CRISPR study questions everything we know about "love hormone" oxytocin

By Rich Haridy

2023 Feb 02
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Using cutting-edge gene editing technology researchers have engineered prairie voles with no oxytocin receptors. These notoriously monogamous mammals were thought to rely on oxytocin to form crucial social bonds but the results of these new experiments suggest this so-called “love hormone” may be less important than suspected.

A few decades ago ecologists discovered male and female pairs of prairie voles, a type of rodent, seemed to consistently appear in traps together. Subsequent study revealed these species were among a small minority of mammals that are monogamous and form pair bonds that can last a lifetime.

Across the 1980s and 1990s lab work with prairie voles uncovered key roles for the hormone oxytocin in shaping the animals’ maternal and bonding behaviors. When drugs were used to block oxytocin receptors, the animals’ ability to effectively form social bonds was reduced.

These prairie vole studies helped inform what we understand today to be the role of oxytocin in social relationships. Informally, oxytocin is even often referred to as the “love hormone” due to the ways we assume the hormone helps mammals solidify trust-filled bonds.

For about 15 years psychiatrist Devanand Manoli has been interested in the brain chemistry behind social bonding. So Manoli joined forces with neurobiologist Nirao Shah to develop a unique experiment. The pair were interested in looking at what would happen to prairie voles if they were genetically modified to completely lack oxytocin receptors from birth.

“Drugs can be dirty, in the sense that they can bind to multiple receptors, and you don’t know which binding action is causing the effect,” explained Manoli. “From a genetics perspective, we now know that the precision of deleting this one receptor, and subsequently eliminating its signaling pathways, does not interfere with these behaviors.”

After lots of hard work, based on recent CRISPR gene editing innovations, the researchers successfully produced prairie voles lacking functional oxytocin receptors. And then they tested the animals’ social ability to form social bonds.

To say the results surprised the researchers would be an understatement. According to Manoli, the patterns of bonding behavior between the genetically modified and normal voles were “indistinguishable.” Even without oxytocin receptors the animals bonded, huddled together and rejected new partners.

“We were all shocked that no matter how many different ways we tried to test this, the voles demonstrated a very robust social attachment with their sexual partner, as strong as their normal counterparts,” said Manoli.

The researchers then moved on to studying the effect of oxytocin receptor signaling on parenting. Again, to the researchers surprise, the animals had no problems giving birth to offspring and subsequently nursing their pups.

The only significant effect the researchers noted was the oxytocin-deprived animals did display some decreases in their milk release. However, according to Shah, based on what we thought we knew about oxytocin and lactation, the genetically modified animals should not have been able to nurse at all. Prior similar studies breeding genetically modified oxytocin-receptor deficient mice showed the animals completely unable to lactate, so these results in voles were deeply unexpected.

“This overturns conventional wisdom about lactation and oxytocin that’s existed for a much longer time than the pair bonding association,” Shah explained. “It’s a standard in medical textbooks that the milk letdown reflex is mediated by the hormone, and here we are saying, ‘Wait a second, there’s more to it than that.’”

So what does all this mean? Well, in a classic case of scientific uncertainty, it suggests oxytocin isn’t the definitive hormonal regulator for bonding and parenting we previously assumed it to be. Manoli says our current models considering oxytocin as a crucial “love hormone” are oversimplified, and it’s likely the hormone plays just one part in the larger story of mammal bonding.

“These behaviors are too important to survival to hinge on this single point of potential failure,” added Manoli. “There are likely other pathways or other genetic wiring to allow for that behavior. Oxytocin receptor signaling could be one part of that program, but it’s not the be-all end-all.”

And beyond this being a merely academic finding that influences scientific textbooks, the research hopes to play a role in driving future clinical studies targeting human treatments for social cognitive impairments. While there has been work in the past investigating whether oxytocin could be used as a therapeutic tool for people with autism or schizophrenia, these findings suggest things may be a little more complex than that. And thanks to this work researchers now have new experimental models using prairie voles to better explore clinical pathways for influencing bonding in mammals.

“New genetic models such as the Oxtr prairie vole mutants we have generated may better allow the rigorous dissection of the molecular and circuit mechanisms mediating attachment behavior and its disruption in disease,” the researchers concluded in the new study. “Whole-animal mutants better represent what may occur in patients with mutations associated with neuropsychiatric disorders, and molecular genetic approaches in prairie voles now permit us to test directly the impact of such genetic disruptions in the context of complex social and attachment behaviors.”

The new study was published in Neuron.

Sources: UCSF, Cell Press
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