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Three distinct brain circuits in the thalamus contribute to Parkinson’s symptoms

Anne Trafton |

Parkinson’s disease is best-known as a disorder of movement. Patients often experience tremors, loss of balance, and difficulty initiating movement. The disease also has lesser-known symptoms that are nonmotor, including depression.

In a study of a small region of the thalamus, MIT neuroscientists have now identified three distinct circuits that influence the development of both motor and nonmotor symptoms of Parkinson’s. Furthermore, they found that by manipulating these circuits, they could reverse Parkinson’s symptoms in mice.

The findings suggest that those circuits could be good targets for new drugs that could help combat many of the symptoms of Parkinson’s disease, the researchers say.

“We know that the thalamus is important in Parkinson’s disease, but a key question is how can you put together a circuit that that can explain many different things happening in Parkinson’s disease. Understanding different symptoms at a circuit level can help guide us in the development of better therapeutics,” says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT.

Feng is the senior author of the study, which appears today in Nature. Ying Zhang, a J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, and Dheeraj Roy, a NIH K99 Awardee and a McGovern Fellow at the Broad Institute, are the lead authors of the paper.

Tracing circuits

The thalamus consists of several different regions that perform a variety of functions. Many of these, including the parafascicular (PF) thalamus, help to control movement. Degeneration of these structures is often seen in patients with Parkinson’s disease, which is thought to contribute to their motor symptoms.

In this study, the MIT team set out to try to trace how the PF thalamus is connected to other brain regions, in hopes of learning more about its functions. They found that neurons of the PF thalamus project to three different parts of the basal ganglia, a cluster of structures involved in motor control and other functions: the caudate putamen (CPu), the subthalamic nucleus (STN), and the nucleus accumbens (NAc).

“We started with showing these different circuits, and we demonstrated that they’re mostly nonoverlapping, which strongly suggests that they have distinct functions,” Roy says.

Further studies revealed those functions. The circuit that projects to the CPu appears to be involved in general locomotion, and functions to dampen movement. When the researchers inhibited this circuit, mice spent more time moving around the cage they were in.

The circuit that extends into the STN, on the other hand, is important for motor learning — the ability to learn a new motor skill through practice. The researchers found that this circuit is necessary for a task in which the mice learn to balance on a rod that spins with increasing speed.

Lastly, the researchers found that, unlike the others, the circuit that connects the PF thalamus to the NAc is not involved in motor activity. Instead, it appears to be linked to motivation. Inhibiting this circuit generates depression-like behaviors in healthy mice, and they will no longer seek a reward such as sugar water.

Druggable targets

Once the researchers established the functions of these three circuits, they decided to explore how they might be affected in Parkinson’s disease. To do that, they used a mouse model of Parkinson’s, in which dopamine-producing neurons in the midbrain are lost.

They found that in this Parkinson’s model, the connection between the PF thalamus and the CPu was enhanced, and that this led to a decrease in overall movement. Additionally, the connections from the PF thalamus to the STN were weakened, which made it more difficult for the mice to learn the accelerating rod task.

Lastly, the researchers showed that in the Parkinson’s model, connections from the PF thalamus to the NAc were also interrupted, and that this led to depression-like symptoms in the mice, including loss of motivation.

Using chemogenetics or optogenetics, which allows them to control neuronal activity with a drug or light, the researchers found that they could manipulate each of these three circuits and in doing so, reverse each set of Parkinson’s symptoms. Then, they decided to look for molecular targets that might be “druggable,” and found that each of the three PF thalamus regions have cells that express different types of cholinergic receptors, which are activated by the neurotransmitter acetylcholine. By blocking or activating those receptors, depending on the circuit, they were also able to reverse the Parkinson’s symptoms.

“We found three distinct cholinergic receptors that can be expressed in these three different PF circuits, and if we use antagonists or agonists to modulate these three different PF populations, we can rescue movement, motor learning, and also depression-like behavior in PD mice,” Zhang says.

Parkinson’s patients are usually treated with L-dopa, a precursor of dopamine. While this drug helps patients regain motor control, it doesn’t help with motor learning or any nonmotor symptoms, and over time, patients become resistant to it.

The researchers hope that the circuits they characterized in this study could be targets for new Parkinson’s therapies. The types of neurons that they identified in the circuits of the mouse brain are also found in the nonhuman primate brain, and the researchers are now using RNA sequencing to find genes that are expressed specifically in those cells.

“RNA-sequencing technology will allow us to do a much more detailed molecular analysis in a cell-type specific way,” Feng says. “There may be better druggable targets in these cells, and once you know the specific cell types you want to modulate, you can identify all kinds of potential targets in them.”

The research was funded, in part, by the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience at MIT, the Stanley Center for Psychiatric Research at the Broad Institute, the James and Patricia Poitras Center for Psychiatric Disorders Research at MIT, the National Institutes of Health BRAIN Initiative, and the National Institute of Mental Health.

Convenience-sized RNA editing

by Sarah CP Williams |

Last year, researchers at MIT’s McGovern Institute discovered and characterized Cas7-11, the first CRISPR enzyme capable of making precise, guided cuts to strands of RNA without harming cells in the process. Now, working with collaborators at the University of Tokyo, the same team has revealed that Cas7-11 can be shrunk to a more compact version, making it an even more viable option for editing the RNA inside living cells. The new, compact Cas7-11 was described today in the journal Cell along with a detailed structural analysis of the original enzyme.

“When we looked at the structure, it was clear there were some pieces that weren’t needed which we could actually remove,” says McGovern Fellow Omar Abudayyeh, who led the new work with McGovern Fellow Jonathan Gootenberg and collaborator Hiroshi Nishimasu from the University of Tokyo. “This makes the enzyme small enough that it fits into a single viral vector for therapeutic applications.”

The authors, who also include postdoctoral researcher Nathan Zhou from the McGovern Institute and Kazuki Kato from the University Tokyo, see the new three-dimensional structure of Cas7-11 as a rich resource toanswer questions about the basic biology of the enzymes and reveal other ways to tweak its function in the future.

Targeting RNA

McGovern Fellows Jonathan Gootenberg and Omar Abudayyeh in their lab. Photo: Caitlin Cunningham

Over the past decade, the CRISPR-Cas9 genome editing technology has given researchers the ability to modify the genes inside human cells—a boon for both basic research and the development of therapeutics to reverse disease-causing genetic mutations. But CRISPR-Cas9 only works to alter DNA, and for some research and clinical purposes, editing RNA is more effective or useful.

A cell retains its DNA for life, and passes an identical copy to daughter cells as it duplicates, so any changes to DNA are relatively permanent. However, RNA is a more transient molecule, transcribed from DNA and degraded not long after.

“There are lots of positives about being able to permanently change DNA, especially when it comes to treating an inherited genetic disease,” Gootenberg says. “But for an infection, an injury or some other temporary disease, being able to temporarily modify a gene through RNA targeting makes more sense.”

Until Abudayyeh, Gootenberg and their colleagues discovered and characterized Cas7-11, the only enzyme that could target RNA had a messy side effect; when it recognized a particular gene, the enzyme—Cas13—began cutting up all the RNA around it. This property makes Cas13 effective for diagnostic tests, where it is used to detect the presence of a piece of RNA, but not very useful for therapeutics, where targeted cuts are required.

The discovery of Cas7-11 opened the doors to a more precise form of RNA editing, analogous to the Cas9 enzyme for DNA. However, the massive Cas7-11 protein was too big to fit inside a single viral vector—the empty shell of a virus that researchers typically use to deliver gene editing machinery into patient’s cells.

Structural insight

To determine the overall structure of Cas7-11, Abudayyeh, Gootenberg and Nishimasu used cryo-electron microscopy, which shines beams of electrons on frozen protein samples and measures how the beams are transmitted. The researchers knew that Cas7-11 was like an amalgamation of five separate Cas enzymes, fused into one single gene, but were not sure exactly how those parts folded and fit together.

“The really fascinating thing about Cas7-11, from a fundamental biology perspective, is that it should be all these separate pieces that come together, but instead you have a fusion into one gene,” Gootenberg says. “We really didn’t know what that would look like.”

The structure of Cas7-11, caught in the act of binding both its target tRNA strand and the guide RNA, which directs that binding, revealed how the pieces assembled and which parts of the protein were critical to recognizing and cutting RNA. This kind of structural insight is critical to figuring out how to make Cas7-11 carry out targeted jobs inside human cells.

The structure also illuminated a section of the protein that wasn’t serving any apparent functional role. This finding suggested the researchers could remove it, re-engineering Cas7-11 to make it smaller without taking away its ability to target RNA. Abudayyeh and Gootenberg tested the impact of removing different bits of this section, resulting in a new compact version of the protein, dubbed Cas7-11S. With Cas7-11S in hand, they packaged the system inside a single viral vector, delivered it into mammalian cells and efficiently targeted RNA.

The team is now planning future studies on other proteins that interact with Cas7-11 in the bacteria that it originates from, and also hopes to continue working towards the use of Cas7-11 for therapeutic applications.

“Imagine you could have an RNA gene therapy, and when you take it, it modifies your RNA, but when you stop taking it, that modification stops,” Abudayyeh says. “This is really just the beginning of enabling that tool set.”

This research was funded, in part, by the McGovern Institute Neurotechnology Program, K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience, G. Harold & Leila Y. Mathers Charitable Foundation, MIT John W. Jarve (1978) Seed Fund for Science Innovation, FastGrants, Basis for Supporting Innovative Drug Discovery and Life Science Research Program, JSPS KAKENHI, Takeda Medical Research Foundation, and Inamori Research Institute for Science.

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.”

A voice for change — in Spanish

by Jennifer Michalowski |

Jessica Chomik-Morales had a bicultural childhood. She was born in Boca Raton, Florida, where her parents had come seeking a better education for their daughter than she would have access to in Paraguay. But when she wasn’t in school, Chomik-Morales was back in that small, South American country with her family. One of the consequences of growing up in two cultures was an early interest in human behavior. “I was always in observer mode,” Chomik-Morales says, recalling how she would tune in to the nuances of social interactions in order to adapt and fit in.

Today, that fascination with human behavior is driving Chomik-Morales as she works with MIT professor of cognitive science Laura Schulz and Walter A. Rosenblith Professor of Cognitive Neuroscience and McGovern Institute for Brain Research investigator Nancy Kanwisher as a post-baccalaureate research scholar, using functional brain imaging to investigate how the brain recognizes and understands causal relationships. Since arriving at MIT last fall, she’s worked with study volunteers to collect functional MRI (fMRI) scans and used computational approaches to interpret the images. She’s also refined her own goals for the future.

Jessica Chomik-Morales (right) with postdoctoral associate Héctor De Jesús-Cortés. Photo: Steph Stevens

She plans to pursue a career in clinical neuropsychology, which will merge her curiosity about the biological basis of behavior with a strong desire to work directly with people. “I’d love to see what kind of questions I could answer about the neural mechanisms driving outlier behavior using fMRI coupled with cognitive assessment,” she says. And she’s confident that her experience in MIT’s two-year post-baccalaureate program will help her get there. “It’s given me the tools I need, and the techniques and methods and good scientific practice,” she says. “I’m learning that all here. And I think it’s going to make me a more successful scientist in grad school.”

The road to MIT

Chomik-Morales’s path to MIT was not a straightforward trajectory through the U.S. school system. When her mom, and later her dad, were unable to return to the U.S., she started eight grade in the capital city of Asunción. It did not go well. She spent nearly every afternoon in the principal’s office, and soon her father was encouraging her to return to the United States. “You are an American,” he told her. “You have a right to the educational system there.”

Back in Florida, Chomik-Morales became a dedicated student, even while she worked assorted jobs and shuffled between the homes of families who were willing to host her. “I had to grow up,” she says. “My parents are sacrificing everything just so I can have a chance to be somebody. People don’t get out of Paraguay often, because there aren’t opportunities and it’s a very poor country. I was given an opportunity, and if I waste that, then that is disrespect not only to my parents, but to my lineage, to my country.”

As she graduated from high school and went on to earn a degree in cognitive neuroscience at Florida Atlantic University, Chomik-Morales found herself experiencing things that were completely foreign to her family. Though she spoke daily with her mom via WhatsApp, it was hard to share what she was learning in school or what she was doing in the lab. And while they celebrated her academic achievements, Chomik-Morales knew they didn’t really understand them. “Neither of my parents went to college,” she says. “My mom told me that she never thought twice about learning about neuroscience. She had this misconception that it was something that she would never be able to digest.”

Chomik-Morales believes that the wonders of neuroscience are for everybody. But she also knows that Spanish speakers like her mom have few opportunities to hear the kinds of accessible, engaging stories that might draw them in. So she’s working to change that. With support from the McGovern Institute, the National Science Foundation funded Science and Technology Center for Brains, Minds, and Machines, Chomik-Morales is hosting and producing a weekly podcast called “Mi Última Neurona” (“My Last Neuron”), which brings conversations with neuroscientists to Spanish speakers around the world.

Listeners hear how researchers at MIT and other institutions are exploring big concepts like consciousness and neurodegeneration, and learn about the approaches they use to study the brain in humans, animals, and computational models. Chomik-Morales wants listeners to get to know neuroscientists on a personal level too, so she talks with her guests about their career paths, their lives outside the lab, and often, their experiences as immigrants in the United States.

After recording an interview with Chomik-Morales that delved into science, art, and the educational system in his home country of Peru, postdoc Arturo Deza thinks “Mi Última Neurona” has the potential to inspire Spanish speakers in Latin America, as well immigrants in other countries. “Even if you’re not a scientist, it’s really going to captivate you and you’re going to get something out of it,” he says. To that point, Chomik-Morales’s mother has quickly become an enthusiastic listener, and even begun seeking out resources to learn more about the brain on her own.

Chomik-Morales hopes the stories her guests share on “Mi Última Neurona” will inspire a future generation of Hispanic neuroscientists. She also wants listeners to know that a career in science doesn’t have to mean leaving their country behind. “Gain whatever you need to gain from outside, and then, if it’s what you desire, you’re able to go back and help your own community,” she says. With “Mi Última Neurona,” she adds, she feels she is giving back to her roots.

How do illusions trick the brain?

by Dana Boebinger | Jarrod Hicks |

As part of our Ask the Brain series, Jarrod Hicks, a graduate student in Josh McDermott‘s lab and Dana Boebinger, a postdoctoral researcher at the University of Rochester (and former graduate student in Josh McDermott’s lab), answer the question, “How do illusions trick the brain?”

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Graduate student Jarrod Hicks studies how the brain processes sound. Photo: M.E. Megan Hicks

Imagine you’re a detective. Your job is to visit a crime scene, observe some evidence, and figure out what happened. However, there are often multiple stories that could have produced the evidence you observe. Thus, to solve the crime, you can’t just rely on the evidence in front of you – you have to use your knowledge about the world to make your best guess about the most likely sequence of events. For example, if you discover cat hair at the crime scene, your prior knowledge about the world tells you it’s unlikely that a cat is the culprit. Instead, a more likely explanation is that the culprit might have a pet cat.

Although it might not seem like it, this kind of detective work is what your brain is doing all the time. As your senses send information to your brain about the world around you, your brain plays the role of detective, piecing together each bit of information to figure out what is happening in the world. The information from your senses usually paints a pretty good picture of things, but sometimes when this information is incomplete or unclear, your brain is left to fill in the missing pieces with its best guess of what should be there. This means that what you experience isn’t actually what’s out there in the world, but rather what your brain thinks is out there. The consequence of this is that your perception of the world can depend on your experience and assumptions.

Optical illusions

Optical illusions are a great way of showing how our expectations and assumptions affect what we perceive. For example, look at the squares labeled “A” and “B” in the image below.

Checkershadow illusion. Image: Edward H. Adelson

Is one of them lighter than the other? Although most people would agree that the square labeled “B” is much lighter than the one labeled “A,” the two squares are actually the exact same color. You perceive the squares differently because your brain knows, from experience, that shadows tend to make things appear darker than what they actually are. So, despite the squares being physically identical, your brain thinks “B” should be lighter.

Auditory illusions

Tricks of perception are not limited to optical illusions. There are also several dramatic examples of how our expectations influence what we hear. For example, listen to the mystery sound below. What do you hear?

Mystery sound

Because you’ve probably never heard a sound quite like this before, your brain has very little idea about what to expect. So, although you clearly hear something, it might be very difficult to make out exactly what that something is. This mystery sound is something called sine-wave speech, and what you’re hearing is essentially a very degraded sound of someone speaking.

Now listen to a “clean” version of this speech in the audio clip below:

Clean speech

You probably hear a person saying, “the floor was quite slippery.” Now listen to the mystery sound above again. After listening to the original audio, your brain has a strong expectation about what you should hear when you listen to the mystery sound again. Even though you’re hearing the exact same mystery sound as before, you experience it completely differently. (Audio clips courtesy of University of Sussex).

 

Dana Boebinger describes the science of illusions in this McGovern Minute.

Subjective perceptions

These illusions have been specifically designed by scientists to fool your brain and reveal principles of perception. However, there are plenty of real-life situations in which your perceptions strongly depend on expectations and assumptions. For example, imagine you’re watching TV when someone begins to speak to you from another room. Because the noise from the TV makes it difficult to hear the person speaking, your brain might have to fill in the gaps to understand what’s being said. In this case, different expectations about what is being said could cause you to hear completely different things.

Which phrase do you hear?

Listen to the clip below to hear a repeating loop of speech. As the sound plays, try to listen for one of the phrases listed in teal below.

Because the audio is somewhat ambiguous, the phrase you perceive depends on which phrase you listen for. So even though it’s the exact same audio each time, you can perceive something totally different! (Note: the original audio recording is from a football game in which the fans were chanting, “that is embarrassing!”)

Illusions like the ones above are great reminders of how subjective our perceptions can be. In order to make sense of the messy information coming in from our senses, our brains are constantly trying to fill in the blanks and with its best guess of what’s out there. Because of this guesswork, our perceptions depend on our experiences, leading each of us to perceive and interact with the world in a way that’s uniquely ours.

Jarrod Hicks is a PhD candidate in the Department of Brain and Cognitive Sciences at MIT working with Josh McDermott in the Laboratory for Computational Audition. He studies sound segregation, a key aspect of real-world hearing in which a sound source of interest is estimated amid a mixture of competing sources. He is broadly interested in teaching/outreach, psychophysics, computational approaches to represent stimulus spaces, and neural coding of high-level sensory representations.

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Do you have a question for The Brain? Ask it here.

Lindsay Case and Guangyu Robert Yang named 2022 Searle Scholars

Anne Trafton |

MIT cell biologist Lindsay Case and computational neuroscientist Guangyu Robert Yang have been named 2022 Searle Scholars, an award given annually to 15 outstanding U.S. assistant professors who have high potential for ongoing innovative research contributions in medicine, chemistry, or the biological sciences.

Case is an assistant professor of biology, while Yang is an assistant professor of brain and cognitive sciences and electrical engineering and computer science, and an associate investigator at the McGovern Institute for Brain Research. They will each receive $300,000 in flexible funding to support their high-risk, high-reward work over the next three years.

Lindsay Case

Case arrived at MIT in 2021, after completing a postdoc at the University of Texas Southwestern Medical Center in the lab of Michael Rosen. Prior to that, she earned her PhD from the University of North Carolina at Chapel Hill, working in the lab of Clare Waterman at the National Heart Lung and Blood Institute.

Situated in MIT’s Building 68, Case’s lab studies how molecules within cells organize themselves, and how such organization begets cellular function. Oftentimes, molecules will assemble at the cell’s plasma membrane — a complex signaling platform where hundreds of receptors sense information from outside the cell and initiate cellular changes in response. Through her experiments, Case has found that molecules at the plasma membrane can undergo a process known as phase separation, condensing to form liquid-like droplets.

As a Searle Scholar, Case is investigating the role that phase separation plays in regulating a specific class of signaling molecules called kinases. Her team will take a multidisciplinary approach to probe what happens when kinases phase separate into signaling clusters, and what cellular changes occur as a result. Because phase separation is emerging as a promising new target for small molecule therapies, this work will help identify kinases that are strong candidates for new therapeutic interventions to treat diseases such as cancer.

“I am honored to be recognized by the Searle Scholars Program, and thrilled to join such an incredible community of scientists,” Case says. “This support will enable my group to broaden our research efforts and take our preliminary findings in exciting new directions. I look forward to better understanding how phase separation impacts cellular function.”

Guangyu Robert Yang

Before coming to MIT in 2021, Yang trained in physics at Peking University, obtained a PhD in computational neuroscience at New York University with Xiao-Jing Wang, and further trained as a postdoc at the Center for Theoretical Neuroscience of Columbia University, as an intern at Google Brain, and as a junior fellow at the Simons Society of Fellows.

His research team at MIT, the MetaConscious Group, develops models of mental functions by incorporating multiple interacting modules. They are designing pipelines to process and compare large-scale experimental datasets that span modalities ranging from behavioral data to neural activity data to molecular data. These datasets are then be integrated to train individual computational modules based on the experimental tasks that were evaluated such as vision, memory, or movement.

Ultimately, Yang seeks to combine these modules into a “network of networks” that models higher-level brain functions such as the ability to flexibly and rapidly learn a variety of tasks. Such integrative models are rare because, until recently, it was not possible to acquire data that spans modalities and brain regions in real time as animals perform tasks. The time is finally right for integrative network models. Computational models that incorporate such multisystem, multilevel datasets will allow scientists to make new predictions about the neural basis of cognition and open a window to a mathematical understanding the mind.

“This is a new research direction for me, and I think for the field too. It comes with many exciting opportunities as well as challenges. Having this recognition from the Searle Scholars program really gives me extra courage to take on the uncertainties and challenges,” says Yang.

Since 1981, 647 scientists have been named Searle Scholars. Including this year, the program has awarded more than $147 million. Eighty-five Searle Scholars have been inducted into the National Academy of Sciences. Twenty scholars have been recognized with a MacArthur Fellowship, known as the “genius grant,” and two Searle Scholars have been awarded the Nobel Prize in Chemistry. The Searle Scholars Program is funded through the Searle Funds at The Chicago Community Trust and administered by Kinship Foundation.

A brain circuit in the thalamus helps us hold information in mind

Anne Trafton |

As people age, their working memory often declines, making it more difficult to perform everyday tasks. One key brain region linked to this type of memory is the anterior thalamus, which is primarily involved in spatial memory — memory of our surroundings and how to navigate them.

In a study of mice, MIT researchers have identified a circuit in the anterior thalamus that is necessary for remembering how to navigate a maze. The researchers also found that this circuit is weakened in older mice, but enhancing its activity greatly improves their ability to run the maze correctly.

This region could offer a promising target for treatments that could help reverse memory loss in older people, without affecting other parts of the brain, the researchers say.

“By understanding how the thalamus controls cortical output, hopefully we could find more specific and druggable targets in this area, instead of generally modulating the prefrontal cortex, which has many different functions,” says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT.

Feng is the senior author of the study, which appears today in the Proceedings of the National Academy of Sciences. Dheeraj Roy, a NIH K99 Awardee and a McGovern Fellow at the Broad Institute, and Ying Zhang, a J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, are the lead authors of the paper.

Spatial memory

The thalamus, a small structure located near the center of the brain, contributes to working memory and many other executive functions, such as planning and attention. Feng’s lab has recently been investigating a region of the thalamus known as the anterior thalamus, which has important roles in memory and spatial navigation.

Previous studies in mice have shown that damage to the anterior thalamus leads to impairments in spatial working memory. In humans, studies have revealed age-related decline in anterior thalamus activity, which is correlated with lower performance on spatial memory tasks.

The anterior thalamus is divided into three sections: ventral, dorsal, and medial. In a study published last year, Feng, Roy and Zhang studied the role of the anterodorsal (AD) thalamus and anteroventral (AV) thalamus in memory formation. They found that the AD thalamus is involved in creating mental maps of physical spaces, while the AV thalamus helps the brain to distinguish these memories from other memories of similar spaces.

In their new study, the researchers wanted to look more deeply at the AV thalamus, exploring its role in a spatial working memory task. To do that, they trained mice to run a simple T-shaped maze. At the beginning of each trial, the mice ran until they reached the T. One arm was blocked off, forcing them to run down the other arm. Then, the mice were placed in the maze again, with both arms open. The mice were rewarded if they chose the opposite arm from the first run. This meant that in order to make the correct decision, they had to remember which way they had turned on the previous run.

As the mice performed the task, the researchers used optogenetics to inhibit activity of either AV or AD neurons during three different parts of the task: the sample phase, which occurs during the first run; the delay phase, while they are waiting for the second run to begin; and the choice phase, when the mice make their decision which way to turn during the second run.

The researchers found that inhibiting AV neurons during the sample or choice phases had no effect on the mice’s performance, but when they suppressed AV activity during the delay phase, which lasted 10 seconds or longer, the mice performed much worse on the task.

This suggests that the AV neurons are most important for keeping information in mind while it is needed for a task. In contrast, inhibiting the AD neurons disrupted performance during the sample phase but had little effect during the delay phase. This finding was consistent with the research team’s earlier study showing that AD neurons are involved in forming memories of a physical space.

“The anterior thalamus in general is a spatial learning region, but the ventral neurons seem to be needed in this maintenance period, during this short delay,” Roy says. “Now we have two subdivisions within the anterior thalamus: one that seems to help with contextual learning and the other that actually helps with holding this information.”

Age-related decline

The researchers then tested the effects of age on this circuit. They found that older mice (14 months) performed worse on the T-maze task and their AV neurons were less excitable. However, when the researchers artificially stimulated those neurons, the mice’s performance on the task dramatically improved.

Another way to enhance performance in this memory task is to stimulate the prefrontal cortex, which also undergoes age-related decline. However, activating the prefrontal cortex also increases measures of anxiety in the mice, the researchers found.

“If we directly activate neurons in medial prefrontal cortex, it will also elicit anxiety-related behavior, but this will not happen during AV activation,” Zhang says. “That is an advantage of activating AV compared to prefrontal cortex.”

If a noninvasive or minimally invasive technology could be used to stimulate those neurons in the human brain, it could offer a way to help prevent age-related memory decline, the researchers say. They are now planning to perform single-cell RNA sequencing of neurons of the anterior thalamus to find genetic signatures that could be used to identify cells that would make the best targets.

The research was funded, in part, by the Stanley Center for Psychiatric Research at the Broad Institute, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, and the James and Patricia Poitras Center for Psychiatric Disorders Research at MIT.

Circuit that focuses attention brings in wide array of inputs

by David Orenstein | Picower Institute |

In a new brain-wide circuit tracing study, scientists at MIT’s Picower Institute for Learning and Memory focused selective attention on a circuit that governs, fittingly enough, selective attention. The comprehensive maps they produced illustrate how broadly the mammalian brain incorporates and integrates information to focus its sensory resources on its goals.

Working in mice, the team traced thousands of inputs into the circuit, a communication loop between the anterior cingulate cortex (ACC) and the lateral posterior (LP) thalamus. In primates the LP is called the pulvinar. Studies in humans and nonhuman primates have indicated that the byplay of these two regions is critical for brain functions like being able to focus on an object of interest in a crowded scene, says study co-lead author Yi Ning Leow, a graduate student in the lab of senior author Mriganka Sur, the Newton Professor in MIT’s Department of Brain and Cognitive Sciences. Research has implicated dysfunction in the circuit in attention-affecting disorders such as autism and attention deficit/hyperactivity disorder.

The new study in the Journal of Comparative Neurology extends what’s known about the circuit by detailing it in mice, Leow says, importantly showing that the mouse circuit is closely analogous to the primate version even if the LP is proportionately smaller and less evolved than the pulvinar.

“In these rodent models we were able to find very similar circuits,” Leow says. “So we can possibly study these higher-order functions in mice as well. We have a lot more genetic tools in mice so we are better able to look at this circuit.”

The study, also co-led by former MIT undergraduate Blake Zhou, therefore provides a detailed roadmap in the experimentally accessible mouse model for understanding how the ACC and LP cooperate to produce selective attention. For instance, now that Leow and Zhou have located all the inputs that are wired into the circuit, Leow is tapping into those feeds to eavesdrop on the information they are carrying. Meanwhile, she is correlating that information flow with behavior.

“This study lays the groundwork for understanding one of the most important, yet most elusive, components of brain function, namely our ability to selectively attend to one thing out of several, as well as switch attention,” Sur says.

Using virally mediated circuit-tracing techniques pioneered by co-author Ian Wickersham, principal research scientist in brain and cognitive sciences and the McGovern Institute for Brain Research at MIT, the team found distinct sources of input for the ACC and the LP. Generally speaking, the detailed study finds that the majority of inputs to the ACC were from frontal cortex areas that typically govern goal-directed planning, and from higher visual areas. The bulk of inputs to the LP, meanwhile, were from deeper regions capable of providing context such as the mouse’s needs, location and spatial cues, information about movement, and general information from a mix of senses.

So even though focusing attention might seem like a matter of controlling the senses, Leow says, the circuit pulls in a lot of other information as well.

“We’re seeing that it’s not just sensory — there are so many inputs that are coming from non-sensory areas as well, both sub-cortically and cortically,” she says. “It seems to be integrating a lot of different aspects that might relate to the behavioral state of the animal at a given time. It provides a way to provide a lot of internal and special context for that sensory information.”

Given the distinct sets of inputs to each region, the ACC may be tasked with focusing attention on a desired object, while the LP is modulating how the ACC goes about making those computations, accounting for what’s going on both inside and outside the animal. Decoding just what that incoming contextual information is, and what the LP tells the ACC, are the key next steps, Leow says. Another clear set of questions the study raises are what are the circuit’s outputs. In other words, after it integrates all this information, what does it do with it?

The paper’s other authors are Heather Sullivan and Alexandria Barlowe.

A National Science Scholarship, the National Institutes of Health, and the JPB Foundation provided support for the study.

Approaching human cognition from many angles

by Alli Armijo | MIT News correspondent |

In January, as the Charles River was starting to freeze over, Keith Murray and the other members of MIT’s men’s heavyweight crew team took to erging on the indoor rowing machine. For 80 minutes at a time, Murray endured one of the most grueling workouts of his college experience. To distract himself from the pain, he would talk with his teammates, covering everything from great philosophical ideas to personal coffee preferences.

For Murray, virtually any conversation is an opportunity to explore how people think and why they think in certain ways. Currently a senior double majoring in computation and cognition, and linguistics and philosophy, Murray tries to understand the human experience based on knowledge from all of these fields.

“I’m trying to blend different approaches together to understand the complexities of human cognition,” he says. “For example, from a physiological perspective, the brain is just billions of neurons firing all at once, but this hardly scratches the surface of cognition.”

Murray grew up in Corydon, Indiana, where he attended the Indiana Academy for Science, Mathematics, and Humanities during his junior year of high school. He was exposed to philosophy there, learning the ideas of Plato, Socrates, and Thomas Aquinas, to name a few. When looking at colleges, Murray became interested in MIT because he wanted to learn about human thought processes from different perspectives. “Coming to MIT, I knew I wanted to do something philosophical. But I wanted to also be on the more technical side of things,” he says.

Once on campus, Murray immediately pursued an opportunity through the Undergraduate Research Opportunity Program (UROP) in the Digital Humanities Lab. There he worked with language-processing technology to analyze gendered language in various novels, with the end goal of displaying the data for an online audience. He learned about the basic mathematical models used for analyzing and presenting data online, to study the social implications of linguistic phrases and expressions.

Murray also joined the Concourse learning community, which brought together different perspectives from the humanities, sciences, and math in a weekly seminar. “I was exposed to some excellent examples of how to do interdisciplinary work,” he recalls.

In the summer before his sophomore year, Murray took a position as a researcher in the Harnett Lab, where instead of working with novels, he was working with mice. Alongside postdoc Lucas Fisher, Murray trained mice to do navigational tasks using virtual reality equipment. His goal was to explore neural encoding in navigation, understanding why the mice behaved in certain ways after being shown certain stimuli on the screens. Spending time in the lab, Murray became increasingly interested in neuroscience and the biological components behind human thought processes.

He sought out other neuroscience-related research experiences, which led him to explore a SuperUROP project in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL). Working under Professor Nancy Lynch, he designed theoretical models of the retina using machine learning. Murray was excited to apply the techniques he learned in 9.40 (Introduction to Neural Computation) to address complex neurological problems. Murray considers this one of his most challenging research experiences, as the experience was entirely online.

“It was during the pandemic, so I had to learn a lot on my own; I couldn’t exactly do research in a lab. It was a big challenge, but at the end, I learned a lot and ended up getting a publication out of it,” he reflects.

This past semester, Murray has worked in the lab of Professor Ila Fiete in the McGovern Institute for Brain Research, constructing deep-learning models of animals performing navigational tasks. Through this UROP, which builds on his final project from Fiete’s class 9.49 (Neural Circuits for Cognition), Murray has been working to incorporate existing theoretical models of the hippocampus to investigate the intersection between artificial intelligence and neuroscience.

Reflecting on his varied research experiences, Murray says they have shown him new ways to explore the human brain from multiple perspectives, something he finds helpful as he tries to understand the complexity of human behavior.

Outside of his academic pursuits, Murray has continued to row with the crew team, where he walked on his first year. He sees rowing as a way to build up his strength, both physically and mentally. “When I’m doing my class work or I’m thinking about projects, I am using the same mental toughness that I developed during rowing,” he says. “That’s something I learned at MIT, to cultivate the dedication you put toward something. It’s all the same mental toughness whether you apply it to physical activities like rowing, or research projects.”

Looking ahead, Murray hopes to pursue a PhD in neuroscience, looking to find ways to incorporate his love of philosophy and human thought into his cognitive research. “I think there’s a lot more to do with neuroscience, especially with artificial intelligence. There are so many new technological developments happening right now,” he says.

Seven from MIT elected to American Academy of Arts and Sciences for 2022

by MIT News Office |

Seven MIT faculty members are among more than 250 leaders from academia, the arts, industry, public policy, and research elected to the American Academy of Arts and Sciences, the academy announced Thursday.

One of the nation’s most prestigious honorary societies, the academy is also a leading center for independent policy research. Members contribute to academy publications, as well as studies of science and technology policy, energy and global security, social policy and American institutions, the humanities and culture, and education.

Those elected from MIT this year are:

  • Alberto Abadie, professor of economics and associate director of the Institute for Data, Systems, and Society
  • Regina Barzilay, the School of Engineering Distinguished Professor for AI and Health
  • Roman Bezrukavnikov, professor of mathematics
  • Michale S. Fee, the Glen V. and Phyllis F. Dorflinger Professor and head of the Department of Brain and Cognitive Sciences
  • Dina Katabi, the Thuan and Nicole Pham Professor
  • Ronald T. Raines, the Roger and Georges Firmenich Professor of Natural Products Chemistry
  • Rebecca R. Saxe, the John W. Jarve Professor of Brain and Cognitive Sciences

“We are celebrating a depth of achievements in a breadth of areas,” says David Oxtoby, president of the American Academy. “These individuals excel in ways that excite us and inspire us at a time when recognizing excellence, commending expertise, and working toward the common good is absolutely essential to realizing a better future.”

Since its founding in 1780, the academy has elected leading thinkers from each generation, including George Washington and Benjamin Franklin in the 18th century, Maria Mitchell and Daniel Webster in the 19th century, and Toni Morrison and Albert Einstein in the 20th century. The current membership includes more than 250 Nobel and Pulitzer Prize winners.