Right off the bats

Among the many devastating impacts of Alzheimer’s disease and other types of dementia is the risk that patients will wander and become lost. Indeed, according to the Alzheimer’s Association, six in 10 people with the disease will wander at least once over the course of their illness — and many do so repeatedly.

For researchers who study and treat people with neurodegenerative disorders, understanding the human neural circuitry that leads to such behavior is among the highest-priority goals. But to better study these and other neurological conditions, the work needs to begin with effective, accessible animal models.

That’s where researchers at the NeuroBat lab — led by Michael Yartsev, assistant professor of bioengineering and of neurobiology — come in. Their studies of the neural circuitry of navigation in Egyptian fruit bats are yielding insights that might one day help explain and prevent dangerous situations for humans.

Egyptian fruit bats are “one of the most superior navigators that exist on our planet,” Yartsev says. He describes how these diminutive, highly social creatures in the wild will travel tens of kilometers, even through dark and stormy nights, seldom if ever getting lost in their search for food. The bats’ complex travel through 3D space, he says, could shed light on the complexity of human behavior in navigating from place to place.

But understanding the neuronal processes at the root of behavior in appropriate animal models goes well beyond studies of navigation. “We have a huge number of questions that we want to understand about the brain,” Yartsev says. And one of his goals as a neuroscientist is to advocate for an expansion of the diversity of animal models researchers have available for their work.

In the current landscape of neuroscience research, Yartsev says, 75% or more of the work focuses on a handful of “standard” organisms, such as rats and mice. The reasons often come down to accessibility of tools and ease of maintenance in laboratory environments. But this overwhelming convergence is not without cost, as it limits the type of questions asked, the discoveries made and the degree to which scientific findings can be generalized beyond those species.

With bats, Yartsev says, their ability to fly, complex social behaviors, patterns of vocalization, long lives and more set them apart as animal models for studying a specific set of basic research problems in neuroscience — such as how the brain processes skills like navigation, sociality and language.

The ultimate flight room

Yartsev’s first encounter with bats as a subject for neuroscience took place some 15 years ago during his Ph.D. studies at the Weizmann Institute of Science in Israel. Yartsev says it was a risky move, then, to pursue a Ph.D. in neuroscience by studying a non-traditional animal. But this work helped establish bats as an important model system for a variety of new research topics.

As befits Yartsev’s biomedical engineering background, the work has included the opportunity to develop new research tools for neuroscience — for example, the first wireless electrophysiology system for recording and studying a bat’s brain activity during flight.

“This was the first single-cell neural recording from a freely flying animal,” Yartsev says, referring to experimental work behind a 2013 Science paper on navigation-related bat neural activity. Bats obviously cannot fly around freely with a cable attached, “so we had to develop the tools needed to do this work — we still do,” he adds, citing, as another example, a piezoelectric device for recording vocalizations that is lightweight enough for the bats to wear as a necklace while communicating with one another.

In 2015, Yartsev brought his pioneering research with Egyptian fruit bats to UC Berkeley, where he has established his own group, the NeuroBat Lab. Studying the neural circuitry of these diminutive creatures, the group continues to build and publish a rich trove of basic research data and neuroscience insight with more to come.

In a continuation of his research work on navigation using bats, the NeuroBat Lab has recently focused on neural mechanisms that could underlie goal-directed navigation, which Alzheimer patients often struggle with. To carry out the study, the Yartsev team used a specialized facility they created called the fully automated flight room. It is a human-free space used to obtain detailed, quantitative understanding of bat navigation and flight behavior by recording activity in relevant neural circuits.

Bioengineering graduate student Madeleine Snyder, one of Yartsev’s team members who also studies the neural mechanisms of navigation in bats, says bats make a good research subject because “they’re both highly social and highly navigationally adept, and that’s very similar to humans in many ways. They will go kilometers and kilometers to forage in a specific tree and then come home together.”

She describes the flight room as “about the size of a large living room” that is outfitted with cameras and other recording devices. Researchers can situate perches for the bats at various places in the room. The perches might be outfitted with beam breakers that, when triggered by a bat alighting on the perch, will trigger some action like the introduction of food. Lights can be programmed to turn on and off, sounds can be introduced — and researchers can simply step back, watch and record how the bats interact with their environment.

In comparison to studies with other animal models, she says, “with bats in the human-free flight room, we’re not constraining the animal but just letting them do what they want to do and seeing what happens.”

As with many animal-model studies, Yartsev says, subtracting humans from the study environment can heighten fidelity of results. That’s because the presence of human investigators may introduce experimental biases, reduce reproducibility of the experiment, prevent the animals from engaging freely in self-paced navigational behavior and limit the complexity of tasks that could be utilized to study neural circuits.

For the navigation study, the team looked at the activity of place cells, specialized cells in the brain that act as a sort of internal global positioning system. Studies of place cells in rats had indicated that the cells primarily encode the animals’ location at the time the cell is firing.

“What we are showing in this paper is that if you align all the place cells that you are recording as they are firing in the hippocampus, there is a continuum of space and time,” Yartsev says, referring to their paper published in Science earlier this year. “The cells are representing where the animal has been, where it will be a half a second into the future, a second into the future and so on.”

One of the hallmarks of Alzheimer’s disease, Yartsev notes, “is that people get lost all the time, even in their own neighborhoods.” Understanding how the brain represents the environment, how a person knows the route to take to get from one place to another remains unknown, he says. The NeuroBat Lab study suggests that the reason a person might get lost is that their brain somehow loses that continuum of space and time — the ability to hold and follow a planned trajectory.

He says the data from their fast-moving bat animal model reveals dynamics of neuronal activity that would be difficult to observe so cleanly by only studying, for example, a slower-moving rodent in a 2D maze.

“We can sometimes make very significant progress with just one experiment with bats, no matter that it can at times be very difficult,” Yartsev says. That’s because the animals can be a highly relevant model system for a specific scientific question that could also be important for humans. For example, bats are specialized for communication at the group level. “They have developed behavioral capacities for group living and the underlying neural circuits that serve those capacities.”

On the same wavelength

In another recent study from the lab, the team became the first to observe synchronized brain activity in a nonhuman species engaging in natural social interactions like grooming, fighting or sniffing each other.

For the study, published in Cell, Yartsev and postdoctoral fellow Wujie Zhang used simultaneous wireless neural recording devices to measure brain activity while multiple bats freely interacted. The specialized recording devices allowed them to capture what modalities like functional MRI and EEG cannot — the full scope of neural activity from brain oscillations to the firing of individual neurons, all at the same time.

The researchers found surprisingly strong correlations between the bats’ brains. That is, as they engaged with one another in social behaviors in the same environment, their brain wave and neuronal electrical activity began to look the same in each bat, even when the bats performed very different actions. The correlations were present whenever the bats shared a social environment and increased before and during their social interactions, Yartsev says.

Their detailed analysis of social interactions allowed them to rule out other possible explanations for the synced-up brain activity, such as that bats were simply reacting to the same environment or engaging in the same activity. For example, bats placed in identical but separate chambers and that were both busy grooming did not show the same synchronization.

“This study is really laying the groundwork for studying inter-brain correlation in animals,” Zhang says.  “We didn’t know if this is something that’s only observed in humans. If we have the same phenomenon in animals, then there’s a lot more experimental techniques we can use to really understand the mechanisms of this phenomenon, including its function.”

“This is a very core phenomenon that, for two decades, people have been excited about in humans,” Yartsev says. “Now that we’ve observed it in an animal model, it opens the door to very detailed research of it.” Importantly, this phenomenon also relates to how humans socialize with one another in social groups and is impacted during diseases such as autism and other neurological disorders. Understanding the neural mechanisms behind it and how it mediates natural group social behavior could lead to future therapeutics in humans.

“And this is exactly where we are going with this,” Yartsev says. In another paper, published in Science this fall, the lab studied social communication among groups of bats for the first time. Led by graduate student Maimon Rose and postdoctoral fellow Boaz Styr, the researchers discovered a rich repertoire of neural signals that represent key components in group communication, findings that could also have significant implications for understanding aspects of human mental health.

“The crown jewel”

Another future area of research interest, Yartsev says, is language — “the crown jewel of humanity.” Humans are the only mammals capable of learning and using language, but they are joined by bats, elephants and cetaceans (whales, dolphins) — out of some 5,400 species of mammals — in the ability to learn new sounds. This process, also known as vocal learning, is the basis for language learning.

“First of all, just understanding that fact about learning language is really important,” he says. “How does our brain allow us to learn a language? It becomes even more important when we think that about 10 percent of the people in the world suffer from language disorders. And this affects them dramatically. These disorders relate to autism, dyslexia and a whole variety of problems related to brain functioning.”

Unfortunately, in the world of neuroscience today, Yartsev says, “we still do not understand the detailed neurobiological mechanisms that allow us to learn a language.”

And beyond biology and human health, the research into complex neurobiological processes in bats might also power new technology development, Yartsev says. For example, insights from the bats might aid development of new machine learning algorithms and sensing technologies critical to the development of fully self-driving cars. Such autonomous vehicles must be able to safely maneuver roadways by sensing and reacting to other moving vehicles, random obstacles and constantly changing environmental conditions. “For some questions, the bats provide us very unique advantages that you simply can’t find in other animal model system — and these are the questions we focus on,” Yartsev says.

Article by William Schulz