Researcher: Guoping Feng

Mapping the brain’s sensory gatekeeper

Anne Trafton |

Many people with autism experience sensory hypersensitivity, attention deficits, and sleep disruption. One brain region that has been implicated in these symptoms is the thalamic reticular nucleus (TRN), which is believed to act as a gatekeeper for sensory information flowing to the cortex.

A team of researchers from MIT and the Broad Institute of MIT and Harvard has now mapped the TRN in unprecedented detail, revealing that the region contains two distinct subnetworks of neurons with different functions. The findings could offer researchers more specific targets for designing drugs that could alleviate some of the sensory, sleep, and attention symptoms of autism, says Guoping Feng, one of the leaders of the research team.

These cross-sections of the thalamic reticular nucleus (TRN) show two distinct populations of neurons, labeled in purple and green. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now mapped the TRN in unprecedented detail.
Image: courtesy of the researchers

“The idea is that you could very specifically target one group of neurons, without affecting the whole brain and other cognitive functions,” says Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT and a member of MIT’s McGovern Institute for Brain Research.

Feng; Zhanyan Fu, associate director of neurobiology at the Broad Institute’s Stanley Center for Psychiatric Research; and Joshua Levin, a senior group leader at the Broad Institute, are the senior authors of the study, which appears today in Nature. The paper’s lead authors are former MIT postdoc Yinqing Li, former Broad Institute postdoc Violeta Lopez-Huerta, and Broad Institute research scientist Xian Adiconis.

Distinct populations

When sensory input from the eyes, ears, or other sensory organs arrives in our brains, it goes first to the thalamus, which then relays it to the cortex for higher-level processing. Impairments of these thalamo-cortical circuits can lead to attention deficits, hypersensitivity to noise and other stimuli, and sleep problems.

One of the major pathways that controls information flow between the thalamus and the cortex is the TRN, which is responsible for blocking out distracting sensory input. In 2016, Feng and MIT Assistant Professor Michael Halassa, who is also an author of the new Nature paper, discovered that loss of a gene called Ptchd1 significantly affects TRN function. In boys, loss of this gene, which is carried on the X chromosome, can lead to attention deficits, hyperactivity, aggression, intellectual disability, and autism spectrum disorders.

In that study, the researchers found that when the Ptchd1 gene was knocked out in mice, the animals showed many of the same behavioral defects seen in human patients. When it was knocked out only in the TRN, the mice showed only hyperactivity, attention deficits, and sleep disruption, suggesting that the TRN is responsible for those symptoms.

In the new study, the researchers wanted to try to learn more about the specific types of neurons found in the TRN, in hopes of finding new ways to treat hyperactivity and attention deficits. Currently, those symptoms are most often treated with stimulant drugs such as Ritalin, which have widespread effects throughout the brain.

“Our goal was to find some specific ways to modulate the function of thalamo-cortical output and relate it to neurodevelopmental disorders,” Feng says. “We decided to try using single-cell technology to dissect out what cell types are there, and what genes are expressed. Are there specific genes that are druggable as a target?”

To explore that possibility, the researchers sequenced the messenger RNA molecules found in neurons of the TRN, which reveals genes that are being expressed in those cells. This allowed them to identify hundreds of genes that could be used to differentiate the cells into two subpopulations, based on how strongly they express those particular genes.

They found that one of these cell populations is located in the core of the TRN, while the other forms a very thin layer surrounding the core. These two populations also form connections to different parts of the thalamus, the researchers found. Based on those connections, the researchers hypothesize that cells in the core are involved in relaying sensory information to the brain’s cortex, while cells in the outer layer appear to help coordinate information that comes in through different senses, such as vision and hearing.

“Druggable targets”

The researchers now plan to study the varying roles that these two populations of neurons may have in a variety of neurological symptoms, including attention deficits, hypersensitivity, and sleep disruption. Using genetic and optogenetic techniques, they hope to determine the effects of activating or inhibiting different TRN cell types, or genes expressed in those cells.

“That can help us in the future really develop specific druggable targets that can potentially modulate different functions,” Feng says. “Thalamo-cortical circuits control many different things, such as sensory perception, sleep, attention, and cognition, and it may be that these can be targeted more specifically.”

This approach could also be useful for treating attention or hypersensitivity disorders even when they aren’t caused by defects in TRN function, the researchers say.

“TRN is a target where if you enhance its function, you might be able to correct problems caused by impairments of the thalamo-cortical circuits,” Feng says. “Of course we are far away from the development of any kind of treatment, but the potential is that we can use single-cell technology to not only understand how the brain organizes itself, but also how brain functions can be segregated, allowing you to identify much more specific targets that modulate specific functions.”

The research was funded by the Simons Center for the Social Brain at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the James and Patricia Poitras Center for Psychiatric Disorders Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute, the National Institutes of Health/National Institute for Mental Health, the Klarman Cell Observatory at the Broad Institute, the Pew Foundation, and the Human Frontiers Science Program.

Optogenetics with SOUL

by Sabbi Lall |

Optogenetics has revolutionized neurobiology, allowing researchers to use light to activate or deactivate neurons that are genetically modified to express a light-sensitive channel. This ability to manipulate neuron activity has allowed causal testing of the function of specific neurons, and also has therapeutic potential to reduce symptoms in brain disorders. However, activating neurons deep within a given brain, especially a large primate brain but even a small mouse brain, is challenging and currently requires implanting fibers that could cause damage or inflammation.

McGovern Investigator Guoping Feng and colleagues have now overcome this challenge, developing optogenetic tools that allow non-invasive stimulation of neurons in the deep brain.

“Neuroscientists have dreamed of methods to turn neurons on and off, to understand the function of different neurons, but also to repair brain malfunctions that lead to psychiatric disorders, and optogenetics made this possible” explained Feng, the James W. (1963) and Patricia T. Poitras Professor in Brain and Cognitive Sciences. “We were trying to improve the light sensitivity of optogenetic tools to broaden applications.”

Engineering with light

In order to stimulate neurons with minimal invasiveness, Feng and colleagues engineered a new type of opsin. The original breakthrough optogenetics protocol used channelrhodopsin, a light-sensitive channel discovered in algae. By expressing this channel in neurons, light of the right wavelength can be used to activate the neuron in a dish or in vivo. However, in vivo application requires the implantation of optical fibers to deliver the light close to the specific brain region being stimulated, especially if the target region is in the deep brain. In addition, if the neuron being targeted is in the deep brain, it is hard for light to reach the region in the absence of invasive tools that can damage tissue and impact the behavior of the animal.

Our study creates a method that can activate any mouse brain region, independent of its location, non-invasively.

“Prior to our study, a few studies have contributed in various ways to the development of optogenetic stimulation methods that would be minimally invasive to the brain. However, all of these studies had various limitations in the extent of brain regions they could activate,” said co-senior study author Robert Desimone, director of the McGovern Institute and the Doris and Don Berkey Professor of Neuroscience at MIT.

Probing the brain with SOUL

Feng and colleagues turned instead to new opsins, in particular SOUL, a new type of opsin that is very sensitive to even low-level light. The Feng group engineered this opsin, based on SSFO a second generation optogenetics tool, to have increased light sensitivity, and took advantage of a second property: that SOUL is activated in multiple steps, and once activated, it stays active for longer than other commonly used opsins. This means that a burst of a few seconds of low-level light can cause neurons to stay active for 10-30 minutes.

In order to put SOUL through its paces, the Feng lab expressed this channel in the lateral hypothalamus of the mouse brain. This is a deep region, challenging to reach with light, but with neurons that have clear functions that will lead to changes in behavior. Feng’s group was able to turn on this region non-invasively with light from outside the skull, and cause changes in feeding behavior.

“We were really surprised that SOUL was able to activate one of the deepest areas in the mouse brain, the lateral hypothalamus, which is 6 mm deep,” explains Feng.

But there were more surprises. When the authors activated a region of the primate brain using SOUL, they saw oscillations, waves of synchronized neuronal activity coming together like a choir. Such waves are believed to be important for many brain functions, and this result suggests that the new opsin can manipulate these brain waves, allowing scientists to study their role in the brain.

The authors are planning to move the study in several directions, studying models of brain disorders to identify circuits that may be suitable targets for therapy, as well as moving the methodology so that it can be used beyond the superficial cortex in larger animals. While it is too early to discuss applying the system to humans, the research brings us one step closer to future treatment of neurological disorders.

The neural basis of sensory hypersensitivity

Anne Trafton |

Many people with autism spectrum disorders are highly sensitive to light, noise, and other sensory input. A new study in mice reveals a neural circuit that appears to underlie this hypersensitivity, offering a possible strategy for developing new treatments.

MIT and Brown University neuroscientists found that mice lacking a protein called Shank3, which has been previously linked with autism, were more sensitive to a touch on their whiskers than genetically normal mice. These Shank3-deficient mice also had overactive excitatory neurons in a region of the brain called the somatosensory cortex, which the researchers believe accounts for their over-reactivity.

There are currently no treatments for sensory hypersensitivity, but the researchers believe that uncovering the cellular basis of this sensitivity may help scientists to develop potential treatments.

“We hope our studies can point us to the right direction for the next generation of treatment development,” says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT and a member of MIT’s McGovern Institute for Brain Research.

Feng and Christopher Moore, a professor of neuroscience at Brown University, are the senior authors of the paper, which appears today in Nature Neuroscience. McGovern Institute research scientist Qian Chen and Brown postdoc Christopher Deister are the lead authors of the study.

Too much excitation

The Shank3 protein is important for the function of synapses — connections that allow neurons to communicate with each other. Feng has previously shown that mice lacking the Shank3 gene display many traits associated with autism, including avoidance of social interaction, and compulsive, repetitive behavior.

In the new study, Feng and his colleagues set out to study whether these mice also show sensory hypersensitivity. For mice, one of the most important sources of sensory input is the whiskers, which help them to navigate and to maintain their balance, among other functions.

The researchers developed a way to measure the mice’s sensitivity to slight deflections of their whiskers, and then trained the mutant Shank3 mice and normal (“wild-type”) mice to display behaviors that signaled when they felt a touch to their whiskers. They found that mice that were missing Shank3 accurately reported very slight deflections that were not noticed by the normal mice.

“They are very sensitive to weak sensory input, which barely can be detected by wild-type mice,” Feng says. “That is a direct indication that they have sensory over-reactivity.”

Once they had established that the mutant mice experienced sensory hypersensitivity, the researchers set out to analyze the underlying neural activity. To do that, they used an imaging technique that can measure calcium levels, which indicate neural activity, in specific cell types.

They found that when the mice’s whiskers were touched, excitatory neurons in the somatosensory cortex were overactive. This was somewhat surprising because when Shank3 is missing, synaptic activity should drop. That led the researchers to hypothesize that the root of the problem was low levels of Shank3 in the inhibitory neurons that normally turn down the activity of excitatory neurons. Under that hypothesis, diminishing those inhibitory neurons’ activity would allow excitatory neurons to go unchecked, leading to sensory hypersensitivity.

To test this idea, the researchers genetically engineered mice so that they could turn off Shank3 expression exclusively in inhibitory neurons of the somatosensory cortex. As they had suspected, they found that in these mice, excitatory neurons were overactive, even though those neurons had normal levels of Shank3.

“If you only delete Shank3 in the inhibitory neurons in the somatosensory cortex, and the rest of the brain and the body is normal, you see a similar phenomenon where you have hyperactive excitatory neurons and increased sensory sensitivity in these mice,” Feng says.

Reversing hypersensitivity

The results suggest that reestablishing normal levels of neuron activity could reverse this kind of hypersensitivity, Feng says.

“That gives us a cellular target for how in the future we could potentially modulate the inhibitory neuron activity level, which might be beneficial to correct this sensory abnormality,” he says.

Many other studies in mice have linked defects in inhibitory neurons to neurological disorders, including Fragile X syndrome and Rett syndrome, as well as autism.

“Our study is one of several that provide a direct and causative link between inhibitory defects and sensory abnormality, in this model at least,” Feng says. “It provides further evidence to support inhibitory neuron defects as one of the key mechanisms in models of autism spectrum disorders.”

He now plans to study the timing of when these impairments arise during an animal’s development, which could help to guide the development of possible treatments. There are existing drugs that can turn down excitatory neurons, but these drugs have a sedative effect if used throughout the brain, so more targeted treatments could be a better option, Feng says.

“We don’t have a clear target yet, but we have a clear cellular phenomenon to help guide us,” he says. “We are still far away from developing a treatment, but we’re happy that we have identified defects that point in which direction we should go.”

The research was funded by the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the Nancy Lurie Marks Family Foundation, the Poitras Center for Psychiatric Disorders Research at the McGovern Institute, the Varanasi Family, R. Buxton, and the National Institutes of Health.

Two CRISPR scientists on the future of gene editing

by Sabbi Lall |

As part of our Ask the Brain series, Martin Wienisch and Jonathan Wilde of the Feng lab look into the crystal ball to predict the future of CRISPR tech.

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Where will CRISPR be in five years?

Jonathan: We’ll definitely have more efficient, more precise, and safer editing tools. An immediate impact on human health may be closer than we think through more nutritious and resilient crops. Also, I think we will have more viable tools available for repairing disease-causing mutations in the brain, which is something that the field is really lacking right now.

Martin: And we can use these technologies with new disease models to help us understand brain disorders such as Huntington’s disease.

Jonathan: There are also incredible tools being discovered in nature: exotic CRISPR systems from newly discovered bacteria and viruses. We could use these to attack disease-causing bacteria.

Martin: We would then be using CRISPR systems for the reason they evolved. Also improved gene drives, CRISPR-systems that can wipe out disease-carrying organisms such as mosquitoes, could impact human health in that time frame.

What will move gene therapy forward?

Martin: A breakthrough on delivery. That’s when therapy will exponentially move forward. Therapy will be tailored to different diseases and disorders, depending on relevant cell types or the location of mutations for example.

Jonathan: Also panning biodiversity even faster: we’ve only looked at one small part of the tree of life for tools. Sequencing and computational advances can help: a future where we collect and analyze genomes in the wild using portable sequencers and laptops can only quicken the pace of new discoveries.

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

CRISPR: From toolkit to therapy

by Sabbi Lall |

Think of the human body as a community of cells with specialized roles. Each cell carries the same blueprint, an array of genes comprising the genome, but different cell types have unique functions — immune cells fight invading bacteria, while neurons transmit information.

But when something goes awry, the specialization of these cells becomes a challenge for treatment. For example, neurons lack active cell repair systems required for promising gene editing techniques like CRISPR.

Can current gene editing tools be modified to work in neurons? Can we reach neurons without impacting healthy cells nearby? McGovern Institute researchers are trying to answer these questions by developing gene editing tools and delivery systems that can target — and repair — faulty brain cells.

Expanding the toolkit

Feng Zhang with folded arms in lab
McGovern Investigator Feng Zhang in his lab.

Natural CRISPR systems help bacteria fend off would-be attackers. Our first glimpse of the impact of such systems was the use of CRISPR-Cas9 to edit human cells.

“Harnessing Cas9 was a major game-changer in the life sciences,” explains Feng Zhang, an investigator at the McGovern Institute and the James and Patricia Poitras Professor of Neuroscience at MIT. “But Cas9 is just one flavor of one kind of bacterial defense system — there is a treasure trove of natural systems that may have enormous potential, just waiting to be unlocked.”

By finding and optimizing new molecular tools, the Zhang lab and others have developed CRISPR tools that can now potentially target neurons and fix diverse mutation types, bringing gene therapy within reach.

Precise in space and time

A single letter change to a gene can be devastating. These genes may function only briefly during development, so a temporary “fix” during this window could be beneficial. For such cases, the Zhang lab and others have engineered tools that target short-lived RNAs. These molecules act as messengers, carrying information from DNA to be converted into functional factors in the cell.

“RNA editing is powerful from an ethical and safety standpoint,” explains Soumya Kannan, a graduate student in the Zhang lab working on these tools. “By targeting RNA molecules, which are only present for a short time, we can avoid permanent changes to the genetic material, and we can make these changes in any type of cell.”

Soumya Kannan in the lab
Graduate student Soumya Kannan is developing smaller CRISPR tools that can be more easily packaged into viral vectors for delivery. Photo: Caitlin Cunningham

Zhang’s team has developed twin RNA-editing tools, REPAIR and RESCUE, which can fix single RNA bases by bringing together a base editor with the CRISPR protein Cas13. These RNA-editing tools can be used in neurons because they do not rely on cellular machinery to make the targeted changes. They also have the potential to tackle a wide array of diseases in other tissue types.

CAST addition

If a gene is severely disrupted, more radical help may be needed: insertion of a normal gene. For this situation, Zhang’s lab recently identified CRISPR-associated transposases (CASTs) from cyanobacteria. CASTs combine Cas12k, which is targeted by a guide RNA to a precise genome location, with an enzyme that can insert gene-sized pieces of DNA.

“With traditional CRISPR you can make simple changes, similar to changing a few letters or words in a Word document. The new system can ‘copy and paste’ entire genes.” – Alim Ladha

Transposases were originally identified as enzymes that help rogue genes “jump” from one place to another in the genome. CAST uses a similar activity to insert entire genes self-sufficiently without help from the target cell so, like REPAIR and RESCUE, it can potentially be used in neurons.

“Our initial work was to fully characterize how this new system works, and test whether it can actually insert genes,” explains Alim Ladha, a graduate fellow in the Tan-Yang Center for Autism Research, who worked on CAST with Jonathan Strecker, a postdoctoral fellow in the Zhang lab.

The goal is now to use CAST to precisely target neurons and other specific cell types affected by disease.

Toward delivery

As the gene-editing toolbox expands, McGovern labs are working on precise delivery systems.Adeno-associated virus (AAV) is an FDA-approved virus for delivering genes, but has limited room to carry the necessary cargo — CRISPR machinery plus templates — to fix genes.

To tackle this problem, McGovern Investigators Guoping Feng and Feng Zhang are working on reducing the cargo needed for therapy. In addition, the Zhang, Gootenberg and Abudayyeh labs are working on methods to precisely deliver the therapeutic packages to neurons, such as new tissue-specific viruses that can carry bigger payloads. Finally, entirely new modalities for delivery are being explored in the effort to develop gene therapy to a point where it can be safely delivered to patients.

“Cas9 has been a very useful tool for the life sciences,” says Zhang. “And it’ll be exciting to see continued progress with the broadening toolkit and delivery systems, as we make further progress toward safe gene therapies.

Brain region linked to altered social interactions in autism model

by Sabbi Lall |

Although psychiatric disorders can be linked to particular genes, the brain regions and mechanisms underlying particular disorders are not well-understood. Mutations or deletions of the SHANK3 gene are strongly associated with autism spectrum disorder (ASD) and a related rare disorder called Phelan-McDermid syndrome. Mice with SHANK3 mutations also display some of the traits associated with autism, including avoidance of social interactions, but the brain regions responsible for this behavior have not been identified.

A new study by neuroscientists at MIT and colleagues in China provides clues to the neural circuits underlying social deficits associated with ASD. The paper, published in Nature Neuroscience, found that structural and functional impairments in the anterior cingulate cortex (ACC) of SHANK3 mutant mice are linked to altered social interactions.

“Neurobiological mechanisms of social deficits are very complex and involve many brain regions, even in a mouse model,” explains Guoping Feng, the James W. and Patricia T. Poitras Professor at MIT and one of the senior authors of the study. “These findings add another piece of the puzzle to mapping the neural circuits responsible for this social deficit in ASD models.”

The Nature Neuroscience paper is the result of a collaboration between Feng, who is also an investigator at MIT’s McGovern Institute and a senior scientist in the Broad Institute’s Stanley Center for Psychiatric Research, and Wenting Wang and Shengxi Wu at the Fourth Military Medical University, Xi’an, China.

A number of brain regions have been implicated in social interactions, including the prefrontal cortex (PFC) and its projections to brain regions including the nucleus accumbens and habenula, but these studies failed to definitively link the PFC to altered social interactions seen in SHANK3 knockout mice.

In the new study, the authors instead focused on the ACC, a brain region noted for its role in social functions in humans and animal models. The ACC is also known to play a role in fundamental cognitive processes, including cost-benefit calculation, motivation, and decision making.

In mice lacking SHANK3, the researchers found structural and functional disruptions at the synapses, or connections, between excitatory neurons in the ACC. The researchers went on to show that the loss of SHANK3 in excitatory ACC neurons alone was enough to disrupt communication between these neurons and led to unusually reduced activity of these neurons during behavioral tasks reflecting social interaction.

Having implicated these ACC neurons in social preferences and interactions in SHANK3 knockout mice, the authors then tested whether activating these same neurons could rescue these behaviors. Using optogenetics and specfic drugs, the researchers activated the ACC neurons and found improved social behavior in the SHANK3 mutant mice.

“Next, we are planning to explore brain regions downstream of the ACC that modulate social behavior in normal mice and models of autism,” explains Wenting Wang, co-corresponding author on the study. “This will help us to better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders.”

Previous clinical studies reported that anatomical structures in the ACC were altered and/or dysfunctional in people with ASD, an initial indication that the findings from SHANK3 mice may also hold true in these individuals.

The research was funded, in part, by the Natural Science Foundation of China. Guoping Feng was supported by NIMH grant no. MH097104, the  Poitras Center for Psychiatric Disorders Research at the McGovern Institute at MIT, and the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute at MIT.

McGovern neuroscientists develop a new model for autism

Anne Trafton |

Using the genome-editing system CRISPR, researchers at MIT and in China have engineered macaque monkeys to express a gene mutation linked to autism and other neurodevelopmental disorders in humans. These monkeys show some behavioral traits and brain connectivity patterns similar to those seen in humans with these conditions.

Mouse studies of autism and other neurodevelopmental disorders have yielded drug candidates that have been tested in clinical trials, but none of them have succeeded. Many pharmaceutical companies have given up on testing such drugs because of the poor track record so far.

The new type of model, however, could help scientists to develop better treatment options for some neurodevelopmental disorders, says Guoping Feng, who is the James W. and Patricia Poitras Professor of Neuroscience, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

“Our goal is to generate a model to help us better understand the neural biological mechanism of autism, and ultimately to discover treatment options that will be much more translatable to humans,” says Feng, who is also an institute member of the Broad Institute of MIT and Harvard and a senior scientist in the Broad’s Stanley Center for Psychiatric Research.

“We urgently need new treatment options for autism spectrum disorder, and treatments developed in mice have so far been disappointing. While the mouse research remains very important, we believe that primate genetic models will help us to develop better medicines and possibly even gene therapies for some severe forms of autism,” says Robert Desimone, the director of MIT’s McGovern Institute for Brain Research, the Doris and Don Berkey Professor of Neuroscience, and an author of the paper.

Huihui Zhou of the Shenzhen Institutes of Advanced Technology, Andy Peng Xiang of Sun Yat-Sen University, and Shihua Yang of South China Agricultural University are also senior authors of the study, which appears in the June 12 online edition of Nature. The paper’s lead authors are former MIT postdoc Yang Zhou, MIT research scientist Jitendra Sharma, Broad Institute group leader Rogier Landman, and Qiong Ke of Sun Yat-Sen University. The research team also includes Mriganka Sur, the Paul and Lilah E. Newton Professor in the Department of Brain and Cognitive Sciences and a member of MIT’s Picower Institute for Learning and Memory.

Gene variants

Scientists have identified hundreds of genetic variants associated with autism spectrum disorder, many of which individually confer only a small degree of risk. In this study, the researchers focused on one gene with a strong association, known as SHANK3. In addition to its link with autism, mutations or deletions of SHANK3 can also cause a related rare disorder called Phelan-McDermid Syndrome, whose most common characteristics include intellectual disability, impaired speech and sleep, and repetitive behaviors. The majority of these individuals are also diagnosed with autism spectrum disorder, as many of the symptoms overlap.

The protein encoded by SHANK3 is found in synapses — the junctions between brain cells that allow them to communicate with each other. It is particularly active in a part of the brain called the striatum, which is involved in motor planning, motivation, and habitual behavior. Feng and his colleagues have previously studied mice with Shank3 mutations and found that they show some of the traits associated with autism, including avoidance of social interaction and obsessive, repetitive behavior.

Although mouse studies can provide a great deal of information on the molecular underpinnings of disease, there are drawbacks to using them to study neurodevelopmental disorders, Feng says. In particular, mice lack the highly developed prefrontal cortex that is the seat of many uniquely primate traits, such as making decisions, sustaining focused attention, and interpreting social cues, which are often affected by brain disorders.

The recent development of the CRISPR genome-editing technique offered a way to engineer gene variants into macaque monkeys, which has previously been very difficult to do. CRISPR consists of a DNA-cutting enzyme called Cas9 and a short RNA sequence that guides the enzyme to a specific area of the genome. It can be used to disrupt genes or to introduce new genetic sequences at a particular location.

Members of the research team based in China, where primate reproductive technology is much more advanced than in the United States, injected the CRISPR components into fertilized macaque eggs, producing embryos that carried the Shank3 mutation.

Researchers at MIT, where much of the data was analyzed, found that the macaques with Shank3 mutations showed behavioral patterns similar to those seen in humans with the mutated gene. They tended to wake up frequently during the night, and they showed repetitive behaviors. They also engaged in fewer social interactions than other macaques.

Magnetic resonance imaging (MRI) scans also revealed similar patterns to humans with autism spectrum disorder. Neurons showed reduced functional connectivity in the striatum as well as the thalamus, which relays sensory and motor signals and is also involved in sleep regulation. Meanwhile, connectivity was strengthened in other regions, including the sensory cortex.

Michael Platt, a professor of neuroscience and psychology at the University of Pennsylvania, says the macaque models should help to overcome some of the limitations of studying neurological disorders in mice, whose behavioral symptoms and underlying neurobiology are often different from those seen in humans.

“Because the macaque model shows a much more complete recapitulation of the human behavioral phenotype, I think we should stand a much greater chance of identifying the degree to which any particular therapy, whether it’s a drug or any other intervention, addresses the core symptoms,” says Platt, who was not involved in the study.

Drug development

Within the next year, the researchers hope to begin testing treatments that may affect autism-related symptoms. They also hope to identify biomarkers, such as the distinctive functional brain connectivity patterns seen in MRI scans, that would help them to evaluate whether drug treatments are having an effect.

A similar approach could also be useful for studying other types of neurological disorders caused by well-characterized genetic mutations, such as Rett Syndrome and Fragile X Syndrome. Fragile X is the most common inherited form of intellectual disability in the world, affecting about 1 in 4,000 males and 1 in 8,000 females. Rett Syndrome, which is more rare and almost exclusively affects girls, produces severe impairments in language and motor skills and can also cause seizures and breathing problems.

“Given the limitations of mouse models, patients really need this kind of advance to bring them hope,” Feng says. “We don’t know whether this will succeed in developing treatments, but we will see in the next few years how this can help us to translate some of the findings from the lab to the clinic.”

The research was funded, in part, by the Shenzhen Overseas Innovation Team Project, the Guangdong Innovative and Entrepreneurial Research Team Program, the National Key R&D Program of China, the External Cooperation Program of the Chinese Academy of Sciences, the Patrick J. McGovern Foundation, the National Natural Science Foundation of China, the Shenzhen Science, Technology Commission, the James and Patricia Poitras Center for Psychiatric Disorders Research at the McGovern Institute at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute at MIT. The research facilities in China where the primate work was conducted are accredited by AAALAC International, a private, nonprofit organization that promotes the humane treatment of animals in science through voluntary accreditation and assessment programs.

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.

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.

How do neurons communicate (so quickly)?

by Sabbi Lall |

Neurons are the most fundamental unit of the nervous system, and yet, researchers are just beginning to understand how they perform the complex computations that underlie our behavior. We asked Boaz Barak, previously a postdoc in Guoping Feng’s lab at the McGovern Institute and now Senior Lecturer at the School of Psychological Sciences and Sagol School of Neuroscience at Tel Aviv University, to unpack the basics of neuron communication for us.

“Neurons communicate with each other through electrical and chemical signals,” explains Barak. “The electrical signal, or action potential, runs from the cell body area to the axon terminals, through a thin fiber called axon. Some of these axons can be very long and most of them are very short. The electrical signal that runs along the axon is based on ion movement. The speed of the signal transmission is influenced by an insulating layer called myelin,” he explains.

Myelin is a fatty layer formed, in the vertebrate central nervous system, by concentric wrapping of oligodendrocyte cell processes around axons. The term “myelin” was coined in 1854 by Virchow (whose penchant for Greek and for naming new structures also led to the terms amyloid, leukemia, and chromatin). In more modern images, the myelin sheath is beautifully visible as concentric spirals surrounding the “tube” of the axon itself. Neurons in the peripheral nervous system are also myelinated, but the cells responsible for myelination are Schwann cells, rather than oligodendrocytes.

“Neurons communicate with each other through electrical and chemical signals,” explains Boaz Barak.

“Myelin’s main purpose is to insulate the neuron’s axon,” Barak says. “It speeds up conductivity and the transmission of electrical impulses. Myelin promotes fast transmission of electrical signals mainly by affecting two factors: 1) increasing electrical resistance, or reducing leakage of the electrical signal and ions along the axon, “trapping” them inside the axon and 2) decreasing membrane capacitance by increasing the distance between conducting materials inside the axon (intracellular fluids) and outside of it (extracellular fluids).”

Adjacent sections of axon in a given neuron are each surrounded by a distinct myelin sheath. Unmyelinated gaps between adjacent ensheathed regions of the axon are called Nodes of Ranvier, and are critical to fast transmission of action potentials, in what is termed “saltatory conduction.” A useful analogy is that if the axon itself is like an electrical wire, myelin is like insulation that surrounds it, speeding up impulse propagation, and overcoming the decrease in action potential size that would occur during transmission along a naked axon due to electrical signal leakage, how the myelin sheath promotes fast transmission that allows neurons to transmit information long distances in a timely fashion in the vertebrate nervous system.

Myelin seems to be critical to healthy functioning of the nervous system; in fact, disruptions in the myelin sheath have been linked to a variety of disorders.

Former McGovern postdoc, Boaz Barak. Photo: Justin Knight

“Abnormal myelination can arise from abnormal development caused by genetic alterations,” Barak explains further. “Demyelination can even occur, due to an autoimmune response, trauma, and other causes. In neurological conditions in which myelin properties are abnormal, as in the case of lesions or plaques, signal transmission can be affected. For example, defects in myelin can lead to lack of neuronal communication, as there may be a delay or reduction in transmission of electrical and chemical signals. Also, in cases of abnormal myelination, it is possible that the synchronicity of brain region activity might be affected, for example, leading to improper actions and behaviors.”

Researchers are still working to fully understand the role of myelin in disorders. Myelin has a long history of being evasive though, with its origins in the central nervous system being unclear for many years. For a period of time, the origin of myelin was thought to be the axon itself, and it was only after initial discovery (by Robertson, 1899), re-discovery (Del Rio-Hortega, 1919), and skepticism followed by eventual confirmation, that the role of oligodendrocytes in forming myelin became clear. With modern imaging and genetic tools, we should be able to increasingly understand its role in the healthy, as well as a compromised, nervous system.

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