Neurotransmitter Switching Affects Social Bond Formation

Birds do it, bees do it…and, as we know all too well, humans do it, too. They all form complex social bonds with parents, siblings, and partners, that is—showing strong preference for those over unfamiliar members of their species. But just how are those bonds formed? How does the brain mediate your having a social preference for one individual over another? How might those bonds change over time? Neuroscientists have been trying to answer these questions for decades, using techniques ranging from the molecular to the behavioral. Research from the University of California San Diego (UCSD) offers new clues about the neurobiological mechanisms underlying social bonds, suggesting a process called neurotransmitter switching may be at the heart of the matter.

The Ties That Bind

It’s long been known that animals seem to innately know parents and siblings—for example, even the youngest lambs can find their mothers when lost among scores of similar-looking sheep. That strong kinship relationship, sometimes referred to as imprinting, has long been thought to be mediated by odor cues.

“Konrad Lorenz was the first to show that geese are imprinted to look for family by first contact out of the egg,” says Ron Stoop, an associate professor in the psychiatric neurosciences at Université de Lausanne in Switzerland, highlighting the 1930s studies on imprinting found in most psychology textbooks. “But later studies have shown that imprinting effects are not necessarily everlasting. Recently, work on the vomeronasal organ, the region of the brain that processes chemical signals, and its receptors have been shown to be important for social preference.”

Variations of social preference and kinship bonding are seen across a swath of animals, including humans. So what may be mediating that original kinship bond that we see in so many animals, and what allows it to change over time? After finding a 1985 study by Bruce Waldman looking at how the vomeronasal organ mediated kinship recognition in tadpoles, Davide Dulcis, a psychiatrist at the UCSD School of Medicine, and Nick Spitzer, a neurobiologist at UCSD, wondered if neurotransmitter switching might be at work.

“Waldman had shown that frog larvae recognize siblings and distinguish them from non-siblings by olfactory stimuli. He did this in an elegant way—he found a way to plug the nostrils and, when he did, the animal no longer had the ability to distinguish siblings from non-siblings. Unplug the nose and it’s all fine again,” Spitzer says. “Then Waldman took the study further and found that if you take a few larvae from one Mom and Dad and exposed them to larvae from another set of parents, after a while, they would now find the non-siblings attractive, too. And we wondered if it might be mediated by neurotransmitter switching. It had all the hallmarks of a situation that might be.”

Neurons As Switch-Hitters

What is neurotransmitter switching, exactly? It’s a paradigm shift: a momentous change in the way neuroscientists thought that neurons do their jobs. We used to think that neurons only released a single type of neurotransmitter, and what transmitter was released was fixed and unchanging. That belief was so pervasive that scientists often described cells by the neurotransmitter they released: for example, neurons that released dopamine might be called dopaminergic cells. But Spitzer says that the evidence has been mounting to show that isn’t always the case. It may not ever be the case—there’s now work to suggest that a cell may release up to five different neurotransmitters.

“Starting in 1993, we got the first evidence that one neurotransmitter might not be constant for the life of a nerve cell. We didn’t know what to make of it,” he says. “But with more evidence, we are coming to understand that neurotransmitters are, as we say in this business, plastic. A cell can change what kind of neurotransmitter it releases. And it has a lot of interesting implications for our understanding of how the brain works,” including the formation of social bonds.

Because of Waldman’s work with tadpoles—and studies that had previously mapped the vomeronasal organ circuitry in the animal—Dulcis hoped that they would be able to see whether neurotransmitter switching might be at work when it came to tadpole’s preferences.

“Could it be that if we altered the exposure of kin early on during development, we could see some changes in their brains? Might it be a switch of neurotransmitter?” he says. “Having a behavior, having a circuit that was already described, we hoped to find the regulators that were making these kinship relationships happen—and that they might involve a neurotransmitter switch.”

Switching Attachment

In a series of experiments spanning eight years, Dulcis, Spitzer, and colleagues looked at the vomeronasal organs of two- to four-day-old tadpoles, which are known to prefer to swim with their kin groups.

“We started by collecting all the tissue from the accessory olfactory bulbs from tadpoles who were raised with siblings, non-siblings, or as orphans,” Dulcis says. “That tissue was then analyzed to isolate the genes that were up- or down-regulated in the different conditions. We saw that a lot of genes were changing. But when we looked at the genes somehow related to gamma-Aminobutyric acid (GABA) or dopamine, the latter which we know is very active when tadpoles form kinship bonds with their siblings, we found that the genes that were changing were microRNAs. Why does this matter? For a neuron to change what kind of neurotransmitter it releases, it requires the simultaneous change or expression of different genes that are involved in the making of that neurotransmitter and the transport of it. That has to be regulated somehow. It would be regulated by microRNAs.”

In a stringent statistical analysis, the researchers found specific microRNAs that regulated what kind of neurotransmitter was released. Those tiny “master regulators” bound to RNA, blocking its ability to release one type of neurotransmitter and then switching it to another. Specifically, those microRNAs worked to stop the cells from releasing dopamine, as they normally do when tadpoles undergo normal bonding with kin, to GABA, which then allowed the tadpoles to bond to those who were not biologically related to them.

“We found that by changing a neurotransmitter, we changed the behavior,” says Dulcis. “So while we may have this innate preference for a sibling or a mate, that isn’t necessarily fixed forever.”

Spitzer is quite pleased with how the study turned out. “This goes from the behavior all the way down to the molecular basis of the regulation,” he says. “It was the right system to try to study, and allowed us to look for changes in the microRNA expressions and then correlate that with the transmitter switch.”

And while both he and Dulcis acknowledge it would be a challenge to try to carry out studies in larger animals like mammals, they think that similar mechanisms are likely in play. A greater understanding of the processes involved in neurotransmitter switching could be important to gaining a better understanding of difficult neurobiological problems like psychiatric and neurodegenerative disease, time will only tell. But, in the meantime, Dulcis hopes that everyone will take one key message from their findings.

“The brain is no different from any other organ. The genes that determine the structure and behavior are not fixed. Genetic predisposition is only one component to how things turn out. Experience is just as effective in sculpting and adapting the brain to the physiological needs of an animal,” he says. “That leaves open the possibility that experience, whether it’s regular experience or some kind of behavioral interventions, might sculpt and gene these genetic schemes in different ways—so knowing how and why it does so is something we need to better understand.”