Researcher: Guoping Feng

Compulsive no more

Anne Trafton |

By activating a brain circuit that controls compulsive behavior, McGovern neuroscientists have shown that they can block a compulsive behavior in mice — a result that could help researchers develop new treatments for diseases such as obsessive-compulsive disorder (OCD) and Tourette’s syndrome.

About 1 percent of U.S. adults suffer from OCD, and patients usually receive antianxiety drugs or antidepressants, behavioral therapy, or a combination of therapy and medication. For those who do not respond to those treatments, a new alternative is deep brain stimulation, which delivers electrical impulses via a pacemaker implanted in the brain.

For this study, the MIT team used optogenetics to control neuron activity with light. This technique is not yet ready for use in human patients, but studies such as this one could help researchers identify brain activity patterns that signal the onset of compulsive behavior, allowing them to more precisely time the delivery of deep brain stimulation.

“You don’t have to stimulate all the time. You can do it in a very nuanced way,” says Ann Graybiel, an Institute Professor at MIT, a member of MIT’s McGovern Institute for Brain Research and the senior author of a Science paper describing the study.

The paper’s lead author is Eric Burguière, a former postdoc in Graybiel’s lab who is now at the Brain and Spine Institute in Paris. Other authors are Patricia Monteiro, a research affiliate at the McGovern Institute, and Guoping Feng, the James W. and Patricia T. Poitras Professor of Brain and Cognitive Sciences and a member of the McGovern Institute.

Controlling compulsion

In earlier studies, Graybiel has focused on how to break normal habits; in the current work, she turned to a mouse model developed by Feng to try to block a compulsive behavior. The model mice lack a particular gene, known as Sapap3, that codes for a protein found in the synapses of neurons in the striatum — a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward.

For this study, the researchers trained mice whose Sapap3 gene was knocked out to groom compulsively at a specific time, allowing the researchers to try to interrupt the compulsion. To do this, they used a Pavlovian conditioning strategy in which a neutral event (a tone) is paired with a stimulus that provokes the desired behavior — in this case, a drop of water on the mouse’s nose, which triggers the mouse to groom. This strategy was based on therapeutic work with OCD patients, which uses this kind of conditioning.

After several hundred trials, both normal and knockout mice became conditioned to groom upon hearing the tone, which always occurred just over a second before the water drop fell. However, after a certain point their behaviors diverged: The normal mice began waiting until just before the water drop fell to begin grooming. This type of behavior is known as optimization, because it prevents the mice from wasting unnecessary effort.

This behavior optimization never appeared in the knockout mice, which continued to groom as soon as they heard the tone, suggesting that their ability to suppress compulsive behavior was impaired.

The researchers suspected that failed communication between the striatum, which is related to habits, and the neocortex, the seat of higher functions that can override simpler behaviors, might be to blame for the mice’s compulsive behavior. To test this idea, they used optogenetics, which allows them to control cell activity with light by engineering cells to express light-sensitive proteins.

When the researchers stimulated light-sensitive cortical cells that send messages to the striatum at the same time that the tone went off, the knockout mice stopped their compulsive grooming almost totally, yet they could still groom when the water drop came. The researchers suggest that this cure resulted from signals sent from the cortical neurons to a very small group of inhibitory neurons in the striatum, which silence the activity of neighboring striatal cells and cut off the compulsive behavior.

“Through the activation of this pathway, we could elicit behavior inhibition, which appears to be dysfunctional in our animals,” Burguière says.

The researchers also tested the optogenetic intervention in mice as they groomed in their cages, with no conditioning cues. During three-minute periods of light stimulation, the knockout mice groomed much less than they did without the stimulation.

Scott Rauch, president and psychiatrist-in-chief of McLean Hospital in Belmont, Mass., says the MIT study “opens the door to a universe of new possibilities by identifying a cellular and circuitry target for future interventions.”

“This represents a major leap forward, both in terms of delineating the brain basis of pathological compulsive behavior and in offering potential avenues for new treatment approaches,” adds Rauch, who was not involved in this study.

Graybiel and Burguière are now seeking markers of brain activity that could reveal when a compulsive behavior is about to start, to help guide the further development of deep brain stimulation treatments for OCD patients.

The research was funded by the Simons Initiative on Autism and the Brain at MIT, the National Institute of Child Health and Human Development, the National Institute of Mental Health, and the Simons Foundation Autism Research Initiative.

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

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.