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Yunyao Xie

CSHL Associate Professor Stephen Shea and Postdoc Yunyao Xie in Shea’s lab. Photo from CSHL/2020

By Daniel Dunaief

Good parenting, at least in mice, is its own reward.

No, mice don’t send their offspring to charter schools, drive them to endless soccer and band practices or provide encouragement during periods of extreme self doubt.

What these rodents do, however, protects their young from danger.

When a young mouse wanders, rolls or strays from the nest, it becomes distressed, calling out mostly to its mother, who is the more effective parent, to bring it back to safety.

Responding to these calls, the mother mouse carries the young back to the safety of the nest.

This behavior involves a reward system in a region of the mouse brain called the ventral tegmental area, or VTA. When the mouse effectively retrieves its young, the VTA releases the neurotransmitter dopamine, which is the brain’s way of saying “well done!”

In a paper published in December in the journal Neuron, Cold Spring Harbor Laboratory Associate Professor Stephen Shea and his postdoctoral researcher Yunyao Xie, who worked in the lab from 2019 to 2021, likened the release of dopamine in this area to a neurological reward for engaging in the kind of behavior that protects their young.

The research “proposes a mechanism that shapes behavior in accordance with that reward,” Shea said. The connection between dopamine in a reward system is an established paradigm.

“There was plenty of smoke there,” he said. “We didn’t pull this out of thin air.”

Indeed, in humans, mothers with postpartum depression have disrupted maternal mood, motivation and caregiving. PPD is linked to dysfunction of the mesolimbic dopamine system, which is a neural circuit that involves the VTA, Xie explained.

“Studies using functional magnetic resonance imaging (fMRI) revealed that the reward brain areas including VTA in healthy mothers have higher response to their own babies’ smiling faces than those in mothers with PPD,” Xie added.

What’s new in this research, however, is that it is “a study of how these signals use mechanisms to shape behavior and social interaction,” Shea said.

How the process works

The feedback loop between dopamine in the VTA and behavior involves a cumulative combination of dopamine interactions.

Dopamine is not at its highest level when the mouse mom is engaging in effective pup retrieval.

“Dopamine is shaping future, not current behavior,” Shea said. “If dopamine was driving the mouse on a current trial, a high dopamine level would be associated with high performance. The trial found the opposite: a low dopamine level was associated with high performance in a given trial, and vice versa.”

Like a skater laying her blades down effortlessly and gracefully across the ice after spending hours exerting energy practicing, the mother mouse engaged in the kind of reinforcement learning that required less dopamine to lead to effective pup saving behavior.

As the performance increases, dopamine diminishes over time, as the reward is “more expected,” reflecting a nuanced dynamic, Shea said.

To test the correlation between dopamine levels in the VTA and behavior, Shea and Xie created an enclosure with two chambers. They put a naive virgin female mouse, which they called surrogates, on one side and played specific sounds behind a door on each side of the chamber. The test mice initially had “no experience in maternal behaviors,” Xie explained.

As these surrogates became more experienced by either observing mothers or practicing on their own, the amplitude of the VTA dopamine signals got smaller.

To provide a control for this experiment, Xie monitored a group of naive virgin female mice who spent less time with pups and had to figure out how to retrieve them on their own under similar neurological monitoring conditions. The dopamine signals in this group stayed elevated over days and their performance in maternal behaviors remained poor.

Through these experiments, Xie and Shea concluded that “there is a negative correlation between the dopamine signals in the VTA and their performance in maternal behaviors,” explained Xie.

‘Mind blowing’ moment

In her experiments, Xie used optogenetic tools that allowed her to inhibit the activity of dopaminergic neurons in the VTA with high temporal precision.

Shea appreciated Xie’s hard work and dedication and suggested the discoveries represent a “lot of her creativity and innovation,” he said.

A native of China, Xie said her grandparents used to have a garden in which they taught her the names and morphologies of different plants during her childhood. She enjoyed drawing these plants.

In graduate school, she became more interested in neuroscience. She recalls how “mind-blowing” it was when she learned about the work by 1963 Nobel laureates Alan Hodgkin, Sir Andrew Fielding Huxley and John Eccles, who established a mathematical model to describe how action potentials in neurons are initiated and propagated.

In the study Xie did with Shea, she found that the dopamine signals in the VTA encoded reward prediction errors in maternal behaviors that was consistent with the mathematical model.

In the bigger picture, Xie is interested in how neural circuits shape behaviors. The neural circuits of most natural behaviors, such as defensive behaviors and maternal behaviors are hard-wired, she added.

Mice can also acquire those behaviors through learning. She is interested in how pup cues are perceived as rewards and subsequently facilitate learning maternal behavior. She found a great fit with Shea’s lab, which focuses on the neural mechanism of maternal behavior.

Xie enjoyed her time at Cold Spring Harbor Laboratory, where she could discuss science with colleagues by the bench, at the dining room or at one of the many on site seminars. She also appreciated the opportunity to attend neuroscience seminars with speakers from other schools, which helped expand her horizons and inspire ideas for research.

Next steps

As for the next steps, Shea said he believes there is considerable additional follow up research that could build on these findings. He would like to apply methods that measure the activity in individual neurons. Additionally, with a number of targets for dopamine, he wants to figure out what areas the neurotransmitter reaches and how the signals are used when they get there. More broadly, he suggested that the implications for this research extend to human diseases. 

Above, from left, CSHL Associate Professor Steven Shea, Yunyao Xie, a former postdoctoral researcher in Shea’s lab, and Roman Dvorkin at work. Photo from CSHL

By Daniel Dunaief

The black box has a blue spot.

Often considered so mysterious that it has been called “the black box,” the brain has a small cluster of cells called the locus coeruleus (LC), or blue spot because it appears blue.

The LC is the predominant source of the neurotransmitter noradrenaline, which plays numerous roles, including triggering the “fight or flight” response, sleep/wake regulation and memory.

Recently, Cold Spring Harbor Laboratory Associate Professor Stephen Shea and his post doctoral researcher Roman Dvorkin demonstrated that the LC was involved in normal maternal social behavior. In the publication Journal of Neuroscience, they demonstrated that surrogate mothers had a spike in this neurotransmitter just at the time when they retrieved young pups that had rolled out of the nest.

“Most of the research on noradrenaline and the LC has been involved in non-social behavior,” said Shea. Researchers have recorded it extensively during “cognitive tasks and memory formation.”

The evidence for its involvement in social behaviors has been more indirect. With the exception of a study 35 years ago that made a few recordings in cats, the current research is the “first time anyone has recorded” the LC during a more normal social behavior, Shea said.

Research on this blue spot could prove valuable in connection with understanding and treating a wide range of diseases and disorders. Noradrenaline (NA) is “one of the systems that is disturbed in anxiety and depression,” Dvorkin said. It also may be involved in other diseases, like autism. Scientists have conducted research on the LC and ADHD, Parkinson’s disease and Alzheimer’s disease, Dvorkin explained.

Some studies have also linked Rett syndrome, for example, which is a rare inherited genetic disorder that affects mostly girls and can alter the ability to speak, walk and eat, to lower levels of noradrenaline.

“There’s evidence that the LC has pathology in Mecp2 mice,” said Shea, referring to a gene traced to Rett. “We are working on that directly.”

Researchers believe studying the structure of the LC could lead to diagnostics and therapeutics for some of these diseases. Dvorkin suggested that this kind of research is “important to see how it works under normal, awake conditions.”

Monitoring the release of this neurotransmitter during a typical social behavior among female mice provides a context-connected understanding of its potential role.

“When people are studying this, they often use investigator-contrived tasks,” Shea said. “This is the system that preexisted for mice to use for other purposes.”

Shea has done earlier work with the LC, particularly as the sense of smell is so prominent in social interactions for mice. He demonstrated that anesthetized mice exposed to the scent of an unfamiliar mouse react as if they have a familiarity with the mouse. 

She believes the LC initiates sensory plasticity or sensory learning. NA can affect the sensory responses in parts of the brain that carry information, creating a stored memory. While his extensive work offers some clues about the role of the LC in mice, all vertebrates have the LC in their brain stems, including humans.

Shea said other research has demonstrated the involvement of the LC in cognitive tasks and memory formation, including during periods of sleep and wakefulness.

Blocking the release of noradrenaline is challenging in part because it is compact and the cells in the brain interact with so many of their neighbors, which makes turning on or off a specific signal from one region especially challenging.

At the University of Washington, Richard D. Palmiter and S.A. Thomas published a visible and definitive paper in 1997 in the journal Cell that brought the LC to other researcher’s attention.

These researchers created complete knockout mice, where they found that rodents lacking noradrenaline were “really bad mothers,” according to Shea.

In their research, Dvorkin and Shea used optogenetics and chemogenetics to inactivate the LC and the release of noradrenaline.

Future experiments

Below, a mouse retrieving a pup that has rolled out of its nest. Photo by Roman Dvorkin

The next step in this research could involve understanding the relative importance of the signal from the LC and noradrenaline.

In typical life settings, mice and other vertebrates confront competing signals, in which a pup rolls out of the nest at the same time that one of their many predators, like a hawk or other bird is circling overhead.

“That could be a next step” in this research, said Dvorkin.

Dvorkin believes it is possible to increase or decrease the threat level for mice gradually, in part because mice learn quickly when the threat is not real or what to avoid if the threat is too risky.

Shea is also looking more closely at courtship behavior.

The LC could be involved in sexual selection and in dominance hierarchies, enhancing the aggressive behavior of alpha males towards less dominant males. 

“We see big signals associated with events in courtship, including when the female and male begin to mate,” said Shea.

A resident of East Northport, Dvorkin lives with his wife Paolina and their nine year-old son Adam, who is in third grade at Pulaski Road School.

Originally from Afula in northern Israel, Dvorkin has been working in Shea’s lab for over five years. Outside the lab, he enjoys spending time with his family, taking pictures, and swimming at the JCC.

Dvorkin has enjoyed his work at CSHL, which he described as a “great experience in a beautiful place,” where he can appreciate the quiet and where he has received considerable support.

In the future, he’d like to apply his expertise in working on neuronal cell cultures and behaving animals to address translative questions, such as neurodegeneration.