Research Area: Systems Neuroscience

​neural circuits, attention, brain disorders, executive function, sensory processing, behavior, timing, plasticity, learning, memory, emotion, habits

Neuroscientists reverse some behavioral symptoms of Williams Syndrome

by Anne Trafton |

Williams Syndrome, a rare neurodevelopmental disorder that affects about 1 in 10,000 babies born in the United States, produces a range of symptoms including cognitive impairments, cardiovascular problems, and extreme friendliness, or hypersociability.

In a study of mice, MIT neuroscientists have garnered new insight into the molecular mechanisms that underlie this hypersociability. They found that loss of one of the genes linked to Williams Syndrome leads to a thinning of the fatty layer that insulates neurons and helps them conduct electrical signals in the brain.

The researchers also showed that they could reverse the symptoms by boosting production of this coating, known as myelin. This is significant, because while Williams Syndrome is rare, many other neurodevelopmental disorders and neurological conditions have been linked to myelination deficits, says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research.

“The importance is not only for Williams Syndrome,” says Feng, who is one of the senior authors of the study. “In other neurodevelopmental disorders, especially in some of the autism spectrum disorders, this could be potentially a new direction to look into, not only the pathology but also potential treatments.”

Zhigang He, a professor of neurology and ophthalmology at Harvard Medical School, is also a senior author of the paper, which appears in the April 22 issue of Nature Neuroscience. Former MIT postdoc Boaz Barak, currently a principal investigator at Tel Aviv University in Israel, is the lead author and a senior author of the paper.

Impaired myelination

Williams Syndrome, which is caused by the loss of one of the two copies of a segment of chromosome 7, can produce learning impairments, especially for tasks that require visual and motor skills, such as solving a jigsaw puzzle. Some people with the disorder also exhibit poor concentration and hyperactivity, and they are more likely to experience phobias.

In this study, the researchers decided to focus on one of the 25 genes in that segment, known as Gtf2i. Based on studies of patients with a smaller subset of the genes deleted, scientists have linked the Gtf2i gene to the hypersociability seen in Williams Syndrome.

Working with a mouse model, the researchers devised a way to knock out the gene specifically from excitatory neurons in the forebrain, which includes the cortex, the hippocampus, and the amygdala (a region important for processing emotions). They found that these mice did show increased levels of social behavior, measured by how much time they spent interacting with other mice. The mice also showed deficits in fine motor skills and increased nonsocial related anxiety, which are also symptoms of Williams Syndrome.

Next, the researchers sequenced the messenger RNA from the cortex of the mice to see which genes were affected by loss of Gtf2i. Gtf2i encodes a transcription factor, so it controls the expression of many other genes. The researchers found that about 70 percent of the genes with significantly reduced expression levels were involved in the process of myelination.

“Myelin is the insulation layer that wraps the axons that extend from the cell bodies of neurons,” Barak says. “When they don’t have the right properties, it will lead to faster or slower electrical signal transduction, which affects the synchronicity of brain activity.”

Further studies revealed that the mice had only about half the normal number of mature oligodendrocytes — the brain cells that produce myelin. However, the number of oligodendrocyte precursor cells was normal, so the researchers suspect that the maturation and differentiation processes of these cells are somehow impaired when Gtf2i is missing in the neurons.

This was surprising because Gtf2i was not knocked out in oligodendrocytes or their precursors. Thus, knocking out the gene in neurons may somehow influence the maturation process of oligodendrocytes, the researchers suggest. It is still unknown how this interaction might work.

“That’s a question we are interested in, but we don’t know whether it’s a secreted factor, or another kind of signal or activity,” Feng says.

In addition, the researchers found that the myelin surrounding axons of the forebrain was significantly thinner than in normal mice. Furthermore, electrical signals were smaller, and took more time to cross the brain in mice with Gtf2i missing.

The study is an example of pioneering research into the contribution of glial cells, which include oligodendrocytes, to neuropsychiatric disorders, says Doug Fields, chief of the nervous system development and plasticity section of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

“Traditionally myelin was only considered in the context of diseases that destroy myelin, such as multiple sclerosis, which prevents transmission of neural impulses. More recently it has become apparent that more subtle defects in myelin can impair neural circuit function, by causing delays in communication between neurons,” says Fields, who was not involved in the research.

Symptom reversal

It remains to be discovered precisely how this reduction in myelination leads to hypersociability. The researchers suspect that the lack of myelin affects brain circuits that normally inhibit social behaviors, making the mice more eager to interact with others.

“That’s probably the explanation, but exactly which circuits and how does it work, we still don’t know,” Feng says.

The researchers also found that they could reverse the symptoms by treating the mice with drugs that improve myelination. One of these drugs, an FDA-approved antihistamine called clemastine fumarate, is now in clinical trials to treat multiple sclerosis, which affects myelination of neurons in the brain and spinal cord. The researchers believe it would be worthwhile to test these drugs in Williams Syndrome patients because they found thinner myelin and reduced numbers of mature oligodendrocytes in brain samples from human subjects who had Williams Syndrome, compared to typical human brain samples.

“Mice are not humans, but the pathology is similar in this case, which means this could be translatable,” Feng says. “It could be that in these patients, if you improve their myelination early on, it could at least improve some of the conditions. That’s our hope.”

Such drugs would likely help mainly the social and fine-motor issues caused by Williams Syndrome, not the symptoms that are produced by deletion of other genes, the researchers say. They may also help treat other disorders, such as autism spectrum disorders, in which myelination is impaired in some cases, Feng says.

“We think this can be expanded into autism and other neurodevelopmental disorders. For these conditions, improved myelination may be a major factor in treatment,” he says. “We are now checking other animal models of neurodevelopmental disorders to see whether they have myelination defects, and whether improved myelination can improve some of the pathology of the defects.”

The research was funded by the Simons Foundation, the Poitras Center for Affective Disorders Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and the Simons Center for the Social Brain at MIT.

How our gray matter tackles gray areas

by Gina Vitale | MIT News correspondent |

When Katie O’Nell’s high school biology teacher showed a NOVA video on epigenetics after the AP exam, he was mostly trying to fill time. But for O’Nell, the video sparked a whole new area of curiosity.

She was fascinated by the idea that certain genes could be turned on and off, controlling what traits or processes were expressed without actually editing the genetic code itself. She was further excited about what this process could mean for the human mind.

But upon starting at MIT, she realized that she was less interested in the cellular level of neuroscience and more fascinated by bigger questions, such as, what makes certain people generous toward certain others? What’s the neuroscience behind morality?

“College is a time you can learn about anything you want, and what I want to know is why humans are really, really wacky,” she says. “We’re dumb, we make super irrational decisions, it makes no sense. Sometimes it’s beautiful, sometimes it’s awful.”

O’Nell, a senior majoring in brain and cognitive sciences, is one of five MIT students to have received a Marshall Scholarship this year. Her quest to understand the intricacies of the wacky human brain will not be limited to any one continent. She will be using the funding to earn her master’s in experimental psychology at Oxford University.

Chocolate milk and the mouse brain

O’Nell’s first neuroscience-related research experience at MIT took place during her sophomore and junior year, in the lab of Institute Professor Ann Graybiel at the McGovern Institute.

The research studied the neurological components of risk-vs-reward decision making, using a key ingredient: chocolate milk. In the experiments, mice were given two options — they could go toward the richer, sweeter chocolate milk, but they would also have to endure a brighter light. Or, they could go toward a more watered-down chocolate milk, with the benefit of a softer light. All the while, a fluorescence microscope tracked when certain cell types were being activated.

“I think that’s probably the closest thing I’ve ever had to a spiritual experience … watching this mouse in this maze deciding what to do, and watching the cells light up on the screen. You can see single-cell evidence of cognition going on. That’s just the coolest thing.”

In her junior spring, O’Nell delved even deeper into questions of morality in the lab of Professor Rebecca Saxe. Her research there centers on how the human brain parses people’s identities and emotional states from their faces alone, and how those computations are related to each other. Part of what interests O’Nell is the fact that we are constantly making decisions, about ourselves and others, with limited information.

“We’re always solving under uncertainty,” she says. “And our brain does it so well, in so many ways.”

International intrigue

Outside of class, O’Nell has no shortage of things to do. For starters, she has been serving as an associate advisor for a first-year seminar since the fall of her sophomore year.

“Basically it’s my job to sit in on a seminar and bully them into not taking seven classes at a time, and reminding them that yes, your first 8.01 exam is tomorrow,” she says with a laugh.

She has also continued an activity she was passionate about in high school — Model United Nations. One of the most fun parts for her is serving on the Historical Crisis Committee, in which delegates must try to figure out a way to solve a real historical problem, like the Cuban Missile Crisis or the French and Indian War.

“This year they failed and the world was a nuclear wasteland,” she says. “Last year, I don’t entirely know how this happened, but France decided that they wanted to abandon the North American theater entirely and just took over all of Britain’s holdings in India.”

She’s also part of an MIT program called the Addir Interfaith Fellowship, in which a small group of people meet each week and discuss a topic related to religion and spirituality. Before joining, she didn’t think it was something she’d be interested in — but after being placed in a first-year class about science and spirituality, she has found discussing religion to be really stimulating. She’s been a part of the group ever since.

O’Nell has also been heavily involved in writing and producing a Mystery Dinner Theater for Campus Preview Weekend, on behalf of her living group J Entry, in MacGregor House. The plot, generally, is MIT-themed — a physics professor might get killed by a swarm of CRISPR nanobots, for instance. When she’s not cooking up murder mysteries, she might be running SAT classes for high school students, playing piano, reading, or spending time with friends. Or, when she needs to go grocery shopping, she’ll be stopping by the Trader Joe’s on Boylston Avenue, as an excuse to visit the Boston Public Library across the street.

Quite excited for the future

O’Nell is excited that the Marshall Scholarship will enable her to live in the country that produced so many of the books she cherished as a kid, like “The Hobbit.” She’s also thrilled to further her research there. However, she jokes that she still needs to get some of the lingo down.

“I need to learn how to use the word ‘quite’ correctly. Because I overuse it in the American way,” she says.

Her master’s research will largely expand on the principles she’s been examining in the Saxe lab. Questions of morality, processing, and social interaction are where she aims to focus her attention.

“My master’s project is going to be basically taking a look at whether how difficult it is for you to determine someone else’s facial expression changes how generous you are with people,” she explains.

After that, she hopes to follow the standard research track of earning a PhD, doing postdoctoral research, and then entering academia as a professor and researcher. Teaching and researching, she says, are two of her favorite things — she’s excited to have the chance to do both at the same time. But that’s a few years ahead. Right now, she hopes to use her time in England to learn all she can about the deeper functions of the brain, with or without chocolate milk.

Guoping Feng elected to American Academy of Arts and Sciences

by MIT News |

Four MIT faculty members are among more than 200 leaders from academia, business, public affairs, the humanities, and the arts elected to the American Academy of Arts and Sciences, the academy announced today.

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:

  • Dimitri A. Antoniadis, Ray and Maria Stata Professor of Electrical Engineering;
  • Anantha P. Chandrakasan, dean of the School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science;
  • Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences; and
  • David R. Karger, professor of electrical engineering.

“We are pleased to recognize the excellence of our new members, celebrate their compelling accomplishments, and invite them to join the academy and contribute to its work,” said David W. Oxtoby, president of the American Academy of Arts and Sciences. “With the election of these members, the academy upholds the ideals of research and scholarship, creativity and imagination, intellectual exchange and civil discourse, and the relentless pursuit of knowledge in all its forms.”

The new class will be inducted at a ceremony in October in Cambridge, Massachusetts.

Since its founding in 1780, the academy has elected leading “thinkers and doers” 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 200 Nobel laureates and 100 Pulitzer Prize winners.

Halassa named Max Planck Fellow

by Sabbi Lall |

Michael Halassa was just appointed as one of the newest Max Planck Fellows. His appointment comes through the Max Planck Florida Institute for Neuroscience (MPFI), which aims to forge collaborations between exceptional neuroscientists from around the world to answer fundamental questions about brain development and function. The Max Planck Society selects cutting edge, active researchers from other institutions to fellow positions for a five-year period to promote interactions and synergies. While the program is a longstanding feature of the Max Planck Society, Halassa, and fellow appointee Yi Guo of the University of California, Santa Cruz, are the first selected fellows that are based at U.S. institutions.

Michael Halassa is an associate investigator at the McGovern Institute and an assistant professor in the Department of Brain and Cognitive Sciences at MIT. Halassa’s research focuses on the neural architectures that underlie complex cognitive processes. He is particularly interested in goal-directed attention, our ability to rapidly switch attentional focus based on high level objectives. For example, when you are in a roomful of colleagues, the mention of your name in a distant conversation can quickly trigger your ‘mind’s ear’ to eavesdrop into that conversation. This contrasts with hearing a name that sounds like yours on television, which does not usually grab your attention in the same way. In certain mental disorders such as schizophrenia, the ability to generate such high-level objectives, while also accounting for context, is perturbed. Recent evidence strongly suggests that impaired function of the prefrontal cortex and its interactions with a region of the brain called the thalamus may be altered in such disorders. It is this thalamocortical network that Halassa has been studying in mice, where his group has uncovered how the thalamus supports the ability of the prefrontal cortex to generate context-appropriate attentional signals.

The fellowship will support extending Halassa’s work into the tree shrew (Tupaia belangeri), which has been shown to have advanced cognitive abilities compared to mice while also offering many of the circuit-interrogation tools that make the mouse an attractive experimental model.

The Max Planck Florida Institute for Neuroscience (MPFI), a not-for-profit research organization, is part of the world-renowned Max Planck Society, Germany’s most successful research organization. The Max Planck Society was founded in 1911, and comprises 84 institutes and research facilities. While primarily located in Germany, there are 4 institutes and one research facility located aboard, including the Florida Institute that Halassa will collaborate with. The fellow positions were created with the goal of increasing interactions between the Max Planck Society and its institutes with faculty engaged in active research at other universities and institutions, which with this appointment now include MIT.

Elephant or chair? How the brain IDs objects

by Anne Trafton |

As visual information flows into the brain through the retina, the visual cortex transforms the sensory input into coherent perceptions. Neuroscientists have long hypothesized that a part of the visual cortex called the inferotemporal (IT) cortex is necessary for the key task of recognizing individual objects, but the evidence has been inconclusive.

In a new study, MIT neuroscientists have found clear evidence that the IT cortex is indeed required for object recognition; they also found that subsets of this region are responsible for distinguishing different objects.

In addition, the researchers have developed computational models that describe how these neurons transform visual input into a mental representation of an object. They hope such models will eventually help guide the development of brain-machine interfaces (BMIs) that could be used for applications such as generating images in the mind of a blind person.

“We don’t know if that will be possible yet, but this is a step on the pathway toward those kinds of applications that we’re thinking about,” says James DiCarlo, the head of MIT’s Department of Brain and Cognitive Sciences, a member of the McGovern Institute for Brain Research, and the senior author of the new study.

Rishi Rajalingham, a postdoc at the McGovern Institute, is the lead author of the paper, which appears in the March 13 issue of Neuron.

Distinguishing objects

In addition to its hypothesized role in object recognition, the IT cortex also contains “patches” of neurons that respond preferentially to faces. Beginning in the 1960s, neuroscientists discovered that damage to the IT cortex could produce impairments in recognizing non-face objects, but it has been difficult to determine precisely how important the IT cortex is for this task.

The MIT team set out to find more definitive evidence for the IT cortex’s role in object recognition, by selectively shutting off neural activity in very small areas of the cortex and then measuring how the disruption affected an object discrimination task. In animals that had been trained to distinguish between objects such as elephants, bears, and chairs, they used a drug called muscimol to temporarily turn off subregions about 2 millimeters in diameter. Each of these subregions represents about 5 percent of the entire IT cortex.

These experiments, which represent the first time that researchers have been able to silence such small regions of IT cortex while measuring behavior over many object discriminations, revealed that the IT cortex is not only necessary for distinguishing between objects, but it is also divided into areas that handle different elements of object recognition.

The researchers found that silencing each of these tiny patches produced distinctive impairments in the animals’ ability to distinguish between certain objects. For example, one subregion might be involved in distinguishing chairs from cars, but not chairs from dogs. Each region was involved in 25 to 30 percent of the tasks that the researchers tested, and regions that were closer to each other tended to have more overlap between their functions, while regions far away from each other had little overlap.

“We might have thought of it as a sea of neurons that are completely mixed together, except for these islands of “face patches.” But what we’re finding, which many other studies had pointed to, is that there is large-scale organization over the entire region,” Rajalingham says.

The features that each of these regions are responding to are difficult to classify, the researchers say. The regions are not specific to objects such as dogs, nor easy-to-describe visual features such as curved lines.

“It would be incorrect to say that because we observed a deficit in distinguishing cars when a certain neuron was inhibited, this is a ‘car neuron,’” Rajalingham says. “Instead, the cell is responding to a feature that we can’t explain that is useful for car discriminations. There has been work in this lab and others that suggests that the neurons are responding to complicated nonlinear features of the input image. You can’t say it’s a curve, or a straight line, or a face, but it’s a visual feature that is especially helpful in supporting that particular task.”

Bevil Conway, a principal investigator at the National Eye Institute, says the new study makes significant progress toward answering the critical question of how neural activity in the IT cortex produces behavior.

“The paper makes a major step in advancing our understanding of this connection, by showing that blocking activity in different small local regions of IT has a different selective deficit on visual discrimination. This work advances our knowledge not only of the causal link between neural activity and behavior but also of the functional organization of IT: How this bit of brain is laid out,” says Conway, who was not involved in the research.

Brain-machine interface

The experimental results were consistent with computational models that DiCarlo, Rajalingham, and others in their lab have created to try to explain how IT cortex neuron activity produces specific behaviors.

“That is interesting not only because it says the models are good, but because it implies that we could intervene with these neurons and turn them on and off,” DiCarlo says. “With better tools, we could have very large perceptual effects and do real BMI in this space.”

The researchers plan to continue refining their models, incorporating new experimental data from even smaller populations of neurons, in hopes of developing ways to generate visual perception in a person’s brain by activating a specific sequence of neuronal activity. Technology to deliver this kind of input to a person’s brain could lead to new strategies to help blind people see certain objects.

“This is a step in that direction,” DiCarlo says. “It’s still a dream, but that dream someday will be supported by the models that are built up by this kind of work.”

The research was funded by the National Eye Institute, the Office of Naval Research, and the Simons Foundation.

Ila Fiete

Neural Coding and Dynamics

Ila Fiete builds tools and mathematical models to expand our knowledge of the brain’s computations. Specifically, her lab focuses on how the brain develops and reshapes its neural connections to perform high-level computations, like those involved in memory and learning. The Fiete lab applies cutting-edge theoretical and quantitative methods—wielding the vast capabilities of computational models, informed by mathematics, machine learning, and physics—digging deeper into how the brain represents and manipulates information. Through these strategies, Fiete hopes to shed new light onto the neural ensembles behind learning, integration of new information, inference-making, and spatial navigation.

Her lab’s findings are pushing the frontiers of neuroscience—while advancing the utility of computational tools in this space—and are building a more robust understanding of complex brain processes.

Alan Jasanoff

Next Generation Brain Imaging

One of the greatest challenges of modern neuroscience is to relate high-level operations of the brain and mind to well-defined biological processes that arise from molecules and cells. The Jasanoff lab is creating a suite of experimental approaches designed to achieve this by permitting brain-wide dynamics of neural signaling and plasticity to be imaged for the first time, with molecular specificity. These potentially transformative approaches use novel probes detectable by magnetic resonance imaging (MRI) and other noninvasive readouts. The probes afford qualitatively new ways to study healthy and pathological aspects of integrated brain function in mechanistically-informative detail, in animals and possibly also people.

Mehrdad Jazayeri

Neurobiology of Mental Computations

How does the brain give rise to the mind? How do neurons, circuits, and synapses in the brain encode knowledge about objects, events, and other structural and causal relationships in the environment? Research in Mehrdad Jazayeri’s lab brings together ideas from cognitive science, neuroscience, and machine learning with experimental data in humans, animals, and computer models to develop a computational understanding of how the brain create internal representations, or models, of the external world.

Michale Fee

Song Circuits

Michale Fee studies how the brain learns and generates complex sequential behaviors, focusing on the songbird as a model system. Birdsong is a complex behavior that young birds learn from their fathers and it provides an ideal system to study the neural basis of learned behavior. Because the parts of the bird’s brain that control song learning are closely related to human circuits that are disrupted in brain disorders such as Parkinson’s and Huntington’s disease, Fee hopes the lessons learned from birdsong will provide new clues to the causes and possible treatment of these conditions.

Guoping Feng

Listening to Synapses

Guoping Feng is interested in how synapses — the connections between neurons — contribute to neurodevelopmental and psychiatric diseases, including autism spectrum disorder (ASD) and schizophrenia. He leads research that uses molecular genetics combined with behavioral and electrophysiological methods to study the components of the synapse.

Feng is perhaps best known for pioneering a gene-based therapy that could reverse a severe form of autism that is caused by a single mutation in the SHANK3 gene. After genetically engineering the SHANK3 mutation in animal models using CRISPR-based technology, Feng’s gene-correction therapy greatly reduced SHANK3 symptoms, restoring the animals’ cognitive, behavioral, and motor functions.

Additionally, the lab has leveraged genetic technologies to help map the cellular diversity in the brain—a valuable tool in neuroscience research. Through understanding the molecular, cellular, and circuit changes underlying brain diseases and disorders, the Feng lab hopes to eventually inform new and more effective treatments for neurodevelopmental and psychiatric disorders.