Caltech: The Caltech Effect February 2021 - Neural Networking

June 25, 2021

The Tianqiao and Chrissy Chen Institute for Neuroscience officially moved into its new building on the Caltech campus in January 2021. Since the institute was inaugurated in 2016, however, researchers from a wide variety of disciplines and interests have been affiliated with Chen, including these five graduate students.

A fruit fly in flight is bombarded by stimuli, from other flies and obstacles it must avoid to signals that will help it to track down a food source. How does an insect with such a small brain adjust instantaneously? Annie Erickson, a Chen Graduate Fellow in the lab of Michael Dickinson, Esther M. and Abe M. Zarem Professor of Bioengineering and Aeronautics, studies the pathways in the fruit fly brain when in flight. “There is a whole class of neurons that project from the brain down to thoracic regions,” Erickson says. These descending neurons get information from sensory areas of the brain, connect with the fly brain’s navigational centers, and send instructions down to motor centers. But the exact ways in which so many different parts of the fly brain collaborate has not been fully understood and mapped. “We’re looking into all these different types of neurons and how they work together.”

Because it would not be practical to image the insect’s brain while in free flight, Erickson and her fellow researchers trick the creature. They keep the fly’s head immobile while allowing its body and wings to move, and then place it within a 360-degree cylindrical panel of LEDs that simulate what the fly would see while flying. Then researchers can look through the top of the insect’s head to see which neurons fire depending on how and in which direction a fly flies.

What Happens When We Go Under?

Caltech graduate student Jonathan D. Kenny studies anesthesia, a medical procedure that, despite its ubiquity and necessity, is shrouded in mystery. In the lab of Thanos Siapas, a professor of computation and neural systems, Kenny pursues the neural circuit dynamics of general anesthesia using very high-density electrodes implanted in the brains of animals. In this way, he can study the brain patterns of animals to understand what the brain is doing under anesthesia and to identify via brain waves the stages of recovery to full consciousness. After all, he says, people regain full awareness in stages rather than simply waking up and feeling normal again. “How can you tell if someone is conscious under anesthesia? Right now, the paradigm in the operating room is to look at things like your heart rate and blood pressure, but we know that anesthetics reduce consciousness by exerting their effects on your brain,” he says. “So, the notion is maybe we should observe brain activity.”

Like many Chen researchers, Kenny relies on the ascendant power of AI. Neural networks help Caltech researchers classify the noisy data from brain recordings to determine which brain wave states an animal or person is cycling through, with the goal of forming a complete picture of the brain under general anesthesia. Such a neural network may also be able to surface new brain states or combinations of brain states that a human researcher could not see amid all the noise.

AI Pushes Neuroscience Forward

Caltech’s Kortschak Scholars program, started with an endowment from businessman and Caltech trustee Walter Kortschak (MS ’82), supports computing mathematical science graduate students who pursue bold research ideas. For Jennifer Sun, that means the place where machine learning intersects with neuroscience.

Sun collaborates with the lab of Seymour Benzer Professor of Biology David Anderson, the Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair and director of the Chen Institute, as researchers there investigate the neural control of social behaviors in mice by imaging in the brains of animals during periods of social interaction.

Identifying and scoring social behaviors from videos of the experiments had required many hours of painstaking manual annotation. Sun is training machine learning models to recognize mouse behavior automatically, allowing researchers to collect and process much larger volumes of behavioral data than was previously possible. “We want to help them reduce annotation effort and accelerate behavior experiments,” she says.

A Neural Network in a Dish

Suppose you grow neurons on a dish and then these brain cells begin to form connections to one another. Could they be trained to perform a computational task in much the same way researchers train machine learning algorithms? In Assistant Professor of Computational Biology Matt Thomson’s lab, graduate student Guruprasad Raghavan tries to do just that in a research project to fabricate “cortical computers.” This is a joint project with graduate student Varun Wadia from the lab of Doris Tsao, Professor of Biology, Chen Center for Systems Neuroscience Leadership Chair, Investigator at the Howard Hughes Medical Institute, and director of the Chen Center for Systems Neuroscience.

Just like training a dog to sniff bombs or training an AI to solve problems, building these cortical computers out of neurons requires positive and negative feedback to effectively tell the cells whether or not they are completing the task. “The biggest challenge,” Raghavan says, “is figuring out what is a reward or what is a punishment for neurons in a dish.” The team plans to find out whether feeding neurons dopamine as a reward is effective.

What the Brain and AI Can Teach Each Other

Artificial intelligence, for all its power and potential, struggles with problems that biological intelligence easily cracks. Sanghyun Yi, a Chen Graduate Fellow in the lab of Caltech psychology professor John P. O’Doherty, says that studying how the human brain solves what appear to be simple problems will illuminate better ways to design machine learning algorithms.

Consider a task like riding the subway. The task consists of multiple sub-tasks that should be solved in a very specific order: first buy a ticket to pass through the gates and board the train before it leaves. Human brains use memory and context to solve such a task in an efficient way. However, for an AI, it may not realize that the steps need to happen in a very specific order unless it runs through a multitude of simulations and figures out the problem by trial and error.

However, Yi says, the converse is also true: sometimes AI can reveal new insights into the inner workings of the brain. In a recently published study, Yi and colleagues sought to understand how the brain evaluates a piece of visual art. Starting with a computer vision analysis of the aesthetic elements and considering subjective human ratings about certain attributes in a work of art, the model could explain how brains would subjectively rate whether they like or dislike a painting or drawing.

Caltech’s David Prober is interested in how the brain regulates sleep. With zebrafish as his model, he has made several breakthrough discoveries about this still-mysterious state. With access to new research facilities and technology, his lab’s move into the new Chen Neuroscience Research Building could open the door to many more.

It is the one bodily need that cannot be denied. More than food or water or sex, sleep is the one activity that seemingly few animals can abstain from for very long.

“The simplest creature that’s been shown to sleep is the upside down jellyfish, and they don’t even have a brain,” says Caltech biology professor David Prober. “So, sleep must be doing something that’s really ancient and central and important. But we don’t know what that is.”

Improved knowledge about this mysterious state that occupies about a third of people’s lives could not only help resolve a central biological mystery, it could also help treat insomnia and other sleep disorders.

Prober is part of a growing cadre of researchers who are taking a fresh approach to investigating sleep by studying it in an unconventional animal model: the zebrafish. Not only do zebrafish sleep, but their brains also are remarkably similar to human brains, only smaller and simpler. “The larval zebrafish brain has about 100,000 neurons. That’s about the same as a fruit fly,” Prober says. “But their brains contain mostly the same structures and genes found in rodent and human brains. We think that zebrafish provide a good model of many aspects of how the human brain regulates sleep.”

Over the last several years, Prober and his team at Caltech have successfully used zebrafish to make breakthough discoveries in the three known ways that sleep is regulated: homeostatic regulation, which is based on internal cues for sleep need; circadian regulation, which responds to external cues tied to the 24-hour circadian rhythm that governs many aspects of animal behavior; and masking, the direct effects of light and dark on sleep and wakefulness.

Prober’s team will soon be able to take their zebrafish sleep studies to the next level when they move into a spacious new lab in the Tianqiao and Chrissy Chen Neuroscience Research Building, which officially opened its doors in January 2021. Prober’s lab houses a custom-built microscope designed to simultaneously monitor the activity of all of the neurons in a zebrafish’s brain during wakefulness and sleep.

The following research highlights from Prober’s group are among the findings that have paved the way for the novel sleep experiments the scientists will perform in the Chen building.

In 2015, Prober and his team discovered the basis for circadian regulation of sleep and a long-sought link between the homeostatic and circadian processes—the internal and external cues, respectively—that regulate sleep. They first showed that larval zebrafish lacking the hormone melatonin had normal circadian rhythms but completely lacked circadian regulation of sleep, demonstrating that melatonin is essential for this mechanism of sleep control. Melatonin had long been suspected to play this role, but the notion was controversial among sleep experts, and it had not been possible to test this hypothesis prior to the Prober lab’s zebrafish study. The team also discovered that melatonin promotes sleep, in part, by stimulating signaling via a biomolecule called adenosine, which was known to mediate homeostatic control of sleep. This discovery provided the first link between the circadian and homeostatic sleep mechanisms.

In 2017, Prober’s lab demonstrated that two previously known neural proteins are crucial for promoting sleep. One, called neuropeptide Y, or NPY, was known to regulate feeding and social interaction in animals, but the Caltech researchers showed that it also promotes sleep, likely by inhibiting neurons in the brainstem that produce noradrenaline, a chemical known to promote wakefulness. The team also showed that a second neuropeptide, called neuropeptide-VF (NPVF), as well as the neurons in the hypothalamus that produce it, promote sleep. The identification of neuropeptides that promote wakefulness or sleep could eventually lead to drugs that target their specific receptors, Prober says.

Also in 2017, Prober’s lab made an important discovery related to the third regulatory process involved in sleep: masking, or the direct effects of light and dark on sleep. They showed that when a specific brain protein known as Prok2 was overexpressed, the fish were more likely to fall asleep during the day and to wake up at night. Surprisingly, the effect was not tied to the animals’ circadian rhythms; rather, it depended only on whether the lights were on or off in their environment. In addition, the Prober lab showed that Prok2 promotes sleep, in part, via a small population of neurons in the hypothalamus that are known to be critical for the homeostatic sleep mechanism. The findings produced one of the first insights into how light and dark interact with the brain to affect sleep and provided a foothold for scientists to begin to explore the genes and neurons that underlie masking.

Serotonin is implicated in a variety of brain processes, including memory, cognition, and emotions such as happiness. In 2019, Prober set out to settle a debate about what role, if any, this crucial chemical plays in sleep. He reasoned that zebrafish would be a good animal model to address this controversy because the larval zebrafish that his lab studies show robust sleep but have not yet developed other complex behaviors that have complicated attempts to understand serotonin’s role in mammalian sleep. In a series of experiments, his lab showed that serotonin produced by regions in the brain collectively known as the raphe nuclei is required for zebrafish to achieve normal amounts of sleep. Since these neurons are most active when animals are awake, the researchers theorized that the release of serotonin by raphe neurons during wakefulness leads to a buildup of pressure to sleep. By performing sleep deprivation experiments, they confirmed this hypothesis and demonstrated that serotonin is essential for homeostatic regulation of sleep. While the Prober lab was performing these experiments using zebrafish, Viviana Gradinaru’s lab obtained similar results using mice. Together, these studies established that serotonin and raphe neurons play a key role in regulating sleep homeostasis in both fish and mammals. The Prober lab is now trying to figure out how they do so.

In 2019, Prober’s lab identified a genetic pathway that is necessary for proper sleep in zebrafish and also appears to regulate sleep in humans. They discovered that this pathway promotes sleep by regulating the level of NPVF, which they previously identified as a sleep-promoting neuropeptide. Perhaps more important than the discovery itself, says Prober, was the process used to arrive at it, which involved examining genetic data from 500,000 people to identify genes associated with human sleep traits. This analysis suggested that the epidermal growth factor receptor (EGFR) pathway might play a key role in sleep, which the Prober lab confirmed using zebrafish experiments. Based on this proof-of-concept study, the Prober lab is using zebrafish to identify other genes that likely contribute to the variation observed in human sleep patterns and to human sleep disorders. This approach has the potential to identify specific drug targets for treating human sleep disorders.

In its new home in the Chen building, researchers in the Prober lab finally have space to perform experiments they could only dream of before. Their new lab has about 6,000 fish tanks capable of holding around 30,000 zebrafish. “So far, we’ve only done experiments with larval fish that are about a week old, but we’d like to do experiments with adult fish as well,” Prober says. “In the new building, we have space for that.”

The centerpiece of the new lab is a microscope that uses invisible infrared light to monitor all of the neurons in a fish’s brain almost simultaneously. The “two-photon selective plane illumination microscope” was designed by Prober’s former Caltech colleague Scott Fraser and requires its own room.

“The way people identify neurons involved in sleep now is fairly painstaking,” Prober explains. “You have to record from different populations of neurons one at a time and hope that you get lucky. Now, we can directly observe the activity state of almost all the neurons in the zebrafish brain at a rate of about once a second and see, all at once, which neurons are active during sleep, wakefulness, and transitions between these states.”

The team will also be able to activate specific populations of neurons and then use the microscope to see how this perturbation affects neurons throughout the brain. “At this point, we have identified about 10 different genetic pathways and neuronal populations that we know induce sleep,” Prober says. “We will now be able to activate each population in turn and ask if they all have similar or different effects on the brain. Effects they have in common could be the ones involved in regulating sleep, which we can then test experimentally.”

99 days to go

With the opening of the Tianqiao and Chrissy Chen Neuroscience Research Building, Caltech students and faculty who seek to understand the intricacies of the brain’s structure and function have a vital new hub for interdisciplinary research. The 150,000-square foot building, a bright, open space with floor-to-ceiling windows, houses research and teaching laboratories, a neurotechnology lab, and a 150-seat lecture hall. As headquarters for the Chen Institute for Neuroscience at Caltech, which reaches across Caltech’s six academic divisions, the new building promises to become an “idea factory” where advances in fundamental science will transform into knowledge that can help humanity.

In this video, Caltech researchers talk about how the new Chen Neuroscience Research Building will increase collaboration and open doors to new discoveries about the brain.

Transcript

Artist and neuroscientist Greg Dunn on his quest to convey the grandeur and intricacy of the human brain.

In the lobby of the newly opened Chen Neuroscience Research Building sits a stunning piece of artwork depicting the human brain. It is a gift from Tianqiao Chen and Chrissy Luo and is the work of Greg Dunn, who earned a doctorate in neuroscience before embarking on his artistic career. The large centerpiece of the triptych, titled Self Reflected, is an NSF-funded project created by Dunn, his applied physicist collaborator Brian Edwards, and a team of scientists over a two-year period. It is an animated and extraordinarily detailed representation of human brain activity designed to mirror the functioning of the viewer’s own mind.

Dunn explains how this piece became the foundation of the larger commission for the Chen building and how the flanking pieces evolved through discussion with Chen faculty.

“I had a meeting with [Bren Professor of Biology and Chemistry] Steve Mayo (PhD ’88) and [Chen Institute director and Seymour Benzer Professor of Biology] David Anderson to talk about what the Chen Neuroscience Institute represents. They particularly wanted to stress Caltech’s emphasis on systems neuroscience and to somehow represent the complexity of that circuitry. In the midst of this discussion, it became obvious that the central piece should be Self Reflected.

“The aim of Self Reflected is to change the way the average person thinks about the brain by presenting an incredibly detailed depiction of the brain’s circuitry. In creating the work, we applied techniques from photolithography and novel gliding, and used mathematical calculations of angular reflections to create animated effects and computer-assisted simulations to map/visualize neural activity. From both a technological and a thematic standpoint, it seemed perfect.”

“Neuroscientists struggle to communicate the complexity of the brain. A billion, 50 billion, 80 billion neurons is difficult to comprehend if you don’t have a frame of reference for numbers that large. When someone directly experiences what half a million animated neurons look like with their own eyes when viewing Self Reflected, it serves as a stepping stone to more directly understanding the brain’s vast complexity. In reality, of course, the brain is many hundreds of millions or billions of times more complicated, but Self Reflected gives us a place to start pondering those gargantuan numbers.”

“The animated effect that the viewer perceives is due to a technique called reflective microetching, a photolighographic technique that involves making millions of tiny etches on the surface of a light-sensitive material that are then gilded. The position and angles of the etches reflect light in such a way as to give the appearance that the neurons are all firing when the viewer moves around the image.

“The reflectivity animates either by moving a light source around the etching or by lighting it with a stationary light source and having the viewer move around it. At Caltech, we decided that the latter was a better solution for the lobby space. As you move around it, you see the beautiful animations of all the different regions of the brain ‘talking’ to one another. It’s like a hard-coded animated GIF encompassing roughly 500 microseconds of time.”

“In discussing the flanking paintings, David Anderson mentioned that he wanted to capture the vertical integration of neuroscience, a vast amount of subject material to capture in a triptych. To explore this ambitious concept, I wanted to draw parallels between the worlds of the brain and the cosmos, marrying these two ideas together.

“The painting on the left, Molecules to Neurons, depicts nebular clouds of trillions of molecules self-assembling into the form of just a single neuron. These building blocks precisely join together to form just one single unit of the brain. Each neuron is in and of itself its own universe of complexity, and yet the brain contains a staggering 86 billion of them!”

“I developed some techniques specifically for Molecules to Neurons involving chaotic dispersions of mica and metallic powders. I used blowing techniques and suspensions in resins to get the cloud-like, almost astronomical images of molecules dispersing in nebula-like forms and then coalescing into a greater superstructure.

“The flanking pieces are made on strategically etched stainless steel, then finished with transparent resins, ink, and 22-karat gold leaf. As you walk around the painting, the thousands of tiny sparkles represent the neural inputs that might be coming into this one single neuron; the synapses flashing on and off that provide the basis for neural communication. This is to portray the profound depth of complexity within even a single working unit of the brain.”

“The triptych concludes with a piece called Brain to Consciousness. It is a celebration of the emergent properties of our brains, the culmination of fathomless intricacies that give us the capacity to love, learn, invent, and explore our world. When viewed from the side, forms explode from the golden brain and coalesce into some of the greatest scientific and artistic ideas in the history of humankind.”

“I was able to plug some of my personal favorites here, ranging from the development of astronomy and rocketry, the discovery of the atom, the golden mean, silicon microchips, a Ramón y Cajal drawing, some of the greatest scientific volumes, and one of my favorite pieces of music ever written. As the viewer moves to the center of the painting, a ghostly blue form of a human head emerges and reminds the viewer that the emergent properties of our brains are inextricable from ourselves, that they are the very fabric of our identities.”

“It has been an incredible honor to work on this commission for Caltech, a world leader in scientific and technical fields, and near to where I grew up. The artwork is a gift for all to enjoy. Having spent many years in the lab, I know firsthand how easy it can be for neuroscientists to get lost in the weeds and lose sight of the bigger picture. I hope this artwork serves as a daily reminder of the audaciousness of our attempts to tackle some of the most difficult and compelling scientific questions of our time, to reinspire us with a sense of awe. I also hope it becomes a useful teaching tool for the casual passerby, to enrich the way they think about their most precious and miraculous possession, their brain.”

Daniel Wagenaar (PhD ’06), director of Caltech’s Kevin Xu Neurotechnology Lab, recounts how the lab came into existence and describes some of the myriad projects he has worked on with Caltech scientists.

Transcript

My name is Daniel Wagenaar, and I run the Neurotechnology Lab in the Chen Neuroscience Research Building. I did my PhD here at Caltech, and it turned out that the experiments I wanted to do required equipment that didn’t exist. So, I first developed software that was clearly missing but clearly required to do what we wanted to do. And then I developed some hardware. It was necessity that brought me to tool building, and I realized I could do the same for other researchers. So, in 2016, Markus Meister and I started the Neurotechnology lab as a machine shop and problem solving center. People come to us with questions, and the answer to whether it’s possible is always, “Yes, we will get traction on it, and we’re not going to take no for an answer.” I’ve worked on 219 projects I think over the last four years, from very small to not so small. I worked with David Anderson to develop a whole suite of little gadgets to make various parts of a complicated system talk together. We built an Arduino-based box that gathered timing information from a couple of cameras, an optical fiber, and a treadmill, making it available in a single stream so researchers could make sure everything was synchronized. One of my favorite ever projects was a fly food mover for Betty Hong’s lab. Betty and I invented this device where the flies would just sit in their usual cylinder, but a dish underneath could be moved back and forth at a very slow pace allowing us to surreptitiously change food sources to control what food was available at what time. The single most popular machine in the lab is the laser cutter. Perhaps because it’s so easy to learn how to use it. It has found so many uses. Front panels for electronic devices; microscope stages. One lab even makes clever jigsaw puzzle pieces to build mazes for behavior experiments. You cut your base plate and all the various walls and you basically slam it together and glue it in place, and it’s done. With our new space in the Chen building, many of the labs we work with will be much closer. It’s surprising how much difference that makes, for people to just be able to walk along the hallway or take an elevator down. It really helps accessibility. And ultimately that’s what this whole thing is about.

Chen researchers talk about the work being done by the scientists they find inspiring.