The deer mouse, believed to be the most common mammal in North America, has a very different view of family values than its evolutionary sibling, the ancient field mouse.
Oldfield mice are monogamous. Fathers care for their young, keep them warm and ensure they don’t stray far from the nest. The deer mouse prefers the swinging lifestyle when it comes to sexual partners. It is not unusual for the puppies in one litter to come from four different fathers. As for the fathers of deer mice, they are downright negligent. Nothing, it seemed, could bring out the warm and fuzzy dad behavior.
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Until now. Researchers at Columbia University examining the two types of mice discovered what appears to be a crucial difference: Oldfield produces an adrenal cell not found in other mice. The cell produces a hormone that, when injected into virgin deer mice of both sexes, prompts 17 percent – even males – to nurse their young and keep them close to the nest.
Unfortunately, it had no effect when it came to the deer mouse’s preference for playing with multiple female partners on the field.
It didn’t make them want to spend more time with their partner, said Andrés Bendesky, one of the authors of a paper published Wednesday in the journal Nature describing the study.
By examining other types of mice, Bendesky and his team determined that the newly discovered cell type had evolved in Oldfield mice about 20,000 years ago, which was essentially “the blink of an eye” on the evolutionary timescale.
Although parenthood and monogamy are different traits, they are linked in biology, says Bendesky, principal investigator at Columbia’s Zuckerman Institute.
The vast majority of mammals – 92 percent, according to Bendesky – are promiscuous, just like the deer mouse. When female deer mice are in heat, they sometimes mate with multiple males in the same night, allowing different fathers to fertilize different eggs.
In most promiscuous species, males do not participate in caring for the young. Bendesky said there are only three outliers; promiscuous species where the males actually help with parenting: the banded mongoose, the gray bamboo lemur and Goeldi’s monkey.
“All three are derived from a recently monogamous ancestor,” Bendesky said, “underscoring the close and enduring bond” between monogamy and shared parenthood.
The topic of monogamy in the animal kingdom remains controversial, with some scientists claiming that only 3 to 5 percent of mammals are monogamous.
Researchers cite two different types of monogamy: social monogamy, in which partners mate and live together for one or more breeding seasons; and genetic monogamy, in which couples mate exclusively with each other.
Several theories exist regarding the evolutionary advantage that monogamy confers on men. Some scientists argue that staying home with a mate, rather than seeking out other females, could have been a way to deter competing males from snacking on their offspring. An alternative explanation is that males simply found it much easier to keep rival males away from one female than from several.
Bendesky, who has been studying the difference between oldfield and deer mice for 12 years, said he found an unexpected clue in the anatomy of the two species. Each of the Oldfield mouse’s two adrenal glands weighs 7 milligrams – more than four times heavier than those of deer mice.
“It’s huge,” Bendesky said of the difference. When scientists have bred mice to exhibit more or less anxiety — a feeling that comes from hormones produced in the adrenal gland — they have never found a difference in gland size of more than 20 percent.
The adrenal glands are one of the main sources of steroid hormones, which act as important regulators of behavior, including parental care. The large difference in the size of the adrenal glands suggested that the Oldfield mice produced more of at least some of the steroid hormones.
When the scientists took a closer look at the differences between the species, they discovered that each adrenal gland in the field mouse has four layers, or zones, instead of the three in the deer mouse. It is the fourth, called the zona inaudita (Latin for “previously unheard zone”) that contains the new adrenal cell.
Scientists determined through genetic analyzes that the newly discovered cell was different from other adrenal gland cells. They found that 194 genes were expressed higher in the newly discovered cells than in other cells. The activity level of genes can be turned up or down, just as a lamp can be adjusted with a dimmer.
In the newly discovered cells, Oldfield mice make a hormone called 20 alpha-hydroxyprogesterone (20alpha-OHP), which was discovered in humans in 1958.
“But no one knew what it really does in people,” Bendesky said.
In this sense, the hormone was much like the organ that produced it. First described in 1564, the adrenal gland was such an enigma to scientists that the Bordeaux Academy of Sciences sponsored an essay competition in 1716 to determine what purpose the organ served. No entry was deemed worthy of the prize.
Only much later did the discovery of diseases such as adrenal insufficiency help clarify its role in the production of hormones involved in regulating metabolism, immunity, blood pressure and the response to stress.
Bendesky and his colleagues’ research revealing the new cell type surprised other scientists.
“It’s extraordinary,” says Steven M. Phelps, a professor of integrative biology at the University of Texas at Austin, who was not involved in the study but has been following Bendesky’s work on deer and oldfield mice for some time. “The most exciting piece is the origin of what appears to be a new cell type.”
Phelps said it was the first time in his 30 years in the field that he could remember such a discovery of a new cell type.
“What was really exciting to me about the paper was the idea that this hormone produced in the adrenal gland” is then broken down and used in the brain to influence caregiving behavior, said Jessica Tollkuhn, an associate professor at the Cold Spring Harbor Laboratory , who was not involved in the study.
“This is really a new aspect of biology that has not been described before,” Tollkuhn said.
Margaret M. McCarthy, a professor of pharmacology at the University of Maryland School of Medicine, was surprised that evolution has hardwired parenting behavior in such a complex way. Regulating the brain with a hormone produced in the adrenal gland, she said, was less direct than simply developing a new neural circuit.
“That’s what’s happened in voles, where you have monogamous and non-monogamous voles,” McCarthy said, referring to the small rodents sometimes mistaken for mice. “Evolution always surprises. There are a million ways to solve a problem.”
The findings in mice could lead to insights when it comes to parenting behavior in humans, scientists say.
In mice, the parenting hormone is often converted into a substance very similar to allopregnanolone, which was approved by the Food and Drug Administration in 2019 to treat postpartum depression. The drug is known as brexanolone and is sold under the brand name Zulresso.
Tali Kimchi, an associate professor at the Weizmann Institute of Science in Israel, said by email that the Nature article raises the possibility for more in-depth research into postpartum depression, “one of the most devastating, incurable psychopathologies known, with long-lasting and sometimes even fatal consequences for both parents and offspring.”
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