Author: Anne Trafton

Study reveals a basis for attention deficits

Anne Trafton |

More than 3 million Americans suffer from attention deficit hyperactivity disorder (ADHD), a condition that usually emerges in childhood and can lead to difficulties at school or work.

A new study from MIT and New York University links ADHD and other attention difficulties to the brain’s thalamic reticular nucleus (TRN), which is responsible for blocking out distracting sensory input. In a study of mice, the researchers discovered that a gene mutation found in some patients with ADHD produces a defect in the TRN that leads to attention impairments.

The findings suggest that drugs boosting TRN activity could improve ADHD symptoms and possibly help treat other disorders that affect attention, including autism.

“Understanding these circuits may help explain the converging mechanisms across these disorders. For autism, schizophrenia, and other neurodevelopmental disorders, it seems like TRN dysfunction may be involved in some patients,” says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute.

Feng and Michael Halassa, an assistant professor of psychiatry, neuroscience, and physiology at New York University, are the senior authors of the study, which appears in the March 23 online edition of Nature. The paper’s lead authors are MIT graduate student Michael Wells and NYU postdoc Ralf Wimmer.

Paying attention

Feng, Halassa, and their colleagues set out to study a gene called Ptchd1, whose loss can produce attention deficits, hyperactivity, intellectual disability, aggression, and autism spectrum disorders. Because the gene is carried on the X chromosome, most individuals with these Ptchd1-related effects are male.

In mice, the researchers found that the part of the brain most affected by the loss of Ptchd1 is the TRN, which is a group of inhibitory nerve cells in the thalamus. It essentially acts as a gatekeeper, preventing unnecessary information from being relayed to the brain’s cortex, where higher cognitive functions such as thought and planning occur.

“We receive all kinds of information from different sensory regions, and it all goes into the thalamus,” Feng says. “All this information has to be filtered. Not everything we sense goes through.”

If this gatekeeper is not functioning properly, too much information gets through, allowing the person to become easily distracted or overwhelmed. This can lead to problems with attention and difficulty in learning.

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, including aggression, hyperactivity, attention deficit, and motor impairments. When the Ptchd1 gene was knocked out only in the TRN, the mice showed only hyperactivity and attention deficits.

Toward new treatments

At the cellular level, the researchers found that the Ptchd1 mutation disrupts channels that carry potassium ions, which prevents TRN neurons from being able to sufficiently inhibit thalamic output to the cortex. The researchers were also able restore the neurons’ normal function with a compound that boosts activity of the potassium channel. This intervention reversed the TRN-related symptoms but not any of the symptoms that appear to be caused by deficits of some other circuit.

“The authors convincingly demonstrate that specific behavioral consequences of the Ptchd1 mutation — attention and sleep — arise from an alteration of a specific protein in a specific brain region, the thalamic reticular nucleus. These findings provide a clear and straightforward pathway from gene to behavior and suggest a pathway toward novel treatments for neurodevelopmental disorders such as autism,” says Joshua Gordon, an associate professor of psychiatry at Columbia University, who was not involved in the research.

Most people with ADHD are now treated with psychostimulants such as Ritalin, which are effective in about 70 percent of patients. Feng and Halassa are now working on identifying genes that are specifically expressed in the TRN in hopes of developing drug targets that would modulate TRN activity. Such drugs may also help patients who don’t have the Ptchd1 mutation, because their symptoms are also likely caused by TRN impairments, Feng says.

The researchers are also investigating when Ptchd1-related problems in the TRN arise and at what point they can be reversed. And, they hope to discover how and where in the brain Ptchd1 mutations produce other abnormalities, such as aggression.

The research was funded by the Simons Foundation Autism Research Initiative, the National Institutes of Health, the Poitras Center for Affective Disorders Research, and the Stanley Center for Psychiatric Research at the Broad Institute.

Toward a better understanding of the brain

Anne Trafton |

In 2011, about a month after joining the MIT faculty, Feng Zhang attended a talk by Harvard Medical School Professor Michael Gilmore, who studies the pathogenic bacterium Enteroccocus. The scientist mentioned that these bacteria protect themselves from viruses with DNA-cutting enzymes known as nucleases, which are part of a defense system known as CRISPR.

“I had no idea what CRISPR was but I was interested in nucleases,” Zhang says. “I went to look up CRISPR, and that’s when I realized you might be able to engineer it for use for genome editing.”

Zhang devoted himself to adapting the system to edit genes in mammalian cells and recruited new members to his nascent lab at the Broad Institute of MIT and Harvard to work with him on this project. In January 2013, they reported their success in the journal Science.

Since then, scientists in fields from medicine to plant biology have begun using CRISPR to study gene function and investigate the possibility of correcting faulty genes that cause disease. Zhang now heads a lab of 19 scientists who continue to develop the system and pursue applications of genome editing, especially in neuroscience.

“The goal is to try to make our lives better by developing new technologies and using them to understand biological systems so that we can improve our treatment of disease and our quality of life,” says Zhang, who is also a member of MIT’s McGovern Institute for Brain Research and recently earned tenure in MIT’s Departments of Biological Engineering and Brain and Cognitive Sciences.

Understanding the brain

Growing up in Des Moines, Iowa, where his parents moved from China when he was 11, Zhang had plenty of opportunities to feed his interest in science. He participated in Science Bowl competitions and took special Saturday science classes, where he got his first introduction to molecular biology. Experiments such as extracting DNA from strawberries and transforming bacteria with genes for drug resistance whetted his appetite for genetic engineering, which was further stimulated by a showing of “Jurassic Park.”

“That really caught my attention,” he recalls. “It didn’t seem that far-fetched. I guess that’s what makes it good science fiction. It kind of tantalizes your imagination.”

As a sophomore in high school, Zhang began working with Dr. John Levy in a gene therapy lab at the Iowa Methodist Medical Center in Des Moines, where he studied green fluorescent protein (GFP). Scientists had recently figured out how to adapt this naturally occurring protein to tag and image proteins inside living cells. Zhang used it to track viral proteins within infected cells to determine how the proteins assemble to form new viruses. He also worked on a project to adapt GFP for a different purpose — protecting DNA from damage induced by ultraviolet light.

At Harvard University, where he earned his undergraduate degree, Zhang majored in chemistry and physics and did research under the mentorship of Xiaowei Zhuang, a professor of chemistry and chemical biology. “I was always interested in biology but I felt that it’s important to get a solid training in chemistry and physics,” he says.

While Zhang was at Harvard, a close friend was severely affected by a psychiatric disorder. That experience made Zhang think about whether such disorders could be approached just like cancer or heart disease, if only scientists knew more about their underlying causes.

“The difference is we’re at a much earlier stage of understanding psychiatric diseases. That got me really interested in trying to understand more about how the brain works,” he says.

At Stanford University, where Zhang earned his PhD in chemistry, he worked with Karl Deisseroth, who was just starting his lab with a focus on developing new technology for studying the brain. Zhang was the second student to join the lab, and he began working on a protein called channelrhodopsin, which he and Deisseroth believed held potential for engineering mammalian cells to respond to light.

The resulting technique, known as optogenetics, has transformed biological research. Collaborating with Edward Boyden, a member of the Deisseroth lab who is now a professor at MIT, Zhang adapted channelrhodopsin so that it could be inserted into neurons and make them light-sensitive. Using this approach, neuroscientists can now selectively activate and de-activate specific neurons in the brain, allowing them to map brain circuits and investigate how disruption of those circuits causes disease.

Better gene editing

After leaving Stanford, Zhang spent a year as a junior fellow at the Harvard Society of Fellows, studying brain development with Professor Paola Arlotta and collaborating with Professor George Church. That’s when he began to focus on gene editing — a type of genetic engineering that allows researchers to selectively delete a gene or replace it with a new one.

He began with zinc finger nucleases — enzymes that can be designed to target and cut specific DNA sequences. However, these proteins turned out to be challenging to work with, in part because it is so time-consuming to design a new protein for each possible DNA target.

That led Zhang to experiment with a different type of nucleases known as transcription activator-like effector nucleases (TALENs), but these also proved laborious to work with. “Learning how to use them is a project on its own,” Zhang says.

When he heard about CRISPR in early 2011, Zhang sensed that harnessing the natural bacterial process held the potential to solve many of the challenges associated with those earlier gene-editing techniques. CRISPR includes a nuclease called Cas9, which can be guided to the correct genetic target by RNA molecules known as guide strands. For each target, scientists need only design and synthesize a new RNA guide, which is much simpler than creating new TALEN and zinc finger proteins.

Since his first CRISPR paper in 2013, Zhang’s lab has devised many enhancements to the original system, such as making the targeting more precise and preventing unintended cuts in the wrong locations. They also recently reported another type of CRISPR system based on a different nuclease called Cpf1, which is simpler and has unique features that further expand the genome editing toolbox.

Zhang’s lab has become a hub for CRISPR research worldwide. It has shared CRISPR-Cas9 components in response to nearly 30,000 requests from academic laboratories around the world and has trained thousands of researchers in the use of CRISPR-Cas9 genome-editing technology through in-person events and online opportunities.

His team is now working on creating animal models of autism, Alzheimer’s, and other neurological disorders, and in the long term, they hope to develop CRISPR for use in humans to potentially cure diseases caused by defective genes.

“There are many genetic diseases that we don’t have any way of treating and this could be one way, but we still have to do a lot of work,” Zhang says.

Neuroscientists discover a gene that controls worms’ behavioral state

Anne Trafton |

In a study of worms, MIT neuroscientists have discovered a gene that plays a critical role in controlling the switch between alternative behavioral states, which for humans include hunger and fullness, or sleep and wakefulness.

This gene, which the researchers dubbed vps-50, helps to regulate neuropeptides — tiny proteins that carry messages between neurons or from neurons to other cells. This kind of signaling is important for controlling physiology and behavior in animals, including humans. Deletions of the human counterpart of the vps-50 gene have been found in some people with autism.

“Given what is reported in this paper about how the gene works, coupled with findings by others concerning the genetics of autism, we suggest that the disruption of the function of this gene could promote autism,” says H. Robert Horvitz, the David H. Koch Professor of Biology and a member of MIT’s McGovern Institute for Brain Research.

Horvitz and Martha Constantine-Paton, an MIT professor of brain and cognitive sciences and member of the McGovern Institute, are the senior authors of the study, which appears in the March 3 issue of the journal Current Biology. The paper’s lead authors are former MIT postdocs Nicolas Paquin and Yasunobu Muruta.

Influencing behavior

Neuropeptides, which are involved in brain functions such as reward, metabolism, and learning and memory, are released from cellular structures called dense-core vesicles.

In the new study, the researchers found that the vps-50 gene encodes a protein that is important in the generation of such vesicles and in the release of neuropeptides from them.

They discovered the protein in the worm Caenorhabditis elegans, where it is found primarily in nerve cells. In those cells, vps-50 associates with both synaptic vesicles and dense-core vesicles, which release neurotransmitters such as dopamine and serotonin. The researchers showed that vps-50 is required for maturation of the dense-core vesicles and also regulates activity of a proton pump that acidifies the vesicles. Without the proper acidity level, the vesicles’ ability to produce neuropeptides is impaired.

The researchers also found distinctive behavioral effects in C. elegans worms, which normally change their speed depending on food availability and whether they have recently eaten.

“Worms are the fastest when food (bacteria) is absent, presumably because they are looking for food,” Paquin says. “When they reach food, they slow down, but when you make them hungry for 30 minutes before putting them on food, they slow down even more.”

Worms lacking vps-50 behaved as if they were hungry — moving slowly through a food-rich area even when they were well fed, the researchers found. This suggests that the worms without vps-50 are unable to signal that they are full and continue to behave as if they are hungry. The researchers also found an equivalent gene in mice and showed that it can compensate for loss of the worm version of vps-50, showing that the two genes have the same function.

Human link

One important question raised by the study is how the mouse and human versions of vps-50 affect behavior in those animals, Horvitz says. Although this study focused on switching between hunger and fullness, neuropeptide signaling has been previously shown to control other alternative behaviors such as sleep and wakefulness and also to control social behaviors, such as anxiety.

The researchers suggest that studies of vps-50 might shed light on aspects of autism, because the human version of the gene is missing in some people with autism. Furthermore, a protein known as UNC-31, which is also located in dense-core vesicles has also been linked with autism in humans and mice. When mutated in worms, UNC-31 produces behavioral effects similar to those caused by vps-50 mutations.

“For these reasons, we hope that our studies of vps-50 will provide insights into human neuropsychiatric disorders,” Horvitz says.

The research was funded by the National Institutes of Health and the Simons Center for the Social Brain at MIT.

McGovern neuroscientists reverse autism symptoms

Anne Trafton |

Autism has diverse genetic causes, most of which are still unknown. About 1 percent of people with autism are missing a gene called Shank3, which is critical for brain development. Without this gene, individuals develop typical autism symptoms including repetitive behavior and avoidance of social interactions.

In a study of mice, MIT researchers have now shown that they can reverse some of those behavioral symptoms by turning the gene back on later in life, allowing the brain to properly rewire itself.

“This suggests that even in the adult brain we have profound plasticity to some degree,” says Guoping Feng, an MIT professor of brain and cognitive sciences. “There is more and more evidence showing that some of the defects are indeed reversible, giving hope that we can develop treatment for autistic patients in the future.”

Feng, who is the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute, is the senior author of the study, which appears in the Feb. 17 issue of Nature. The paper’s lead authors are former MIT graduate student Yuan Mei and former Broad Institute visiting graduate student Patricia Monteiro, now at the University of Coimbra in Portugal.

Boosting communication

The Shank3 protein is found in synapses — the connections that allow neurons to communicate with each other. As a scaffold protein, Shank3 helps to organize the hundreds of other proteins that are necessary to coordinate a neuron’s response to incoming signals.

Studying rare cases of defective Shank3 can help scientists gain insight into the neurobiological mechanisms of autism. Missing or defective Shank3 leads to synaptic disruptions that can produce autism-like symptoms in mice, including compulsive behavior, avoidance of social interaction, and anxiety, Feng has previously found. He has also shown that some synapses in these mice, especially in a part of the brain called the striatum, have a greatly reduced density of dendritic spines — small buds on neurons’ surfaces that help with the transmission of synaptic signals.

In the new study, Feng and colleagues genetically engineered mice so that their Shank3 gene was turned off during embryonic development but could be turned back on by adding tamoxifen to the mice’s diet.
When the researchers turned on Shank3 in young adult mice (two to four and a half months after birth), they were able to eliminate the mice’s repetitive behavior and their tendency to avoid social interaction. At the cellular level, the team found that the density of dendritic spines dramatically increased in the striatum of treated mice, demonstrating the structural plasticity in the adult brain.

However, the mice’s anxiety and some motor coordination symptoms did not disappear. Feng suspects that these behaviors probably rely on circuits that were irreversibly formed during early development.
When the researchers turned on Shank3 earlier in life, only 20 days after birth, the mice’s anxiety and motor coordination did improve. The researchers are now working on defining the critical periods for the formation of these circuits, which could help them determine the best time to try to intervene.

“Some circuits are more plastic than others,” Feng says. “Once we understand which circuits control each behavior and understand what exactly changed at the structural level, we can study what leads to these permanent defects, and how we can prevent them from happening.”

Gordon Fishell, a professor of neuroscience at New York University School of Medicine, praises the study’s “elegant approach” and says it represents a major advance in understanding the circuitry and cellular physiology that underlie autism. “The combination of behavior, circuits, physiology, and genetics is state-of-the art,” says Fishell, who was not involved in the research. “Moreover, Dr. Feng’s demonstration that restoration of Shank3 function reverses autism symptoms in adult mice suggests that gene therapy may ultimately prove an effective therapy for this disease.”

Early intervention

For the small population of people with Shank3 mutations, the findings suggest that new genome-editing techniques could in theory be used to repair the defective Shank3 gene and improve these individuals’ symptoms, even later in life. These techniques are not yet ready for use in humans, however.

Feng believes that scientists may also be able to develop more general approaches that would apply to a larger population. For example, if the researchers can identify defective circuits that are specific for certain behavioral abnormalities in some autism patients, and figure out how to modulate those circuits’ activity, that could also help other people who may have defects in the same circuits even though the problem arose from a different genetic mutation.

“That’s why it’s important in the future to identify what subtype of neurons are defective and what genes are expressed in these neurons, so we can use them as a target without affecting the whole brain,” Feng says.

How maternal inflammation might lead to autism-like behavior

Anne Trafton |

In 2010, a large study in Denmark found that women who suffered an infection severe enough to require hospitalization while pregnant were much more likely to have a child with autism (even though the overall risk of delivering a child with autism remained low).

Now research from MIT, the University of Massachusetts Medical School, the University of Colorado, and New York University Langone Medical Center reveals a possible mechanism for how this occurs. In a study of mice, the researchers found that immune cells activated in the mother during severe inflammation produce an immune effector molecule called IL-17 that appears to interfere with brain development.

The researchers also found that blocking this signal could restore normal behavior and brain structure.

“In the mice, we could treat the mother with antibodies that block IL-17 after inflammation had set in, and that could ameliorate some of the behavioral symptoms that were observed in the offspring. However, we don’t know yet how much of that could be translated into humans,” says Gloria Choi, an assistant professor of brain and cognitive sciences, a member of MIT’s McGovern Institute for Brain Research, and the lead author of the study, which appears in the Jan. 28 online edition of Science.

Finding the link

In the 2010 study, which included all children born in Denmark between 1980 and 2005, severe infections (requiring hospitalization) that correlated with autism risk included influenza, viral gastroenteritis, and urinary tract infections. Severe viral infections during the first trimester translated to a threefold risk for autism, and serious bacterial infections during the second trimester were linked with a 1.5-fold increase in risk.

Choi and her husband, Jun Huh, were graduate students at Caltech when they first heard about this study during a lecture by Caltech professor emeritus Paul Patterson, who had discovered that an immune signaling molecule called IL-6 plays a role in the link between infection and autism-like behaviors in rodents.

Huh, now an assistant professor at the University of Massachusetts Medical School and one of the paper’s senior authors, was studying immune cells called Th17 cells, which are well known for contributing to autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases, and rheumatoid arthritis. He knew that Th17 cells are activated by IL-6, so he wondered if these cells might also be involved in cases of animal models of autism associated with maternal infection.

“We wanted to find the link,” Choi says. “How do you go all the way from the immune system in the mother to the child’s brain?”

Choi and Huh launched the study as postdocs at Columbia University and New York University School of Medicine, respectively. Working with Dan Littman, a professor of molecular immunology at NYU and one of the paper’s senior authors, they began by injecting pregnant mice with a synthetic analog of double-stranded RNA, which activates the immune system in a similar way to viruses.

Confirming the results of previous studies in mice, the researchers found behavioral abnormalities in the offspring of the infected mothers, including deficits in sociability, repetitive behaviors, and abnormal communication. They then disabled Th17 cells in the mothers before inducing inflammation and found that the offspring mice did not show those behavioral abnormalities. The abnormalities also disappeared when the researchers gave the infected mothers an antibody that blocks IL-17, which is produced by Th17 cells.

The researchers next asked how IL-17 might affect the developing fetus. They found that brain cells in the fetuses of mothers experiencing inflammation express receptors for IL-17, and they believe that exposure to the chemical provokes cells to produce even more receptors for IL-17, amplifying its effects.

In the developing mice, the researchers found irregularities in the normally well-defined layers of cells in the brain’s cortex, where most cognition and sensory processing take place. These patches of irregular structure appeared in approximately the same cortical regions in all of the affected offspring, but they did not occur when the mothers’ Th17 cells were blocked.

Disorganized cortical layers have also been found in studies of human patients with autism.

Preventing autism

The researchers are now investigating whether and how these cortical patches produce the behavioral abnormalities seen in the offspring.

“We’ve shown correlation between these cortical patches and behavioral abnormalities, but we don’t know whether the cortical patches actually are responsible for the behavioral abnormalities,” Choi says. “And if it is responsible, what is being dysregulated within this patch to produce this behavior?”

The researchers hope their work may lead to a way to reduce the chances of autism developing in the children of women who experience severe infections during pregnancy. They also plan to investigate whether genetic makeup influences mice’s susceptibility to maternal inflammation, because autism is known to have a very strong genetic component.

Charles Hoeffer, a professor of integrative physiology at the University of Colorado, is a senior author of the paper, and other authors include MIT postdoc Yeong Yim, NYU graduate student Helen Wong, UMass Medical School visiting scholars Sangdoo Kim and Hyunju Kim, and NYU postdoc Sangwon Kim.

Diagnosing depression before it starts

Anne Trafton |

A new brain imaging study from MIT and Harvard Medical School may lead to a screen that could identify children at high risk of developing depression later in life.

In the study, the researchers found distinctive brain differences in children known to be at high risk because of family history of depression. The finding suggests that this type of scan could be used to identify children whose risk was previously unknown, allowing them to undergo treatment before developing depression, says John Gabrieli, the Grover M. Hermann Professor in Health Sciences and Technology and a professor of brain and cognitive sciences at MIT.

“We’d like to develop the tools to be able to identify people at true risk, independent of why they got there, with the ultimate goal of maybe intervening early and not waiting for depression to strike the person,” says Gabrieli, an author of the study, which appears in the journal Biological Psychiatry.

Early intervention is important because once a person suffers from an episode of depression, they become more likely to have another. “If you can avoid that first bout, maybe it would put the person on a different trajectory,” says Gabrieli, who is a member of MIT’s McGovern Institute for Brain Research.

The paper’s lead author is McGovern Institute postdoc Xiaoqian Chai, and the senior author is Susan Whitfield-Gabrieli, a research scientist at the McGovern Institute.

Distinctive patterns

The study also helps to answer a key question about the brain structures of depressed patients. Previous imaging studies have revealed two brain regions that often show abnormal activity in these patients: the subgenual anterior cingulate cortex (sgACC) and the amygdala. However, it was unclear if those differences caused depression or if the brain changed as the result of a depressive episode.

To address that issue, the researchers decided to scan brains of children who were not depressed, according to their scores on a commonly used diagnostic questionnaire, but had a parent who had suffered from the disorder. Such children are three times more likely to become depressed later in life, usually between the ages of 15 and 30.

Gabrieli and colleagues studied 27 high-risk children, ranging in age from eight to 14, and compared them with a group of 16 children with no known family history of depression.

Using functional magnetic resonance imaging (fMRI), the researchers measured synchronization of activity between different brain regions. Synchronization patterns that emerge when a person is not performing any particular task allow scientists to determine which regions naturally communicate with each other.

The researchers identified several distinctive patterns in the at-risk children. The strongest of these links was between the sgACC and the default mode network — a set of brain regions that is most active when the mind is unfocused. This abnormally high synchronization has also been seen in the brains of depressed adults.

The researchers also found hyperactive connections between the amygdala, which is important for processing emotion, and the inferior frontal gyrus, which is involved in language processing. Within areas of the frontal and parietal cortex, which are important for thinking and decision-making, they found lower than normal connectivity.

Cause and effect

These patterns are strikingly similar to those found in depressed adults, suggesting that these differences arise before depression occurs and may contribute to the development of the disorder, says Ian Gotlib, a professor of psychology at Stanford University.

“The findings are consistent with an explanation that this is contributing to the onset of the disease,” says Gotlib, who was not involved in the research. “The patterns are there before the depressive episode and are not due to the disorder.”

The MIT team is continuing to track the at-risk children and plans to investigate whether early treatment might prevent episodes of depression. They also hope to study how some children who are at high risk manage to avoid the disorder without treatment.

Other authors of the paper are Dina Hirshfeld-Becker, an associate professor of psychiatry at Harvard Medical School; Joseph Biederman, director of pediatric psychopharmacology at Massachusetts General Hospital (MGH); Mai Uchida, an assistant professor of psychiatry at Harvard Medical School; former MIT postdoc Oliver Doehrmann; MIT graduate student Julia Leonard; John Salvatore, a former McGovern technical assistant; MGH research assistants Tara Kenworthy and Elana Kagan; Harvard Medical School postdoc Ariel Brown; and former MIT technical assistant Carlo de los Angeles.

Study finds altered brain chemistry in people with autism

Anne Trafton |

MIT and Harvard University neuroscientists have found a link between a behavioral symptom of autism and reduced activity of a neurotransmitter whose job is to dampen neuron excitation. The findings suggest that drugs that boost the action of this neurotransmitter, known as GABA, may improve some of the symptoms of autism, the researchers say.

Brain activity is controlled by a constant interplay of inhibition and excitation, which is mediated by different neurotransmitters. GABA is one of the most important inhibitory neurotransmitters, and studies of animals with autism-like symptoms have found reduced GABA activity in the brain. However, until now, there has been no direct evidence for such a link in humans.

“This is the first connection in humans between a neurotransmitter in the brain and an autistic behavioral symptom,” says Caroline Robertson, a postdoc at MIT’s McGovern Institute for Brain Research and a junior fellow of the Harvard Society of Fellows. “It’s possible that increasing GABA would help to ameliorate some of the symptoms of autism, but more work needs to be done.”

Robertson is the lead author of the study, which appears in the Dec. 17 online edition of Current Biology. The paper’s senior author is Nancy Kanwisher, the Walter A. Rosenblith Professor of Brain and Cognitive Sciences and a member of the McGovern Institute. Eva-Maria Ratai, an assistant professor of radiology at Massachusetts General Hospital, also contributed to the research.

Too little inhibition

Many symptoms of autism arise from hypersensitivity to sensory input. For example, children with autism are often very sensitive to things that wouldn’t bother other children as much, such as someone talking elsewhere in the room, or a scratchy sweater. Scientists have speculated that reduced brain inhibition might underlie this hypersensitivity by making it harder to tune out distracting sensations.

In this study, the researchers explored a visual task known as binocular rivalry, which requires brain inhibition and has been shown to be more difficult for people with autism. During the task, researchers show each participant two different images, one to each eye. To see the images, the brain must switch back and forth between input from the right and left eyes.

For the participant, it looks as though the two images are fading in and out, as input from each eye takes its turn inhibiting the input coming in from the other eye.

“Everybody has a different rate at which the brain naturally oscillates between these two images, and that rate is thought to map onto the strength of the inhibitory circuitry between these two populations of cells,” Robertson says.

She found that nonautistic adults switched back and forth between the images nine times per minute, on average, and one of the images fully suppressed the other about 70 percent of the time. However, autistic adults switched back and forth only half as often as nonautistic subjects, and one of the images fully suppressed the other only about 50 percent of the time.

Performance on this task was also linked to patients’ scores on a clinical evaluation of communication and social interaction used to diagnose autism: Worse symptoms correlated with weaker inhibition during the visual task.

The researchers then measured GABA activity using a technique known as magnetic resonance spectroscopy, as autistic and typical subjects performed the binocular rivalry task. In nonautistic participants, higher levels of GABA correlated with a better ability to suppress the nondominant image. But in autistic subjects, there was no relationship between performance and GABA levels. This suggests that GABA is present in the brain but is not performing its usual function in autistic individuals, Robertson says.

“GABA is not reduced in the autistic brain, but the action of this inhibitory pathway is reduced,” she says. “The next step is figuring out which part of the pathway is disrupted.”

“This is a really great piece of work,” says Richard Edden, an associate professor of radiology at the Johns Hopkins University School of Medicine. “The role of inhibitory dysfunction in autism is strongly debated, with different camps arguing for elevated and reduced inhibition. This kind of study, which seeks to relate measures of inhibition directly to quantitative measures of function, is what we really to need to tease things out.”

Early diagnosis

In addition to offering a possible new drug target, the new finding may also help researchers develop better diagnostic tools for autism, which is now diagnosed by evaluating children’s social interactions. To that end, Robertson is investigating the possibility of using EEG scans to measure brain responses during the binocular rivalry task.

“If autism does trace back on some level to circuitry differences that affect the visual cortex, you can measure those things in a kid who’s even nonverbal, as long as he can see,” she says. “We’d like it to move toward being useful for early diagnostic screenings.”

Music in the brain

Anne Trafton |

Scientists have long wondered if the human brain contains neural mechanisms specific to music perception. Now, for the first time, MIT neuroscientists have identified a neural population in the human auditory cortex that responds selectively to sounds that people typically categorize as music, but not to speech or other environmental sounds.

“It has been the subject of widespread speculation,” says Josh McDermott, the Frederick A. and Carole J. Middleton Assistant Professor of Neuroscience in the Department of Brain and Cognitive Sciences at MIT. “One of the core debates surrounding music is to what extent it has dedicated mechanisms in the brain and to what extent it piggybacks off of mechanisms that primarily serve other functions.”

The finding was enabled by a new method designed to identify neural populations from functional magnetic resonance imaging (fMRI) data. Using this method, the researchers identified six neural populations with different functions, including the music-selective population and another set of neurons that responds selectively to speech.

“The music result is notable because people had not been able to clearly see highly selective responses to music before,” says Sam Norman-Haignere, a postdoc at MIT’s McGovern Institute for Brain Research.

“Our findings are hard to reconcile with the idea that music piggybacks entirely on neural machinery that is optimized for other functions, because the neural responses we see are highly specific to music,” says Nancy Kanwisher, the Walter A. Rosenblith Professor of Cognitive Neuroscience at MIT and a member of MIT’s McGovern Institute for Brain Research.

Norman-Haignere is the lead author of a paper describing the findings in the Dec. 16 online edition of Neuron. McDermott and Kanwisher are the paper’s senior authors.

Mapping responses to sound

For this study, the researchers scanned the brains of 10 human subjects listening to 165 natural sounds, including different types of speech and music, as well as everyday sounds such as footsteps, a car engine starting, and a telephone ringing.

The brain’s auditory system has proven difficult to map, in part because of the coarse spatial resolution of fMRI, which measures blood flow as an index of neural activity. In fMRI, “voxels” — the smallest unit of measurement — reflect the response of hundreds of thousands or millions of neurons.

“As a result, when you measure raw voxel responses you’re measuring something that reflects a mixture of underlying neural responses,” Norman-Haignere says.

To tease apart these responses, the researchers used a technique that models each voxel as a mixture of multiple underlying neural responses. Using this method, they identified six neural populations, each with a unique response pattern to the sounds in the experiment, that best explained the data.

“What we found is we could explain a lot of the response variation across tens of thousands of voxels with just six response patterns,” Norman-Haignere says.

One population responded most to music, another to speech, and the other four to different acoustic properties such as pitch and frequency.

The key to this advance is the researchers’ new approach to analyzing fMRI data, says Josef Rauschecker, a professor of physiology and biophysics at Georgetown University.

“The whole field is interested in finding specialized areas like those that have been found in the visual cortex, but the problem is the voxel is just not small enough. You have hundreds of thousands of neurons in a voxel, and how do you separate the information they’re encoding? This is a study of the highest caliber of data analysis,” says Rauschecker, who was not part of the research team.

Layers of sound processing

The four acoustically responsive neural populations overlap with regions of “primary” auditory cortex, which performs the first stage of cortical processing of sound. Speech and music-selective neural populations lie beyond this primary region.

“We think this provides evidence that there’s a hierarchy of processing where there are responses to relatively simple acoustic dimensions in this primary auditory area. That’s followed by a second stage of processing that represents more abstract properties of sound related to speech and music,” Norman-Haignere says.

The researchers believe there may be other brain regions involved in processing music, including its emotional components. “It’s inappropriate at this point to conclude that this is the seat of music in the brain,” McDermott says. “This is where you see most of the responses within the auditory cortex, but there’s a lot of the brain that we didn’t even look at.”

Kanwisher also notes that “the existence of music-selective responses in the brain does not imply that the responses reflect an innate brain system. An important question for the future will be how this system arises in development: How early it is found in infancy or childhood, and how dependent it is on experience?”

The researchers are now investigating whether the music-selective population identified in this study contains subpopulations of neurons that respond to different aspects of music, including rhythm, melody, and beat. They also hope to study how musical experience and training might affect this neural population.

 

How a single gene contributes to autism and schizophrenia

Anne Trafton |

Although it is known that psychiatric disorders have a strong genetic component, untangling the web of genes contributing to each disease is a daunting task. Scientists have found hundreds of genes that are mutated in patients with disorders such as autism, but each patient usually has only a handful of these variations.

To further complicate matters, some of these genes contribute to more than one disorder. One such gene, known as Shank3, has been linked to both autism and schizophrenia.

MIT neuroscientists have now shed some light on how a single gene can play a role in more than one disease. In a study appearing in the Dec. 10 online edition of Neuron, they revealed that two different mutations of the Shank3 gene produce some distinct molecular and behavioral effects in mice.

“This study gives a glimpse into the mechanism by which different mutations within the same gene can cause distinct defects in the brain, and may help to explain how they may contribute to different disorders,” says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT, a member of MIT’s McGovern Institute for Brain Research, a member of the Stanley Center for Psychiatric Research at the Broad Institute, and the senior author of the study.

The findings also suggest that identifying the brain circuits affected by mutated genes linked to psychiatric disease could help scientists develop more personalized treatments for patients in the future, Feng says.

The paper’s lead authors are McGovern Institute research scientist Yang Zhou, graduate students Tobias Kaiser and Xiangyu Zhang, and research affiliate Patricia Monteiro.

Disrupted communication

The protein encoded by Shank3 is found in synapses — the junctions between neurons that allow them to communicate with each other. Shank3 is a scaffold protein, meaning it helps to organize hundreds of other proteins clustered on the postsynaptic cell membrane, which are required to coordinate the cell’s response to signals from the presynaptic cell.

In 2011, Feng and colleagues showed that by deleting Shank3 in mice they could induce two of the most common traits of autism — avoidance of social interaction, and compulsive, repetitive behavior. A year earlier, researchers at the University of Montreal identified a Shank3 mutation in patients suffering from schizophrenia, which is characterized by hallucinations, cognitive impairment, and abnormal social behavior.

Feng wanted to find out how these two different mutations in the Shank3 gene could play a role in such different disorders. To do that, he and his colleagues engineered mice with each of the two mutations: The schizophrenia-related mutation results in a truncated version of the Shank3 protein, while the autism-linked mutation leads to a total loss of the Shank3 protein.

Behaviorally, the mice shared many defects, including strong anxiety. However, the mice with the autism mutation had very strong compulsive behavior, manifested by excessive grooming, which was rarely seen in mice with the schizophrenia mutation.

In the mice with the schizophrenia mutation, the researchers saw a type of behavior known as social dominance. These mice trimmed the whiskers and facial hair of the genetically normal mice sharing their cages, to an extreme extent. This is a typical way for mice to display their social dominance, Feng says.

By activating the mutations in different parts of the brain and at different stages of development, the researchers found that the two mutations affected brain circuits in different ways. The autism mutation exerted its effects early in development, primarily in a part of the brain known as the striatum, which is involved in coordinating motor planning, motivation, and habitual behavior. Feng believes that disruption of synapses in the striatum contributes to the compulsive behavior seen in those mice.

In mice carrying the schizophrenia-associated mutation, early development was normal, suggesting that truncated Shank3 can adequately fill in for the normal version during this stage. However, later in life, the truncated version of Shank3 interfered with synaptic functions and connections in the brain’s cortex, where executive functions such as thought and planning occur. This suggests that different segments of the protein — including the stretch that is missing in the schizophrenia-linked mutation — may be crucial for different roles, Feng says.

The new paper represents an important first step in understanding how different mutations in the same gene can lead to different diseases, says Joshua Gordon, an associate professor of psychiatry at Columbia University.

“The key is to identify how the different mutations alter brain function in different ways, as done here,” says Gordon, who was not involved in the research. “Autism strikes early in childhood, while schizophrenia typically arises in adolescence or early adulthood. The finding that the autism-associated mutation has effects at a younger age than the schizophrenia-associated mutation is particularly intriguing in this context.”

Modeling disease

Although only a small percentage of autism patients have mutations in Shank3, many other variant synaptic proteins have been associated with the disorder. Future studies should help to reveal more about the role of the many genes and mutations that contribute to autism and other disorders, Feng says. Shank3 alone has at least 40 identified mutations, he says.

“We cannot consider them all to be the same,” he says. “To really model these diseases, precisely mimicking each human mutation is critical.”

Understanding exactly how these mutations influence brain circuits should help researchers develop drugs that target those circuits and match them with the patients who would benefit most, Feng says, adding that a tremendous amount of work needs to be done to get to that point.

His lab is now investigating what happens in the earliest stages of the development of mice with the autism-related Shank3 mutation, and whether any of those effects can be reversed either during development or later in life.

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

Singing in the brain

Anne Trafton |

Male zebra finches, small songbirds native to central Australia, learn their songs by copying what they hear from their fathers. These songs, often used as mating calls, develop early in life as juvenile birds experiment with mimicking the sounds they hear.

MIT neuroscientists have now uncovered the brain activity that supports this learning process. Sequences of neural activity that encode the birds’ first song syllable are duplicated and altered slightly, allowing the birds to produce several variations on the original syllable. Eventually these syllables are strung together into the bird’s signature song, which remains constant for life.

“The advantage here is that in order to learn new syllables, you don’t have to learn them from scratch. You can reuse what you’ve learned and modify it slightly. We think it’s an efficient way to learn various types of syllables,” says Tatsuo Okubo, a former MIT graduate student and lead author of the study, which appears in the Nov. 30 online edition of Nature.

Okubo and his colleagues believe that this type of neural sequence duplication may also underlie other types of motor learning. For example, the sequence used to swing a tennis racket might be repurposed for a similar motion such as playing Ping-Pong. “This seems like a way that sequences might be learned and reused for anything that involves timing,” says Emily Mackevicius, an MIT graduate student who is also an author of the paper.

The paper’s senior author is Michale Fee, a professor of brain and cognitive sciences at MIT and a member of the McGovern Institute for Brain Research.

Bursting into song

Previous studies from Fee’s lab have found that a part of the brain’s cortex known as the HVC is critical for song production.

Typically, each song lasts for about one second and consists of multiple syllables. Fee’s lab has found that in adult birds, individual HVC neurons show a very brief burst of activity — about 10 milliseconds or less — at one moment during the song. Different sets of neurons are active at different times, and collectively the song is represented by this sequence of bursts.

In the new Nature study, the researchers wanted to figure out how those neural patterns develop in newly hatched zebra finches. To do that, they recorded electrical activity in HVC neurons for up to three months after the birds hatched.

When zebra finches begin to sing, about 30 days after hatching, they produce only nonsense syllables known as subsong, similar to the babble of human babies. At first, the duration of these syllables is highly variable, but after a week or so they turn into more consistent sounds called protosyllables, which last about 100 milliseconds. Each bird learns one protosyllable that forms a scaffold for subsequent syllables.

The researchers found that within the HVC, neurons fire in a sequence of short bursts corresponding to the first protosyllable that each bird learns. Most of the neurons in the HVC participate in this original sequence, but as time goes by, some of these neurons are extracted from the original sequence and produce a new, very similar sequence. This chain of neural sequences can be repurposed to produce different syllables.

“From that short sequence it splits into new sequences for the next new syllables,” Mackevicius says. “It starts with that short chain that has a lot of redundancy in it, and splits off some neurons for syllable A and some neurons for syllable B.”

This splitting of neural sequences happens repeatedly until the birds can produce between three and seven different syllables, the researchers found. This entire process takes about two months, at which point each bird has settled on its final song.

Evolution by duplication

The researchers note that this process is similar to what is believed to drive the production of new genes and traits during evolution.

“If you duplicate a gene, then you could have separate mutations in both copies of the gene and they could eventually do different functions,” Okubo says. “It’s similar with motor programs. You can duplicate the sequence and then independently modify the two daughter motor programs so that they can now each do slightly different things.”

Mackevicius is now studying how input from sound-processing parts of the brain to the HVC contributes to the formation of these neural sequences.