Researcher: Fan Wang

How the brain coordinates speaking and breathing

Anne Trafton |

MIT researchers have discovered a brain circuit that drives vocalization and ensures that you talk only when you breathe out, and stop talking when you breathe in.

McGovern Investigator Fan Wang. Photo: Caitliin Cunningham

The newly discovered circuit controls two actions that are required for vocalization: narrowing of the larynx and exhaling air from the lungs. The researchers also found that this vocalization circuit is under the command of a brainstem region that regulates the breathing rhythm, which ensures that breathing remains dominant over speech.

“When you need to breathe in, you have to stop vocalization. We found that the neurons that control vocalization receive direct inhibitory input from the breathing rhythm generator,” says Fan Wang, an MIT professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study.

Jaehong Park, a Duke University graduate student who is currently a visiting student at MIT, is the lead author of the study, which appears today in Science. Other authors of the paper include MIT technical associates Seonmi Choi and Andrew Harrahill, former MIT research scientist Jun Takatoh, and Duke University researchers Shengli Zhao and Bao-Xia Han.

Vocalization control

Located in the larynx, the vocal cords are two muscular bands that can open and close. When they are mostly closed, or adducted, air exhaled from the lungs generates sound as it passes through the cords.

The MIT team set out to study how the brain controls this vocalization process, using a mouse model. Mice communicate with each other using sounds known as ultrasonic vocalizations (USVs), which they produce using the unique whistling mechanism of exhaling air through a small hole between nearly closed vocal cords.

“We wanted to understand what are the neurons that control the vocal cord adduction, and then how do those neurons interact with the breathing circuit?” Wang says.

To figure that out, the researchers used a technique that allows them to map the synaptic connections between neurons. They knew that vocal cord adduction is controlled by laryngeal motor neurons, so they began by tracing backward to find the neurons that innervate those motor neurons.

This revealed that one major source of input is a group of premotor neurons found in the hindbrain region called the retroambiguus nucleus (RAm). Previous studies have shown that this area is involved in vocalization, but it wasn’t known exactly which part of the RAm was required or how it enabled sound production.

Image of green and magenta cells under a microscope.
Laryngeal premotor neurons (green) and Fos (magenta) labeling in the RAm. Image: Fan Wang

The researchers found that these synaptic tracing-labeled RAm neurons were strongly activated during USVs. This observation prompted the team to use an activity-dependent method to target these vocalization-specific RAm neurons, termed as RAmVOC. They used chemogenetics and optogenetics to explore what would happen if they silenced or stimulated their activity. When the researchers blocked the RAmVOC neurons, the mice were no longer able to produce USVs or any other kind of vocalization. Their vocal cords did not close, and their abdominal muscles did not contract, as they normally do during exhalation for vocalization.

Conversely, when the RAmVOC neurons were activated, the vocal cords closed, the mice exhaled, and USVs were produced. However, if the stimulation lasted two seconds or longer, these USVs would be interrupted by inhalations, suggesting that the process is under control of the same part of the brain that regulates breathing.

“Breathing is a survival need,” Wang says. “Even though these neurons are sufficient to elicit vocalization, they are under the control of breathing, which can override our optogenetic stimulation.”

Rhythm generation

Additional synaptic mapping revealed that neurons in a part of the brainstem called the pre-Bötzinger complex, which acts as a rhythm generator for inhalation, provide direct inhibitory input to the RAmVOC neurons.

“The pre-Bötzinger complex generates inhalation rhythms automatically and continuously, and the inhibitory neurons in that region project to these vocalization premotor neurons and essentially can shut them down,” Wang says.

This ensures that breathing remains dominant over speech production, and that we have to pause to breathe while speaking.

The researchers believe that although human speech production is more complex than mouse vocalization, the circuit they identified in mice plays the conserved role in speech production and breathing in humans.

“Even though the exact mechanism and complexity of vocalization in mice and humans is really different, the fundamental vocalization process, called phonation, which requires vocal cord closure and the exhalation of air, is shared in both the human and the mouse,” Park says.

The researchers now hope to study how other functions such as coughing and swallowing food may be affected by the brain circuits that control breathing and vocalization.

The research was funded by the National Institutes of Health.

Ariel Furst and Fan Wang receive 2023 National Institutes of Health awards

by MIT School of Science |

The National Institutes of Health (NIH) has awarded grants to MIT’s Ariel Furst and Fan Wang, through its High-Risk, High-Reward Research program. The NIH High-Risk, High-Reward Research program awarded 85 new research grants to support exceptionally creative scientists pursuing highly innovative behavioral and biomedical research projects.

Ariel Furst was selected as the recipient of the NIH Director’s New Innovator Award, which has supported unusually innovative research since 2007. Recipients are early-career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Furst, the Paul M. Cook Career Development Assistant Professor of Chemical Engineering at MIT, invents technologies to improve human and environmental health by increasing equitable access to resources. Her lab develops transformative technologies to solve problems related to health care and sustainability by harnessing the inherent capabilities of biological molecules and cells. She is passionate about STEM outreach and increasing the participation of underrepresented groups in engineering.

After completing her PhD at Caltech, where she developed noninvasive diagnostics for colorectal cancer, Furst became an A. O. Beckman Postdoctoral Fellow at the University of California at Berkeley. There she developed sensors to monitor environmental pollutants. In 2022, Furst was awarded the MIT UROP Outstanding Faculty Mentor Award for her work with undergraduate researchers. She is a now a 2023 Marion Milligan Mason Awardee, a CIFAR Azrieli Global Scholar for Bio-Inspired Solar Energy, and an ARO Early Career Grantee. She is also a co-founder of the regenerative agriculture company, Seia Bio.

Fan Wang received the Pioneer Award, which has been challenging researchers at all career levels to pursue new directions and develop groundbreaking, high impact approaches to a broad area of biomedical and behavioral sciences since 2004.

Wang, a professor in the Department of Brain and Cognitive Sciences and an investigator in the McGovern Institute for Brain Research, is uncovering the neural circuit mechanisms that govern bodily sensations, like touch, pain, and posture, as well as the mechanisms that control sensorimotor behaviors. Researchers in the Wang lab aim to generate an integrated understanding of the sensation-perception-action process, hoping to find better treatments for diseases like chronic pain, addiction, and movement disorders. Wang’s lab uses genetic, viral, in vivo large-scale electrophysiology and imaging techniques to gain traction in these pursuits.

Wang obtained her PhD at Columbia University, working with Professor Richard Axel. She conducted her postdoctoral work at Stanford University with Mark Tessier-Lavigne, and then subsequently joined Duke University as faculty in 2003. Wang was later appointed as the Morris N. Broad Distinguished Professor of Neurobiology at the Duke University School of Medicine. In January 2023, she joined the faculty of the MIT School of Science and the McGovern Institute.

The High-Risk, High-Reward Research program is funded through the NIH Common Fund, which supports a series of exceptionally high-impact programs that cross NIH Institutes and Centers.

“The HRHR program is a pillar for innovation here at NIH, providing support to transformational research, with advances in biomedical and behavioral science,” says Robert W. Eisinger, acting director of the Division of Program Coordination, Planning, and Strategic Initiatives, which oversees the NIH Common Fund. “These awards align with the Common Fund’s mandate to support science expected to have exceptionally high and broadly applicable impact.”

NIH issued eight Pioneer Awards, 58 New Innovator Awards, six Transformative Research Awards, and 13 Early Independence Awards in 2023. Funding for the awards comes from the NIH Common Fund; the National Institute of General Medical Sciences; the National Institute of Mental Health; the National Library of Medicine; the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Office of Dietary Supplements.

How touch dampens the brain’s response to painful stimuli

by Jennifer Michalowski |

McGovern Investigator Fan Wang. Photo: Caitliin Cunningham

When we press our temples to soothe an aching head or rub an elbow after an unexpected blow, it often brings some relief. It is believed that pain-responsive cells in the brain quiet down when these neurons also receive touch inputs, say scientists at MIT’s McGovern Institute, who for the first time have watched this phenomenon play out in the brains of mice.

The team’s discovery, reported November 16, 2022, in the journal Science Advances, offers researchers a deeper understanding of the complicated relationship between pain and touch and could offer some insights into chronic pain in humans. “We’re interested in this because it’s a common human experience,” says McGovern Investigator Fan Wang. “When some part of your body hurts, you rub it, right? We know touch can alleviate pain in this way.” But, she says, the phenomenon has been very difficult for neuroscientists to study.

Modeling pain relief

Touch-mediated pain relief may begin in the spinal cord, where prior studies have found pain-responsive neurons whose signals are dampened in response to touch. But there have been hints that the brain was involved too. Wang says this aspect of the response has been largely unexplored, because it can be hard to monitor the brain’s response to painful stimuli amidst all the other neural activity happening there—particularly when an animal moves.

So while her team knew that mice respond to a potentially painful stimulus on the cheek by wiping their faces with their paws, they couldn’t follow the specific pain response in the animals’ brains to see if that rubbing helped settle it down. “If you look at the brain when an animal is rubbing the face, movement and touch signals completely overwhelm any possible pain signal,” Wang explains.

She and her colleagues have found a way around this obstacle. Instead of studying the effects of face-rubbing, they have focused their attention on a subtler form of touch: the gentle vibrations produced by the movement of the animals’ whiskers. Mice use their whiskers to explore, moving them back and forth in a rhythmic motion known as whisking to feel out their environment. This motion activates touch receptors in the face and sends information to the brain in the form of vibrotactile signals. The human brain receives the same kind of touch signals when a person shakes their hand as they pull it back from a painfully hot pan—another way we seek touch-mediate pain relief.

If you look at the brain when an animal is rubbing the face, movement and touch signals completely overwhelm any possible pain signal, says Wang.

Wang and her colleagues found that this whisker movement alters the way mice respond to bothersome heat or a poke on the face—both of which usually lead to face rubbing. “When the unpleasant stimuli were applied in the presence of their self-generated vibrotactile whisking…they respond much less,” she says. Sometimes, she says, whisking animals entirely ignore these painful stimuli.

In the brain’s somatosensory cortex, where touch and pain signals are processed, the team found signaling changes that seem to underlie this effect. “The cells that preferentially respond to heat and poking are less frequently activated when the mice are whisking,” Wang says. “They’re less likely to show responses to painful stimuli.” Even when whisking animals did rub their faces in response to painful stimuli, the team found that neurons in the brain took more time to adopt the firing patterns associated with that rubbing movement. “When there is a pain stimulation, usually the trajectory the population dynamics quickly moved to wiping. But if you already have whisking, that takes much longer,” Wang says.

Wang notes that even in the fraction of a second before provoked mice begin rubbing their faces, when the animals are relatively still, it can be difficult to sort out which brain signals are related to perceiving heat and poking and which are involved in whisker movement. Her team developed computational tools to disentangle these, and are hoping other neuroscientists will use the new algorithms to make sense of their own data.

Whisking’s effects on pain signaling seem to depend on dedicated touch-processing circuitry that sends tactile information to the somatosensory cortex from a brain region called the ventral posterior thalamus. When the researchers blocked that pathway, whisking no longer dampened the animals’ response to painful stimuli. Now, Wang says, she and her team are eager to learn how this circuitry works with other parts of the brain to modulate the perception and response to painful stimuli.

Wang says the new findings might shed light on a condition called thalamic pain syndrome, a chronic pain disorder that can develop in patients after a stroke that affects the brain’s thalamus. “Such strokes may impair the functions of thalamic circuits that normally relay pure touch signals and dampen painful signals to the cortex,” she says.

Personal pursuits

by Jennifer Michalowski |

This story originally appeared in the Fall 2022 issue of BrainScan.

***

Many neuroscientists were drawn to their careers out of curiosity and wonder. Their deep desire to understand how the brain works drew them into the lab and keeps them coming back, digging deeper and exploring more each day. But for some, the work is more personal.

Several McGovern faculty say they entered their field because someone in their lives was dealing with a brain disorder that they wanted to better understand. They are committed to unraveling the basic biology of those conditions, knowing that knowledge is essential to guide the development of better treatments.

The distance from basic research to clinical progress is shortening, and many young neuroscientists hope not just to deepen scientific understanding of the brain, but to have direct impact on the lives of patients. Some want to know why people they love are suffering from neurological disorders or mental illness; others seek to understand the ways in which their own brains work differently than others. But above all, they want better treatments for people affected by such disorders.

Seeking answers

That’s true for Kian Caplan, a graduate student in MIT’s Department of Brain and Cognitive Sciences who was diagnosed with Tourette syndrome around age 13. At the time, learning that the repetitive, uncontrollable movements and vocal tics he had been making for most of his life were caused by a neurological disorder was something of a relief. But it didn’t take long for Caplan to realize his diagnosis came with few answers.

Graduate student Kian Caplan studies the brain circuits associated with Tourette syndrome and obsessive-compulsive disorder in Guoping Feng and Fan Wang’s labs at the McGovern Institute. Photo: Steph Stevens

Tourette syndrome has been estimated to occur in about six of every 1,000 children, but its neurobiology remains poorly understood.

“The doctors couldn’t really explain why I can’t control the movements and sounds I make,” he says. “They couldn’t really explain why my symptoms wax and wane, or why the tics I have aren’t always the same.”

That lack of understanding is not just frustrating for curious kids like Caplan. It means that researchers have been unable to develop treatments that target the root cause of Tourette syndrome. Drugs that dampen signaling in parts of the brain that control movement can help suppress tics, but not without significant side effects. Caplan has tried those drugs. For him, he says, “they’re not worth the suppression.”

Advised by Fan Wang and McGovern Associate Director Guoping Feng, Caplan is looking for answers. A mouse model of obsessive-compulsive disorder developed in Feng’s lab was recently found to exhibit repetitive movements similar to those of people with Tourette syndrome, and Caplan is working to characterize those tic-like movements. He will use the mouse model to examine the brain circuits underlying the two conditions, which often co-occur in people. Broadly, researchers think Tourette syndrome arises due to dysregulation of cortico-striatal-thalamo-cortical circuits, which connect distant parts of the brain to control movement. Caplan and Wang suspect that the brainstem — a structure found where the brain connects to the spinal cord, known for organizing motor movement into different modules — is probably involved, too.

Wang’s research group studies the brainstem’s role in movement, but she says that like most researchers, she hadn’t considered its role in Tourette syndrome until Caplan joined her lab. That’s one reason Caplan, who has long been a mentor and advocate for students with neurodevelopmental disorders, thinks neuroscience needs more neurodiversity.

“I think we need more representation in basic science research by the people who actually live with those conditions,” he says. Their experiences can lead to insights that may be inaccessible to others, he says, but significant barriers in academia often prevent this kind of representation. Caplan wants to see institutions make systemic changes to ensure that neurodiverse and otherwise minority individuals are able to thrive in academia. “I’m not an exception,” he says, “there should be more people like me here, but the present system makes that incredibly difficult.”

Overcoming adversity

Like Caplan, Lace Riggs faced significant challenges in her pursuit to study the brain. She grew up in Southern California’s Inland Empire, where issues of social disparity, chronic stress, drug addiction, and mental illness were a part of everyday life.

Postdoctoral fellow Lace Riggs studies the origins of neurodevelopmental conditions in Guoping Feng’s lab at the McGovern Institute. Photo: Lace Riggs

“Living in severe poverty and relying on government assistance without access to adequate education and resources led everyone I know and love to suffer tremendously, myself included,” says Riggs, a postdoctoral fellow in the Feng lab.

“There are not a lot of people like me who make it to this stage,” says Riggs, who has lost friends and family members to addiction, mental illness, and suicide. “There’s a reason for that,” she adds. “It’s really, really difficult to get through the educational system and to overcome socioeconomic barriers.”

Today, Riggs is investigating the origins of neurodevelopmental conditions, hoping to pave the way to better treatments for brain disorders by uncovering the molecular changes that alter the structure and function of neural circuits.

Riggs says that the adversities she faced early in life offered valuable insights in the pursuit of these goals. She first became interested in the brain because she wanted to understand how our experiences have a lasting impact on who we are — including in ways that leave people vulnerable to psychiatric problems.

“While the need for more effective treatments led me to become interested in psychiatry, my fascination with the brain’s unique ability to adapt is what led me to neuroscience,” says Riggs.

After finishing high school, Riggs attended California State University in San Bernardino and became the only member of her family to attend university or attempt a four-year degree. Today, she spends her days working with mice that carry mutations linked to autism or ADHD in humans, studying the animals’ behavior and monitoring their neural activity. She expects that aberrant neural circuit activity in these conditions may also contribute to mood disorders, whose origins are harder to tease apart because they often arise when genetic and environmental factors intersect. Ultimately, Riggs says, she wants to understand how our genes dictate whether an experience will alter neural signaling and impact mental health in a long-lasting way.

Riggs uses patch clamp electrophysiology to record the strength of inhibitory and excitatory synaptic input onto individual neurons (white arrow) in an animal model of autism. Image: Lace Riggs

“If we understand how these long-lasting synaptic changes come about, then we might be able to leverage these mechanisms to develop new and more effective treatments.”

While the turmoil of her childhood is in the past, Riggs says it is not forgotten — in part, because of its lasting effects on her own mental health.  She talks openly about her ongoing struggle with social anxiety and complex post-traumatic stress disorder because she is passionate about dismantling the stigma surrounding these conditions. “It’s something I have to deal with every day,” Riggs says. That means coping with symptoms like difficulty concentrating, hypervigilance, and heightened sensitivity to stress. “It’s like a constant hum in the background of my life, it never stops,” she says.

“I urge all of us to strive, not only to make scientific discoveries to move the field forward,” says Riggs, “but to improve the accessibility of this career to those whose lived experiences are required to truly accomplish that goal.”

How the brain generates rhythmic behavior

Anne Trafton |

Many of our bodily functions, such as walking, breathing, and chewing, are controlled by brain circuits called central oscillators, which generate rhythmic firing patterns that regulate these behaviors.

MIT neuroscientists have now discovered the neuronal identity and mechanism underlying one of these circuits: an oscillator that controls the rhythmic back-and-forth sweeping of tactile whiskers, or whisking, in mice. This is the first time that any such oscillator has been fully characterized in mammals.

The MIT team found that the whisking oscillator consists of a population of inhibitory neurons in the brainstem that fires rhythmic bursts during whisking. As each neuron fires, it also inhibits some of the other neurons in the network, allowing the overall population to generate a synchronous rhythm that retracts the whiskers from their protracted positions.

“We have defined a mammalian oscillator molecularly, electrophysiologically, functionally, and mechanistically,” says Fan Wang, an MIT professor of brain and cognitive sciences and a member of MIT’s McGovern Institute for Brain Research. “It’s very exciting to see a clearly defined circuit and mechanism of how rhythm is generated in a mammal.”

Wang is the senior author of the study, which appears today in Nature. The lead authors of the paper are MIT research scientists Jun Takatoh and Vincent Prevosto.

Rhythmic behavior

Most of the research that clearly identified central oscillator circuits has been done in invertebrates. For example, Eve Marder’s lab at Brandeis University found cells in the stomatogastric ganglion in lobsters and crabs that generate oscillatory activity to control rhythmic motion of the digestive tract.

Characterizing oscillators in mammals, especially in awake behaving animals, has proven to be highly challenging. The oscillator that controls walking is believed to be distributed throughout the spinal cord, making it difficult to precisely identify the neurons and circuits involved. The oscillator that generates rhythmic breathing is located in a part of the brain stem called the pre-Bötzinger complex, but the exact identity of the oscillator neurons is not fully understood.

“There haven’t been detailed studies in awake behaving animals, where one can record from molecularly identified oscillator cells and manipulate them in a precise way,” Wang says.

Whisking is a prominent rhythmic exploratory behavior in many mammals, which use their tactile whiskers to detect objects and sense textures. In mice, whiskers extend and retract at a frequency of about 12 cycles per second. Several years ago, Wang’s lab set out try to identify the cells and the mechanism that control this oscillation.

To find the location of the whisking oscillator, the researchers traced back from the motor neurons that innervate whisker muscles. Using a modified rabies virus that infects axons, the researchers were able to label a group of cells presynaptic to these motor neurons in a part of the brainstem called the vibrissa intermediate reticular nucleus (vIRt). This finding was consistent with previous studies showing that damage to this part of the brain eliminates whisking.

The researchers then found that about half of these vIRt neurons express a protein called parvalbumin, and that this subpopulation of cells drives the rhythmic motion of the whiskers. When these neurons are silenced, whisking activity is abolished.

Next, the researchers recorded electrical activity from these parvalbumin-expressing vIRt neurons in brainstem in awake mice, a technically challenging task, and found that these neurons indeed have bursts of activity only during the whisker retraction period. Because these neurons provide inhibitory synaptic inputs to whisker motor neurons, it follows that rhythmic whisking is generated by a constant motor neuron protraction signal interrupted by the rhythmic retraction signal from these oscillator cells.

“That was a super satisfying and rewarding moment, to see that these cells are indeed the oscillator cells, because they fire rhythmically, they fire in the retraction phase, and they’re inhibitory neurons,” Wang says.

A maximum projection image showing tracked whiskers on the mouse muzzle. The right (control) side shows the back-and-forth rhythmic sweeping of the whiskers, while the experimental side where the whisking oscillator neurons are silenced, the whiskers move very little. Image: Wang Lab

“New principles”

The oscillatory bursting pattern of vIRt cells is initiated at the start of whisking. When the whiskers are not moving, these neurons fire continuously. When the researchers blocked vIRt neurons from inhibiting each other, the rhythm disappeared, and instead the oscillator neurons simply increased their rate of continuous firing.

This type of network, known as recurrent inhibitory network, differs from the types of oscillators that have been seen in the stomatogastric neurons in lobsters, in which neurons intrinsically generate their own rhythm.

“Now we have found a mammalian network oscillator that is formed by all inhibitory neurons,” Wang says.

The MIT scientists also collaborated with a team of theorists led by David Golomb at Ben-Gurion University, Israel, and David Kleinfeld at the University of California at San Diego. The theorists created a detailed computational model outlining how whisking is controlled, which fits well with all experimental data. A paper describing that model is appearing in an upcoming issue of Neuron.

Wang’s lab now plans to investigate other types of oscillatory circuits in mice, including those that control chewing and licking.

“We are very excited to find oscillators of these feeding behaviors and compare and contrast to the whisking oscillator, because they are all in the brain stem, and we want to know whether there’s some common theme or if there are many different ways to generate oscillators,” she says.

The research was funded by the National Institutes of Health.

New research center focused on brain-body relationship established at MIT

by Julie Pryor |

The inextricable link between our brains and our bodies has been gaining increasing recognition among researchers and clinicians over recent years. Studies have shown that the brain-body pathway is bidirectional — meaning that our mental state can influence our physical health and vice versa. But exactly how the two interact is less clear.

A new research center at MIT, funded by a $38 million gift to the McGovern Institute for Brain Research from philanthropist K. Lisa Yang, aims to unlock this mystery by creating and applying novel tools to explore the multidirectional, multilevel interplay between the brain and other body organ systems. This gift expands Yang’s exceptional philanthropic support of human health and basic science research at MIT over the past five years.

“Lisa Yang’s visionary gift enables MIT scientists and engineers to pioneer revolutionary technologies and undertake rigorous investigations into the brain’s complex relationship with other organ systems,” says MIT President L. Rafael Reif.  “Lisa’s tremendous generosity empowers MIT scientists to make pivotal breakthroughs in brain and biomedical research and, collectively, improve human health on a grand scale.”

The K. Lisa Yang Brain-Body Center will be directed by Polina Anikeeva, professor of materials science and engineering and brain and cognitive sciences at MIT and an associate investigator at the McGovern Institute. The center will harness the power of MIT’s collaborative, interdisciplinary life sciences research and engineering community to focus on complex conditions and diseases affecting both the body and brain, with a goal of unearthing knowledge of biological mechanisms that will lead to promising therapeutic options.

“Under Professor Anikeeva’s brilliant leadership, this wellspring of resources will encourage the very best work of MIT faculty, graduate fellows, and research — and ultimately make a real impact on the lives of many,” Reif adds.

microscope image of gut
Mouse small intestine stained to reveal cell nucleii (blue) and peripheral nerve fibers (red).
Image: Polina Anikeeva, Marie Manthey, Kareena Villalobos

Center goals  

Initial projects in the center will focus on four major lines of research:

  • Gut-Brain: Anikeeva’s group will expand a toolbox of new technologies and apply these tools to examine major neurobiological questions about gut-brain pathways and connections in the context of autism spectrum disorders, Parkinson’s disease, and affective disorders.
  • Aging: CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and investigator at the McGovern Institute, will lead a group in developing molecular tools for precision epigenomic editing and erasing accumulated “errors” of time, injury, or disease in various types of cells and tissues.
  • Pain: The lab of Fan Wang, investigator at the McGovern Institute and professor of brain and cognitive sciences, will design new tools and imaging methods to study autonomic responses, sympathetic-parasympathetic system balance, and brain-autonomic nervous system interactions, including how pain influences these interactions.
  • Acupuncture: Wang will also collaborate with Hilda (“Scooter”) Holcombe, a veterinarian in MIT’s Division of Comparative Medicine, to advance techniques for documenting changes in brain and peripheral tissues induced by acupuncture in mouse models. If successful, these techniques could lay the groundwork for deeper understandings of the mechanisms of acupuncture, specifically how the treatment stimulates the nervous system and restores function.

A key component of the K. Lisa Yang Brain-Body Center will be a focus on educating and training the brightest young minds who aspire to make true breakthroughs for individuals living with complex and often devastating diseases. A portion of center funding will endow the new K. Lisa Yang Brain-Body Fellows Program, which will support four annual fellowships for MIT graduate students and postdocs working to advance understanding of conditions that affect both the body and brain.

Mens sana in corpore sano

“A phrase I remember reading in secondary school has always stuck with me: ‘mens sana in corpore sano’ — ‘a healthy mind in a healthy body,’” says Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities. “When we look at how stress, nutrition, pain, immunity, and other complex factors impact our health, we truly see how inextricably linked our brains and bodies are. I am eager to help MIT scientists and engineers decode these links and make real headway in creating therapeutic strategies that result in longer, healthier lives.”

“This center marks a once-in-a-lifetime opportunity for labs like mine to conduct bold and risky studies into the complexities of brain-body connections,” says Anikeeva, who works at the intersection of materials science, electronics, and neurobiology. “The K. Lisa Yang Brain-Body Center will offer a pathbreaking, holistic approach that bridges multiple fields of study. I have no doubt that the center will result in revolutionary strides in our understanding of the inextricable bonds between the brain and the body’s peripheral organ systems, and a bold new way of thinking in how we approach human health overall.”

On a mission to alleviate chronic pain

Anne Trafton |

About 50 million Americans suffer from chronic pain, which interferes with their daily life, social interactions, and ability to work. MIT Professor Fan Wang wants to develop new ways to help relieve that pain, by studying and potentially modifying the brain’s own pain control mechanisms.

Her recent work has identified an “off switch” for pain, located in the brain’s amygdala. She hopes that finding ways to control this switch could lead to new treatments for chronic pain.

“Chronic pain is a major societal issue,” Wang says. “By studying pain-suppression neurons in the brain’s central amygdala, I hope to create a new therapeutic approach for alleviating pain.”

Wang, who joined the MIT faculty in January 2021, is also the leader of a new initiative at the McGovern Institute for Brain Research that is studying drug addiction, with the goal of developing more effective treatments for addiction.

“Opioid prescription for chronic pain is a major contributor to the opioid epidemic. With the Covid pandemic, I think addiction and overdose are becoming worse. People are more anxious, and they seek drugs to alleviate such mental pain,” Wang says. “As scientists, it’s our duty to tackle this problem.”

Sensory circuits

Wang, who grew up in Beijing, describes herself as “a nerdy child” who loved books and math. In high school, she took part in science competitions, then went on to study biology at Tsinghua University. She arrived in the United States in 1993 to begin her PhD at Columbia University. There, she worked on tracing the connection patterns of olfactory receptor neurons in the lab of Richard Axel, who later won the Nobel Prize for his discoveries of odorant receptors and how the olfactory system is organized.

After finishing her PhD, Wang decided to switch gears. As a postdoc at the University of California at San Francisco and then Stanford University, she began studying how the brain perceives touch.

In 2003, Wang joined the faculty at Duke University School of Medicine. There, she began developing techniques to study the brain circuits that underlie the sense of touch, tracing circuits that carry sensory information from the whiskers of mice to the brain. She also studied how the brain integrates movements of touch organs with signals of sensory stimuli to generate perception (such as using stretching movements to sense elasticity).

As she pursued her sensory perception studies, Wang became interested in studying pain perception, but she felt she needed to develop new techniques to tackle it. While at Duke, she invented a technique called CANE (capturing activated neural ensembles), which can identify networks of neurons that are activated by a particular stimulus.

Using this approach in mice, she identified neurons that become active in response to pain, but so many neurons across the brain were activated that it didn’t offer much useful information. As a way to indirectly get at how the brain controls pain, she decided to use CANE to explore the effects of drugs used for general anesthesia. During general anesthesia, drugs render a patient unconscious, but Wang hypothesized that the drugs might also shut off pain perception.

“At that time, it was just a wild idea,” Wang recalls. “I thought there may be other mechanisms — that instead of just a loss of consciousness, anesthetics may do something to the brain that actually turns pain off.”

Support for the existence of an “off switch” for pain came from the observation that wounded soldiers on a battlefield can continue to fight, essentially blocking out pain despite their injuries.

In a study of mice treated with anesthesia drugs, Wang discovered that the brain does have this kind of switch, in an unexpected location: the amygdala, which is involved in regulating emotion. She showed that this cluster of neurons can turn off pain when activated, and when it is suppressed, mice become highly sensitive to ordinary gentle touch.

“There’s a baseline level of activity that makes the animals feel normal, and when you activate these neurons, they’ll feel less pain. When you silence them, they’ll feel more pain,” Wang says.

Turning off pain

That finding, which Wang reported in 2020, raised the possibility of somehow modulating that switch in humans to try to treat chronic pain. This is a long-term goal of Wang’s, but more work is required to achieve it, she says. Currently her lab is working on analyzing the RNA expression patterns of the neurons in the cluster she identified. They also are measuring the neurons’ electrical activity and how they interact with other neurons in the brain, in hopes of identifying circuits that could be targeted to tamp down the perception of pain.

One way of modulating these circuits could be to use deep brain stimulation, which involves implanting electrodes in certain areas of the brain. Focused ultrasound, which is still in early stages of development and does not require surgery, could be a less invasive alternative.

Another approach Wang is interested in exploring is pairing brain stimulation with a context such as looking at a smartphone app. This kind of pairing could help train the brain to shut off pain using the app, without the need for the original stimulation (deep brain stimulation or ultrasound).

“Maybe you don’t need to constantly stimulate the brain. You may just need to reactivate it with a context,” Wang says. “After a while you would probably need to be restimulated, or reconditioned, but at least you have a longer window where you don’t need to go to the hospital for stimulation, and you just need to use a context.”

Wang, who was drawn to MIT in part by its focus on fostering interdisciplinary collaborations, is now working with several other McGovern Institute members who are taking different angles to try to figure out how the brain generates the state of craving that occurs in drug addiction, including opioid addiction.

“We’re going to focus on trying to understand this craving state: how it’s created in the brain and how can we sort of erase that trace in the brain, or at least control it. And then you can neuromodulate it in real time, for example, and give people a chance to get back their control,” she says.

The craving state

by Jennifer Michalowski |

This story originally appeared in the Winter 2022 issue of BrainScan.

***

For people struggling with substance use disorders — and there are about 35 million of them worldwide — treatment options are limited. Even among those who seek help, relapse is common. In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A 2019 survey found that 1.6 million people nationwide had an opioid use disorder, and the crisis has surged since the start of the COVID-19 pandemic. The Centers for Disease Control and Prevention estimates that more than 100,000 people died of drug overdose between April 2020 and April 2021 — nearly 30 percent more overdose deaths than occurred during the same period the previous year.

In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A deeper understanding of what addiction does to the brain and body is urgently needed to pave the way to interventions that reliably release affected individuals from its grip. At the McGovern Institute, researchers are turning their attention to addiction’s driving force: the deep, recurring craving that makes people prioritize drug use over all other wants and needs.

McGovern Institute co-founder, Lore Harp McGovern.

“When you are in that state, then it seems nothing else matters,” says McGovern Investigator Fan Wang. “At that moment, you can discard everything: your relationship, your house, your job, everything. You only want the drug.”

With a new addiction initiative catalyzed by generous gifts from Institute co-founder Lore Harp McGovern and others, McGovern scientists with diverse expertise have come together to begin clarifying the neurobiology that underlies the craving state. They plan to dissect the neural transformations associated with craving at every level — from the drug-induced chemical changes that alter neuronal connections and activity to how these modifications impact signaling brain-wide. Ultimately, the McGovern team hopes not just to understand the craving state, but to find a way to relieve it — for good.

“If we can understand the craving state and correct it, or at least relieve a little bit of the pressure,” explains Wang, who will help lead the addiction initiative, “then maybe we can at least give people a chance to use their top-down control to not take the drug.”

The craving cycle

For individuals suffering from substance use disorders, craving fuels a cyclical pattern of escalating drug use. Following the euphoria induced by a drug like heroin or cocaine, depression sets in, accompanied by a drug craving motivated by the desire to relieve that suffering. And as addiction progresses, the peaks and valleys of this cycle dip lower: the pleasant feelings evoked by the drug become weaker, while the negative effects a person experiences in its absence worsen. The craving remains, and increasing use of the drug are required to relieve it.

By the time addiction sets in, the brain has been altered in ways that go beyond a drug’s immediate effects on neural signaling.

These insidious changes leave individuals susceptible to craving — and the vulnerable state endures. Long after the physical effects of withdrawal have subsided, people with substance use disorders can find their craving returns, triggered by exposure to a small amount of the drug, physical or social cues associated with previous drug use, or stress. So researchers will need to determine not only how different parts of the brain interact with one another during craving and how individual cells and the molecules within them are affected by the craving state — but also how things change as addiction develops and progresses.

Circuits, chemistry and connectivity

One clear starting point is the circuitry the brain uses to control motivation. Thanks in part to decades of research in the lab of McGovern Investigator Ann Graybiel, neuroscientists know a great deal about how these circuits learn which actions lead to pleasure and which lead to pain, and how they use that information to establish habits and evaluate the costs and benefits of complex decisions.

Graybiel’s work has shown that drugs of abuse strongly activate dopamine-responsive neurons in a part of the brain called the striatum, whose signals promote habit formation. By increasing the amount of dopamine that neurons release, these drugs motivate users to prioritize repeated drug use over other kinds of rewards, and to choose the drug in spite of pain or other negative effects. Her group continues to investigate the naturally occurring molecules that control these circuits, as well as how they are hijacked by drugs of abuse.

Distribution of opioid receptors targeted by morphine (shown in blue) in two regions in the dorsal striatum and nucleus accumbens of the mouse brain. Image: Ann Graybiel

In Fan Wang’s lab, work investigating the neural circuits that mediate the perception of physical pain has led her team to question the role of emotional pain in craving. As they investigated the source of pain sensations in the brain, they identified neurons in an emotion-regulating center called the central amygdala that appear to suppress physical pain in animals. Now, Wang wants to know whether it might be possible to modulate neurons involved in emotional pain to ameliorate the negative state that provokes drug craving.

These animal studies will be key to identifying the cellular and molecular changes that set the brain up for recurring cravings. And as McGovern scientists begin to investigate what happens in the brains of rodents that have been trained to self-administer addictive drugs like fentanyl or cocaine, they expect to encounter tremendous complexity.

McGovern Associate Investigator Polina Anikeeva, whose lab has pioneered new technologies that will help the team investigate the full spectrum of changes that underlie craving, says it will be important to consider impacts on the brain’s chemistry, firing patterns, and connectivity. To that end, multifunctional research probes developed in her lab will be critical to monitoring and manipulating neural circuits in animal models.

Imaging technology developed by investigator Ed Boyden will also enable nanoscale protein visualization brain-wide. An important goal will be to identify a neural signature of the craving state. With such a signal, researchers can begin to explore how to shut off that craving — possibly by directly modulating neural signaling.

Targeted treatments

“One of the reasons to study craving is because it’s a natural treatment point,” says McGovern Associate Investigator Alan Jasanoff. “And the dominant kind of approaches that people in our team think about are approaches that relate to neural circuits — to the specific connections between brain regions and how those could be changed.” The hope, he explains, is that it might be possible to identify a brain region whose activity is disrupted during the craving state, then use clinical brain stimulation methods to restore normal signaling — within that region, as well as in other connected parts of the brain.

To identify the right targets for such a treatment, it will be crucial to understand how the biology uncovered in laboratory animals reflects what’s happens in people with substance use disorders. Functional imaging in John Gabrieli’s lab can help bridge the gap between clinical and animal research by revealing patterns of brain activity associated with the craving state in both humans and rodents. A new technique developed in Jasanoff’s lab makes it possible to focus on the activity between specific regions of an animal’s brain. “By doing that, we hope to build up integrated models of how information passes around the brain in craving states, and of course also in control states where we’re not experiencing craving,” he explains.

In delving into the biology of the craving state, McGovern scientists are embarking on largely unexplored territory — and they do so with both optimism and urgency. “It’s hard to not appreciate just the size of the problem, and just how devastating addiction is,” says Anikeeva. “At this point, it just seems almost irresponsible to not work on it, especially when we do have the tools and we are interested in the general brain regions that are important for that problem. I would say that there’s almost a civic duty.”

How general anesthesia reduces pain

by Sabbi Lall |

General anesthesia is medication that suppresses pain and renders patients unconscious during surgery, but whether pain suppression is simply a side effect of loss of consciousness has been unclear. Fan Wang and colleagues have now identified the circuits linked to pain suppression under anesthesia in mouse models, showing that this effect is separable from the unconscious state itself.

“Existing literature suggests that the brain may contain a switch that can turn off pain perception,” explains Fan Wang, a professor at Duke University and lead author of the study. “I had always wanted to find this switch, and it occurred to me that general anesthetics may activate this switch to produce analgesia.”

Wang, who will join the McGovern Institute in January 2021, set out to test this idea with her student, Thuy Hua, and postdoc, Bin Chen.

Pain suppressor

Loss of pain, or analgesia, is an important property of anesthetics that helps to make surgical and invasive medical procedures humane and bearable. In spite of their long use in the medical world, there is still very little understanding of how anesthetics work. It has generally been assumed that a side effect of loss of consciousness is analgesia, but several recent observations have brought this idea into question, and suggest that changes in consciousness might be separable from pain suppression.

A key clue that analgesia is separable from general anesthesia comes from the accounts of patients that regain consciousness during surgery. After surgery, these patients can recount conversations between staff or events that occurred in the operating room, despite not feeling any pain. In addition, some general anesthetics, such as ketamine, can be deployed at low concentrations for pain suppression without loss of consciousness.

Following up on these leads, Wang and colleagues set out to uncover which neural circuits might be involved in suppressing pain during exposure to general anesthetics. Using CANE, a procedure developed by Wang that can detect which neurons activate in response to an event, Wang discovered a new population of GABAergic neurons activated by general anesthetic in the mouse central amygdala.

These neurons become activated in response to different anesthetics, including ketamine, dexmedetomidine, and isoflurane. Using optogenetics to manipulate the activity state of these neurons, Wang and her lab found that they led to marked changes in behavioral responses to painful stimuli.

“The first time we used optogenetics to turn on these cells, a mouse that was in the middle of taking care of an injury simply stopped and started walked around with no sign of pain,” Wang explains.

Specifically, activating these cells blocks pain in multiple models and tests, whereas inhibiting these neurons rendered mice aversive to gentle touch — suggesting that they are involved in a newly uncovered central pain circuit.

The study has implications for both anesthesia and pain. It shows that general anesthetics have complex, multi-faceted effects and that the brain may contain a central pain suppression system.

“We want to figure out how diverse general anesthetics activate these neurons,” explains Wang. “That way we can find compounds that can specifically activate these pain-suppressing neurons without sedation. We’re now also testing whether placebo analgesia works by activating these same central neurons.”

The study also has implications for addiction as it may point to an alternative system for central pain suppression that could be a target of drugs that do not have the devastating side effects of opioids.

Fan Wang joins the McGovern Institute

by Sabbi Lall |

The McGovern Institute is pleased to announce that Fan Wang, currently a Professor at Duke University, will be joining its team of investigators in 2021. Wang is well-known for her work on sensory perception, pain, and behavior. She takes a broad, and very practical approach to these questions, knowing that sensory perception has broad implications for biomedicine when it comes to pain management, addiction, anesthesia, and hypersensitivity.

“McGovern is a dream place for doing innovative and transformative neuroscience.” – Fan Wang

“I am so thrilled that Fan is coming to the McGovern Institute,” says Robert Desimone, director of the institute and the Doris and Don Berkey Professor of Neuroscience at MIT. “I’ve followed her work for a number of years, and she is making inroads into questions that are relevant to a number of societal problems, such as how we can turn off the perception of chronic pain.”

Wang brings with her a range of techniques developed in her lab, including CANE, which precisely highlights neurons that become activated in response to a stimulus. CANE is highlighting new neuronal subtypes in long-studied brain regions such as the amygdala, and recently elucidated previously undefined neurons in the lateral parabrachial nucleus involved in pain processing.

“I am so excited to join the McGovern Institute,” says Wang. “It is a dream place for doing innovative and transformative neuroscience. McGovern researchers are known for using the most cutting-edge, multi-disciplinary technologies to understand how the brain works. I can’t wait to join the team.”

Wang earned her PhD in 1998 with Richard Axel at Columbia University, subsequently conducting postdoctoral research at Stanford University with Mark Tessier-Lavigne. Wang joined Duke University as a Professor in the Department of Neurobiology in 2003, and was later appointed the Morris N. Broad Distinguished Professor of Neurobiology at Duke University School of Medicine. Wang will join the McGovern Institute as an investigator in January 2021.