The hormone oxytocin is responsible for uterine contractions during the birth process, the release of milk during lactation, modulation of social behavior and the formation of social and affective ties. And until recently, oxytocin was thought to be immutable in mammals—not surprising, given its important functions. But in recent years, researchers have discovered variations in primates that have now been corroborated and expanded upon by a group led by geneticist Maria Cátira Bortolini of the Federal University of Rio Grande do Sul (UFRGS). Moreover, the findings connect the changes to paternal caregiving activities. “The challenge that Bortolini is putting out there is central to the role of the father,” says physiologist Aldo Lucion, her UFRGS colleague and research collaborator, who is enthused by these findings that lead to new questions.
The study analyzed the composition of oxytocin and its receptor in 29 primate species, including 20 New World (South and Central America) monkeys, from samples submitted by veterinarian Alcides Pissinatti of the Primatology Center of Rio de Janeiro. Bortolini’s group analyzed the genetic sequences that provide instructions for making molecules, using a statistical model that compares changes in lineages against what would be expected if natural selection did not nudge evolution in one direction or another and mutations were to occur randomly—a neutral situation, in evolutionary jargon. “We saw that in Cebidae, the pattern deviates from neutrality,” the researcher notes, in reference to the family that includes many South American monkeys and 16 of the species studied. The paper was the product of the master’s thesis of Pedro Vargas-Pinilla, a Colombian student co-advised by Bortolini and geneticist Vanessa Paixão Côrtes, also from the state of Rio Grande do Sul, who implemented this type of analysis at UFRGS and is now a professor at the Federal University of Bahia (UFBA).
The discovery of a specific act of natural selection in such an essential hormone draws attention in and of itself—evolution adheres to the maxim, “Don’t mess with a winning formula” in fail-safe systems. Until now, variations in oxytocin have been found only in the lineage that emerged some 30 million years ago and gave rise to the New World monkeys. There are five different types, with small differences, that are manifested uniformly in the lineages in which they were established: when the study analyzed more than one individual of the same species, the same variant was present in all of them. Oxytocin in humans—primates that originated in the Old World (Africa)—is the same as mouse oxytocin. The common ancestor of these two animals is estimated to have lived 70 million years ago.
The discovery is even more interesting when we compare the genetic changes against the behavior of the parents. In nearly all of the 12 species of tamarins and capuchin monkeys considered in the study (members of the Cebidae family), the gestation and birth of twins is common, and in all of them the males tend to care for their offspring—an uncommon behavior among mammals overall. One need only imagine a small animal such as a marmoset leaping from branch to branch carrying two offspring whose combined weight at birth is nearly 20% of that of the female. These mothers obviously need help. “The adaptive value of a modification is greater in that group of organisms,” explains Bortolini, reflecting on the fact that oxytocin is no longer held to be immutable in that lineage. In her view, molecular variants are unquestionably responsible for this behavior, and we need to identify them. “Connecting genotype and phenotype is a challenge for the biological sciences,” she says, referring to the manifestation of genetic information in the organism.
Night monkeys, another Cebidae, also have modified oxytocin and fathers that are active caregivers, although they don’t usually have twins. Squirrel monkeys have the modification, but they are not characterized by paternal caregiving—one example indicating the lack of an absolute correlation between the hormone and the behavior.
To understand the effect of these changes, scientists still need to ascertain precisely how differently the modified oxytocin works. In a preliminary analysis, the group at UFRGS compared the modified molecules to the three-dimensional structure that was already available for that hormone, and they saw that the main configurations responsible for interactions between proteins, which are essential to the basic functioning of the oxytocin, remain unchanged (see article on page 54). But there are subtle differences in the molecular side chains. “We think that these changes affect oxytocin-receptor affinity, or increase the number of receptors with which the oxytocin is able to interact,” Bortolini conjectures.
She plans to test receptor affinity with molecules that will be synthesized in the laboratory by biologist Claudio da Costa Neto of the Ribeirão Preto School of Medicine at the University of São Paulo (FMRP-USP). The same molecules will also be used in behavorial experiments conducted by the group headed by Aldo Lucion. “We’re going to spray the substance into the nostrils of male rats and observe their parental caregiving behavior,” says the UFRGS physiologist. The experiment is expected to begin soon, as soon as he obtains ethics permission to handle the animals and they adapt to the experimental environment—a process that could take about two months.
In Lucion’s experience, male laboratory rats do not attend to their offspring directly, but “they enable the mother to develop maternal caregiving during pregnancy.” For example, the males concede the best—i.e., most protected—areas of their artificial burrow to the females and their young during the lactation period. “We think it is possible to develop a more complete affiliative behavior.” This happens with many primates, as revealed in the study by his geneticist colleagues headed by Bortolini.
Over the years, Lucion’s laboratory has carried out experimental studies on the effect of oxytocin on behavior, mainly in rats. “We know that this hormone is responsible for the formation of affective ties and that it plays a fundamental role from the time of birth,” he explains. “When a mammalian offspring is born, its first challenge is to find the mother’s breast,” he notes by way of example. When there is a deficiency in oxytocin production, as happens in people with Prader-Willi syndrome, a genetic disorder, the baby does not go to the breast. In nature, a newborn with this problem will probably not survive.
Lucion underscores the importance of maternal care in the evolution of mammals, most of which concentrate on producing a small number of offspring and investing more effort in the survival of each one. The situation is different among fish, for example, which release hundreds of eggs into the water—each one on its own. Oxytocin, he says, is responsible for ensuring maternal dedication, which ignores discomfort and overcomes enormous energy demands.
Earlier experiments conducted by the group have also shown that experiences during the gestation period affect the way oxytocin works. Prenatal stress alters the number of receptors for oxytocin and vasopressin (which also interacts with oxytocin) in embryos and causes deficiencies in social memory and in interaction, as shown in a 2013 article published in the journal Neurochemical Research.
These findings, in the aggregate, are mere suggestions of the complexity and importance of the formation of social ties and the relationship between parents and their offspring. The rare encounter between an evolutionary study—of the type usually confined to the molecular laboratory and the computer—and behavioral experiments makes all the difference in advancing our understanding a little further.
VARGAS-PINILLA, P. et al. Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints. PNAS. V. 112, No. 1, p. 88-93. Jan. 6, 2015.
SOUZA, M. A. de et al. Prenatal stress produces social behaviour deficits and alters the number of oxytocin and vasopressin neurons in adult rats. Neurochemical Research. V. 38, No. 7, p. 1479-89. Apr 30, 2013.