Research Area: Systems Neuroscience

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

Calcium reveals connections between neurons

Anne Trafton |

A team led by MIT neuroscientists has developed a way to monitor how brain cells coordinate with each other to control specific behaviors, such as initiating movement or detecting an odor.

The researchers’ new imaging technique, based on the detection of calcium ions in neurons, could help them map the brain circuits that perform such functions. It could also provide new insights into the origins of autism, obsessive-compulsive disorder and other psychiatric diseases, says Guoping Feng, senior author of a paper appearing in the Oct. 18 issue of the journal Neuron.

“To understand psychiatric disorders we need to study animal models, and to find out what’s happening in the brain when the animal is behaving abnormally,” says Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of the McGovern Institute for Brain Research at MIT. “This is a very powerful tool that will really help us understand animal models of these diseases and study how the brain functions normally and in a diseased state.”

The lead author of the Neuron paper is McGovern Institute postdoc Qian Chen.

Performing any kind of brain function requires many neurons in different parts of the brain to communicate with each other. They achieve this communication by sending electrical signals, triggering an influx of calcium ions into active cells. Using dyes that bind to calcium, researchers have imaged neural activity in neurons. However, the brain contains thousands of cell types, each with distinct functions, and the dye is taken up nonselectively by all cells, making it impossible to pinpoint calcium in specific cell types with this approach.

To overcome this, the MIT-led team created a calcium-imaging system that can be targeted to specific cell types, using a type of green fluorescent protein (GFP). Junichi Nakai of Saitama University in Japan first developed a GFP that is activated when it binds to calcium, and one of the Neuron paper authors, Loren Looger of the Howard Hughes Medical Institute, modified the protein so its signal is strong enough to use in living animals.

The MIT researchers then genetically engineered mice to express this protein in a type of neuron known as pyramidal cells, by pairing the gene with a regulatory DNA sequence that is only active in those cells. Using two-photon microscopy to image the cells at high speed and high resolution, the researchers can identify pyramidal cells that are active when the brain is performing a specific task or responding to a certain stimulus.

In this study, the team was able to pinpoint cells in the somatosensory cortex that are activated when a mouse’s whiskers are touched, and olfactory cells that respond to certain aromas.

This system could be used to study brain activity during many types of behavior, including long-term phenomena such as learning, says Matt Wachowiak, an associate professor of physiology at the University of Utah. “These mouse lines should be really useful to many different research groups who want to measure activity in different parts of the brain,” says Wachowiak, who was not involved in this research.

The researchers are now developing mice that express the calcium-sensitive proteins and also exhibit symptoms of autistic behavior and obsessive-compulsive disorder. Using these mice, the researchers plan to look for neuron firing patterns that differ from those of normal mice. This could help identify exactly what goes wrong at the cellular level, offering mechanistic insights into those diseases.

“Right now, we only know that defects in neuron-neuron communications play a key role in psychiatric disorders. We do not know the exact nature of the defects and the specific cell types involved,” Feng says. “If we knew what cell types are abnormal, we could find ways to correct abnormal firing patterns.”

The researchers also plan to combine their imaging technology with optogenetics, which enables them to use light to turn specific classes of neurons on or off. By activating specific cells and then observing the response in target cells, they will be able to precisely map brain circuits.

The research was funded by the Poitras Center for Affective Disorders Research, the National Institutes of Health and the McNair Foundation

Stroke disrupts how brain controls muscle synergies

Anne Trafton |

The simple act of picking up a pencil requires the coordination of dozens of muscles: The eyes and head must turn toward the object as the hand reaches forward and the fingers grasp it. To make this job more manageable, the brain’s motor cortex has implemented a system of shortcuts. Instead of controlling each muscle independently, the cortex is believed to activate muscles in groups, known as “muscle synergies.” These synergies can be combined in different ways to achieve a wide range of movements.

A new study from MIT, Harvard Medical School and the San Camillo Hospital in Venice finds that after a stroke, these muscle synergies are activated in altered ways. Furthermore, those disruptions follow specific patterns depending on the severity of the stroke and the amount of time that has passed since the stroke.

The findings, published this week in the Proceedings of the National Academy of Sciences, could lead to improved rehabilitation for stroke patients, as well as a better understanding of how the motor cortex coordinates movements, says Emilio Bizzi, an Institute Professor at MIT and senior author of the paper.

“The cortex is responsible for motor learning and for controlling movement, so we want to understand what’s going on there,” says Bizzi, who is a member of the McGovern Institute for Brain Research at MIT. “How does the cortex translate an idea to move into a series of commands to accomplish a task?”

Coordinated control

One way to explore motor cortical functions is to study how motor patterns are disrupted in stroke patients who suffered damage to the motor areas.

In 2009, Bizzi and his colleagues first identified muscle synergies in the arms of people who had suffered mild strokes by measuring electrical activity in each muscle as the patients moved. Then, by utilizing a specially designed factorization algorithm, the researchers identified characteristic muscle synergies in both the stroke-affected and unaffected arms.

“To control, precisely, each muscle needed for the task would be very hard. What we have proven is that the central nervous system, when it programs the movement, makes use of these modules,” Bizzi says. “Instead of activating simultaneously 50 muscles for a single action, you will combine a few synergies to achieve that goal.”

In the 2009 study, and again in the new paper, the researchers showed that synergies in the affected arms of patients who suffered mild strokes in the cortex are very similar to those seen in their unaffected arms even though the muscle activation patterns are different. This shows that muscle synergies are structured within the spinal cord, and that cortical stroke alters the ability of the brain to activate these synergies in the appropriate combinations.

However, the new study found a much different pattern in patients who suffered more severe strokes. In those patients, synergies in the affected arm merged to form a smaller number of larger synergies. And in a third group of patients, who had suffered their stroke many years earlier, the muscle synergies of the affected arm split into fragments of the synergies seen in the unaffected arm.

This phenomenon, known as fractionation, does not restore the synergies to what they would have looked like before the stroke. “These fractionations appear to be something totally new,” says Vincent Cheung, a research scientist at the McGovern Institute and lead author of the new PNAS paper. “The conjecture would be that these fragments could be a way that the nervous system tries to adapt to the injury, but we have to do further studies to confirm that.”

This is the first time that fractionation of muscle synergies identified by factorization has been seen in chronic stroke patients, says Simon Giszter, a professor of neurobiology and anatomy at Drexel University. “It raises the question of how this occurs and if it’s a compensatory process. If it is, we can use this measurement to study how the recovery process can be accelerated,” says Giszter, who was not involved in this study.

Toward better rehabilitation

The researchers believe that these patterns of synergies, which are determined by both the severity of the deficit and the time since the stroke occurred, could be used as markers to more fully describe individual patients’ impaired status. “In some of the patients, we see a mixture of these patterns. So you can have severe but chronic patients, for instance, who show both merging and fractionation,” Cheung says.

The findings could also help doctors design better rehabilitation programs. The MIT team is now working with several hospitals to establish new therapeutic protocols based on the discovered markers.

About 700,000 people suffer strokes in the United States every year, and many different rehabilitation programs exist to treat them. Choosing one is currently more of an art than a science, Bizzi says. “There is a great deal of need to sharpen current procedures for rehabilitation by turning to principles derived from the most advanced brain research,” he says. “It is very likely that different strategies of rehabilitation will have to be used in patients who have one type of marker versus another.”

The research was funded by the National Institutes of Health and the Italian Ministry of Health.

Re-creating autism, in mice

Anne Trafton |

By mutating a single gene, researchers at MIT and Duke have produced mice with two of the most common traits of autism — compulsive, repetitive behavior and avoidance of social interaction.

They further showed that this gene, which is also implicated in many cases of human autism, appears to produce autistic behavior by interfering with communication between brain cells. The finding, reported in the March 20 online edition of Nature, could help researchers find new pathways for developing drugs to treat autism, says senior author Guoping Feng, professor of brain and cognitive sciences and member of the McGovern Institute for Brain Research at MIT.

About one in 110 children in the United States has an autism spectrum disorder, which can range in severity and symptoms but usually includes difficulties with language in addition to social avoidance and repetitive behavior. There are currently no effective drugs to treat autism, but the new finding could help uncover new drug targets, Feng says.

“We now have a very robust model with a known cause for autistic-like behaviors. We can figure out the neural circuits responsible for these behaviors, which could lead to novel targets for treatment,” he says.

The new mouse model also gives researchers a new way to test potential autism drugs before trying them in human patients.

A genetic disorder

In the past 10 years, large-scale genetic studies have identified hundreds of gene mutations that occur more frequently in autistic patients than in the general population. However, each patient has only one or a handful of those mutations, making it difficult to develop drugs against the disease.

In this study, the researchers focused on one of the most common of those genes, known as Shank3. The protein encoded by Shank3 is found in synapses — the junctions between brain cells that allow them to communicate with each other. Feng, who joined MIT and the McGovern Institute last year, began studying Shank3 a few years ago because he thought that synaptic proteins might contribute to autism and similar brain disorders, such as obsessive compulsive disorder.

At a synapse, one cell sends messages by releasing chemicals called neurotransmitters, which interact with the cell receiving the signal (known as the postsynaptic cell). This signal provokes the postsynaptic cell to alter its activity in some way — for example, turning a gene on or off. Shank3 is a “scaffold” protein, meaning that it helps to organize the hundreds of other proteins clustered on the postsynaptic cell membrane, which are necessary to coordinate the cell’s response to synaptic signals.

Feng targeted Shank3 because it is found primarily in a part of the brain called the striatum, which is involved in motor activity, decision-making and the emotional aspects of behavior. Malfunctions in the striatum are associated with several brain disorders, including autism and OCD. Feng theorized that those disorders might be caused by faulty synapses.

In a 2007 study, Feng showed that another postsynaptic protein found in the striatum, Sapap3, can cause OCD-like behavior in mice when mutated.

Communication problems

In the new Nature study, Feng and his colleagues found that Shank3 mutant mice showed compulsive behavior (specifically, excessive grooming) and avoidance of social interaction. “They’re just not interested in interacting with other mice,” he says.

The study, funded in part by the Simons Foundation Autism Research Initiative, offers the first direct evidence that mutations in Shank3 produce autistic-like behavior.

Guy Rouleau, professor of medicine at the University of Montreal, says the mouse model should give autism researchers a chance to understand the disease better and potentially develop new treatments. “It looks like this is going to be a good model that will be used to explore, more deeply, the physiology of the disorder,” says Rouleau, who was not involved in this research.

Even though only a small percentage of autistic patients have mutations in Shank3, Feng believes that many other cases may be caused by disruptions of other synaptic proteins. He is now doing a study, with researchers from the Broad Institute, to determine whether mutations in a group of other synaptic genes are associated with autism in human patients.

If that turns out to be the case, it should be possible to develop treatments that restore synaptic function, regardless of which particular synaptic protein is defective in the individual patient, Feng says.

Feng performed some of the research while at Duke, and several of his former Duke colleagues are authors on the Nature paper, including lead author Joao Peca and Professor Christopher Lascola.

McGovern Institute to present inaugural Edward M. Scolnick Prize in Neuroscience Research

Anne Trafton |

The Edward M. Scolnick Prize in Neuroscience Research will be awarded on Friday April 23rd at the McGovern Institute at MIT, a leading research and teaching institute committed to advancing understanding of the human mind and communications. According to Dr. Phillip A. Sharp, Director of the Institute, this annual research prize will recognize outstanding discoveries or significant advances in the field of neuroscience.

The inaugural prize will be presented to Dr. Masakazu Konishi, Bing Professor of Behavioral Biology at the California Institute of Technology. As part of the day’s events, Dr. Konishi will present a free public lecture, “Non-linear steps to high stimulus selectivity in different sensory systems” at 1:30 PM on Friday, April 23rd at MIT (building E25, room 111.) Following the lecture, The McGovern Institute is hosting an invitation-only reception and dinner honoring Dr. Konishi at the MIT Faculty Club. Speakers for the evening award presentation include: Dr. Sharp; Patrick J. McGovern, Founder and Chairman of International Data Group (IDG) and trustee of MIT and the Institute; Edward Scolnick, former President of Merck Research Laboratories; and Torsten Wiesel, President Emeritus of Rockefeller University.

“I am pleased, on behalf of the McGovern Institute, to recognize the important work that Dr. Mark Konishi is doing,” said Dr. Sharp. “Dr. Konishi is being recognized for his fundamental discoveries concerning mechanisms in the brain for sound location such as a neural topographic map of auditory space. Through a combination of his discoveries, the positive influence of his rigorous approach, and the cadre of young scientists he has mentored and trained, Dr. Konishi has improved our knowledge of how the brain works, and the future of neuroscience research. Mark is truly a leader, and well-deserving of this prestigious honor.”

Dr. Konishi received his B.S and M.S degrees from Hokkaido University in Sapporo, Japan and his Doctorate from the University of California, Berkeley in 1963. After holding positions at the University of Tubingen and the Max-Planck Institute in Germany, Dr. Konishi returned to the United States, where he worked at the University of Wisconsin and Princeton University before coming to the California Institute of Technology in 1975 as Professor of Biology. He has been the Bing Professor of Behavioral Biology at Caltech since 1980. With scores of publications dating back to 1971, and as the recipient of fourteen previous awards, Dr. Konishi has forged a deserved reputation as an outstanding investigator.

Among his many findings, Dr. Konishi is known for his fundamental discoveries concerning sound location by the barn owl and the song system in the bird. He discovered that in the inferior colliculus of the brain of the barn owl there is a map of auditory space and he identified the computational principles and the neural mechanisms that underlie the workings of the map.

The creation of the Edward M. Scolnick Prize was announced last year, with the first presentation scheduled for 2004. The annual prize consists of an award equal to $50,000 and will be given each year to an outstanding leader in the international neuroscience research community. The McGovern Institute will host a public lecture by Dr. Konishi in the spring of 2004, followed by an award presentation ceremony.

The award is named in honor of Dr. Edward M. Scolnick, who stepped down as President of Merck Research Laboratories in December 2002, after holding Merck & Co., Inc.’s top research post for 17 years. During his tenure, Dr. Scolnick led the discovery, development and introduction of 29 new medicines and vaccines. While many of the medicines and vaccines have contributed to improving patient health, some have revolutionized the ways in which certain diseases are treated.

About the McGovern Institute at MIT

The McGovern Institute at MIT is a research and teaching institute committed to advancing human understanding and communications. The goal of the McGovern Institute is to investigate and ultimately understand the biological basis of all higher brain function in humans. The McGovern Institute conducts integrated research in neuroscience, genetic and cellular neurobiology, cognitive science, computation, and related areas.

By determining how the brain works, from the level of gene expression in individual neurons to the interrelationships between complex neural networks, the McGovern Institute’s efforts work to improve human health, discover the basis of learning and recognition, and enhance education and communication. The McGovern Institute contributes to the most basic knowledge of the fundamental mysteries of human awareness, decisions, and actions.