Oxytocin shapes both mouse mom and pup behavior

Mouse pups, like other infants across the animal kingdom, cry to get their mother’s attention. The oxytocin system drives this communication and shapes how baby mice interact when reunited with their mothers, according to a study out today in Science.

Oxytocin, known colloquially as the “love” or “cuddle” hormone, stimulates milk release during nursing and promotes maternal care behaviors. But most oxytocin research thus far has focused solely on the mother, overlooking the neuropeptide’s potential effects on an infant’s brain and behavior.

This new study shows “the other half of the equation to what we already knew,” says Zoe Donaldson, associate professor of behavioral neuroscience at the University of Colorado Boulder, who was not involved with the study. Oxytocin is “this social signal that ultimately reinforces relationships,” she says.

The work employed a novel optogenetic tool that enabled the team to turn off neurons deep in the hypothalamus of mouse pups. After being separated from their mothers for three hours, the pups vocalized more using distinct patterns when reunited with their mothers than did pups that had not been separated, a process controlled by oxytocin neurons in the pups’ hypothalamus, the team found.

“It would make sense if oxytocin is on both sides of this: making moms want to take care of their pups that are calling, and making pups call in a manner that makes mom want to take care of them,” Donaldson says. “Then we have this sort of convergence where oxytocin is once again doing everything.”

M

ice use ultrasonic vocalizations to communicate, cries that “are extremely powerful and drive a lot of animal behavior,” says Robert Froemke, professor of genetics at New York University, who was not involved in the study.

For example, the pups’ vocalizations can elicit strong activation of oxytocin neurons in their mothers’ hypothalamus, previous work shows. To spur this communication, the team behind the new study separated 15-day-old pups from their mothers for three hours.

“If you really want to look at the motivation to seek out care from mom, then this is a great paradigm,” Donaldson says, because it triggers a state of “‘Oh, my God, Mom’s not here. I need her.’”

During separation, pups increased their distress calls, which were tightly linked to oxytocin neuron activity in the paraventricular nucleus of the hypothalamus, the researchers found using two different techniques. This brain structure regulates stress responses and other homeostatic processes. When reunited, the pups again increased their ultrasonic vocalizations, particularly when they were close to their mothers. Pups emitted two main types of state-dependent vocalizations, one emitted before or after nipple attachment and another associated with nipple attachment and feeding.

Next the team wanted to block that activity to determine oxytocin’s role in these communications, but the field lacked tools to selectively manipulate circuits at such an early age, says the study’s principal investigator, Ofer Yizhar, who is principal investigator at the Weizmann Institute of Science. Mothers would quickly remove any optogenetics implant from their pups or ultimately reject such modified pups. And accessing deep brain structures such as the hypothalamus felt like a “stretch,” Yizhar says.

But a new wireless optogenetic tool that takes advantage of a highly light-sensitive mosquito opsin that responds to red light enabled the researchers to transcranially access the brain without the need for traditional, bulky and highly invasive optogenetics implants. Using this strategy, they were able to find a sweet spot within the developmental timeline: mice that were young enough to still be reliant on maternal care but big enough to tolerate the infrared light needed to penetrate the hypothalamus and inhibit the oxytocin neurons there, Donaldson says. “That was pretty cool.”

Silencing oxytocin neurons optogenetically during separation did not change the total number of vocalizations. But silencing them during reunion did change how female pups’ vocalizations related to their behavior. Similarly, newly reunited pups of either sex injected systemically with an oxytocin inhibitor emitted calls that were higher pitched and quieter than usual, and they spent less time attached to the nipple. The tight link between the different vocalizations and nipple attachment disappeared.

Without oxytocin, the communication and feeding behavior between the pups and the mothers became warped, which adds a “much more nuanced and sophisticated view of how the [oxytocin] system is working to reinforce these relationships,” Donaldson says. (The role of oxytocin might be nuanced in species-specific ways, as the hormone does not appear to be required for pair bonding or nurturing young in prairie voles but is crucial for establishing friendships.)

Next, it will be interesting to identify where that oxytocin released by the cells is going and what type of downstream behaviors it elicits in the pups, Froemke says. The goal would be to understand the oxytocin system as a whole and why it has evolved to contribute to so many different behaviors, he adds. “Is this really a singular function of the oxytocin system?” he wonders. “Is oxytocin just convenient in terms of changes of behavior, or are there really good reasons baked into the biology from evolution that require the oxytocin system to be the one leading the way for regulating vocalizations like this?”