Getz, L. L. (1993). Monogamy and the prairie vole. Scientific American, 268(6), 100–106. https://doi.org/10.1038/scientificamerican0693-100

⁸VanderLinden, M. (2002). Microtus ochrogaster (prairie vole). Animal Diversity Web. Retrieved February 1, 2023, from https://animaldiversity.org/accounts/Microtus_ochrogaster/

⁹Rowe, S. (2017). Microtus pennsylvanicus (meadow vole). Animal Diversity Web. Retrieved February 9, 2023, from https://animaldiversity.org/accounts/Microtus_pennsylvanicus/

¹⁰Berendzen, K. M., Sharma, R., Mandujano, M. A., Wei, Y., Rogers, F. D., Simmons, T. C., Seelke, A. M. H., Bond, J. M., Larios, R., Goodwin, N. L., Sherman, M., Parthasarthy, S., Espineda, I., Knoedler, J. R., Beery, A., Bales, K. L., Shah, N. M., & Manoli, D. S. (2023). Oxytocin receptor is not required for social attachment in prairie voles. Neuron. https://doi.org/10.1016/j.neuron.2022.12.011

¹¹Stanford Medicine. (2023). Three-chamber sociability and social novelty test. Behavioral and Functional Neuroscience Laboratory. Retrieved February 1, 2023, from https://med.stanford.edu/sbfnl/services/bm/si/three-chamber.html

¹²Young, L., Wang, Z. The neurobiology of pair bonding. Nat Neurosci 7, 1048–1054 (2004). https://doi.org/10.1038/nn1327

¹³Watson, S. (2021, July 20). Oxytocin: The love hormone. Harvard Health. Retrieved February 1, 2023, from https://www.health.harvard.edu/mind-and-mood/oxytocin-the-love-hormone

¹⁴Oxytocin: What it is, Function & Effects. Cleveland Clinic. (2022). Retrieved February 1, 2023, from https://my.clevelandclinic.org/health/articles/22618-oxytocin

¹⁵Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435(7042), 673–676. https://doi.org/10.1038/nature03701

¹⁶Lane, A., Luminet, O., Rimé, B., Gross, J. J., de Timary, P., & Mikolajczak, M. (2013). Oxytocin increases willingness to socially share one’s emotions. International Journal of Psychology, 48(4), 676–681. https://doi.org/10.1080/00207594.2012.677540

¹⁷Ophir, A. G., Gessel, A., Zheng, D.-J., & Phelps, S. M. (2012). Oxytocin receptor density is associated with male mating tactics and social monogamy. Hormones and Behavior, 61(3), 445–453. https://doi.org/10.1016/j.yhbeh.2012.01.007