Research Area: Neurotechnology

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Delving deep into the brain

Anne Trafton |

Launched in 2013, the national BRAIN Initiative aims to revolutionize our understanding of cognition by mapping the activity of every neuron in the human brain, revealing how brain circuits interact to create memories, learn new skills, and interpret the world around us.

Before that can happen, neuroscientists need new tools that will let them probe the brain more deeply and in greater detail, says Alan Jasanoff, an MIT associate professor of biological engineering. “There’s a general recognition that in order to understand the brain’s processes in comprehensive detail, we need ways to monitor neural function deep in the brain with spatial, temporal, and functional precision,” he says.

Jasanoff and colleagues have now taken a step toward that goal: They have established a technique that allows them to track neural communication in the brain over time, using magnetic resonance imaging (MRI) along with a specialized molecular sensor. This is the first time anyone has been able to map neural signals with high precision over large brain regions in living animals, offering a new window on brain function, says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research.

His team used this molecular imaging approach, described in the May 1 online edition of Science, to study the neurotransmitter dopamine in a region called the ventral striatum, which is involved in motivation, reward, and reinforcement of behavior. In future studies, Jasanoff plans to combine dopamine imaging with functional MRI techniques that measure overall brain activity to gain a better understanding of how dopamine levels influence neural circuitry.

“We want to be able to relate dopamine signaling to other neural processes that are going on,” Jasanoff says. “We can look at different types of stimuli and try to understand what dopamine is doing in different brain regions and relate it to other measures of brain function.”

Tracking dopamine

Dopamine is one of many neurotransmitters that help neurons to communicate with each other over short distances. Much of the brain’s dopamine is produced by a structure called the ventral tegmental area (VTA). This dopamine travels through the mesolimbic pathway to the ventral striatum, where it combines with sensory information from other parts of the brain to reinforce behavior and help the brain learn new tasks and motor functions. This circuit also plays a major role in addiction.
To track dopamine’s role in neural communication, the researchers used an MRI sensor they had previously designed, consisting of an iron-containing protein that acts as a weak magnet. When the sensor binds to dopamine, its magnetic interactions with the surrounding tissue weaken, which dims the tissue’s MRI signal. This allows the researchers to see where in the brain dopamine is being released. The researchers also developed an algorithm that lets them calculate the precise amount of dopamine present in each fraction of a cubic millimeter of the ventral striatum.

After delivering the MRI sensor to the ventral striatum of rats, Jasanoff’s team electrically stimulated the mesolimbic pathway and was able to detect exactly where in the ventral striatum dopamine was released. An area known as the nucleus accumbens core, known to be one of the main targets of dopamine from the VTA, showed the highest levels. The researchers also saw that some dopamine is released in neighboring regions such as the ventral pallidum, which regulates motivation and emotions, and parts of the thalamus, which relays sensory and motor signals in the brain.

Each dopamine stimulation lasted for 16 seconds and the researchers took an MRI image every eight seconds, allowing them to track how dopamine levels changed as the neurotransmitter was released from cells and then disappeared. “We could divide up the map into different regions of interest and determine dynamics separately for each of those regions,” Jasanoff says.

He and his colleagues plan to build on this work by expanding their studies to other parts of the brain, including the areas most affected by Parkinson’s disease, which is caused by the death of dopamine-generating cells. Jasanoff’s lab is also working on sensors to track other neurotransmitters, allowing them to study interactions between neurotransmitters during different tasks.

The paper’s lead author is postdoc Taekwan Lee. Technical assistant Lili Cai and postdocs Victor Lelyveld and Aviad Hai also contributed to the research, which was funded by the National Institutes of Health and the Defense Advanced Research Projects Agency.

MRI reveals genetic activity

Anne Trafton |

Doctors commonly use magnetic resonance imaging (MRI) to diagnose tumors, damage from stroke, and many other medical conditions. Neuroscientists also rely on it as a research tool for identifying parts of the brain that carry out different cognitive functions.

Now, a team of biological engineers at MIT is trying to adapt MRI to a much smaller scale, allowing researchers to visualize gene activity inside the brains of living animals. Tracking these genes with MRI would enable scientists to learn more about how the genes control processes such as forming memories and learning new skills, says Alan Jasanoff, an MIT associate professor of biological engineering and leader of the research team.

“The dream of molecular imaging is to provide information about the biology of intact organisms, at the molecule level,” says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research. “The goal is to not have to chop up the brain, but instead to actually see things that are happening inside.”

To help reach that goal, Jasanoff and colleagues have developed a new way to image a “reporter gene” — an artificial gene that turns on or off to signal events in the body, much like an indicator light on a car’s dashboard. In the new study, the reporter gene encodes an enzyme that interacts with a magnetic contrast agent injected into the brain, making the agent visible with MRI. This approach, described in a recent issue of the journal Chemical Biology, allows researchers to determine when and where that reporter gene is turned on.

An on/off switch

MRI uses magnetic fields and radio waves that interact with protons in the body to produce detailed images of the body’s interior. In brain studies, neuroscientists commonly use functional MRI to measure blood flow, which reveals which parts of the brain are active during a particular task. When scanning other organs, doctors sometimes use magnetic “contrast agents” to boost the visibility of certain tissues.

The new MIT approach includes a contrast agent called a manganese porphyrin and the new reporter gene, which codes for a genetically engineered enzyme that alters the electric charge on the contrast agent. Jasanoff and colleagues designed the contrast agent so that it is soluble in water and readily eliminated from the body, making it difficult to detect by MRI. However, when the engineered enzyme, known as SEAP, slices phosphate molecules from the manganese porphyrin, the contrast agent becomes insoluble and starts to accumulate in brain tissues, allowing it to be seen.

The natural version of SEAP is found in the placenta, but not in other tissues. By injecting a virus carrying the SEAP gene into the brain cells of mice, the researchers were able to incorporate the gene into the cells’ own genome. Brain cells then started producing the SEAP protein, which is secreted from the cells and can be anchored to their outer surfaces. That’s important, Jasanoff says, because it means that the contrast agent doesn’t have to penetrate the cells to interact with the enzyme.

Researchers can then find out where SEAP is active by injecting the MRI contrast agent, which spreads throughout the brain but accumulates only near cells producing the SEAP protein.

Exploring brain function

In this study, which was designed to test this general approach, the detection system revealed only whether the SEAP gene had been successfully incorporated into brain cells. However, in future studies, the researchers intend to engineer the SEAP gene so it is only active when a particular gene of interest is turned on.

Jasanoff first plans to link the SEAP gene with so-called “early immediate genes,” which are necessary for brain plasticity — the weakening and strengthening of connections between neurons, which is essential to learning and memory.

“As people who are interested in brain function, the top questions we want to address are about how brain function changes patterns of gene expression in the brain,” Jasanoff says. “We also imagine a future where we might turn the reporter enzyme on and off when it binds to neurotransmitters, so we can detect changes in neurotransmitter levels as well.”

Assaf Gilad, an assistant professor of radiology at Johns Hopkins University, says the MIT team has taken a “very creative approach” to developing noninvasive, real-time imaging of gene activity. “These kinds of genetically engineered reporters have the potential to revolutionize our understanding of many biological processes,” says Gilad, who was not involved in the study.

The research was funded by the Raymond and Beverly Sackler Foundation, the National Institutes of Health, and an MIT-Germany Seed Fund grant. The paper’s lead author is former MIT postdoc Gil Westmeyer; other authors are former MIT technical assistant Yelena Emer and Jutta Lintelmann of the German Research Center for Environmental Health.

Optogenetic toolkit goes multicolor

Anne Trafton |

Optogenetics is a technique that allows scientists to control neurons’ electrical activity with light by engineering them to express light-sensitive proteins. Within the past decade, it has become a very powerful tool for discovering the functions of different types of cells in the brain.

Most of these light-sensitive proteins, known as opsins, respond to light in the blue-green range. Now, a team led by MIT has discovered an opsin that is sensitive to red light, which allows researchers to independently control the activity of two populations of neurons at once, enabling much more complex studies of brain function.

“If you want to see how two different sets of cells interact, or how two populations of the same cell compete against each other, you need to be able to activate those populations independently,” says Ed Boyden, a member of the McGovern Institute for Brain Research at MIT and a senior author of the new study.

The new opsin is one of about 60 light-sensitive proteins found in a screen of 120 species of algae. The study, which appears in the Feb. 9 online edition of Nature Methods, also yielded the fastest opsin, enabling researchers to study neuron activity patterns with millisecond timescale precision.

Boyden and Gane Ka-Shu Wong, a professor of medicine and biological sciences at the University of Alberta, are the paper’s senior authors, and the lead author is MIT postdoc Nathan Klapoetke. Researchers from the Howard Hughes Medical Institute’s Janelia Farm Research Campus, the University of Pennsylvania, the University of Cologne, and the Beijing Genomics Institute also contributed to the study.

In living color

Opsins occur naturally in many algae and bacteria, which use the light-sensitive proteins to help them respond to their environment and generate energy.

To achieve optical control of neurons, scientists engineer brain cells to express the gene for an opsin, which transports ions across the cell’s membrane to alter its voltage. Depending on the opsin used, shining light on the cell either lowers the voltage and silences neuron firing, or boosts voltage and provokes the cell to generate an electrical impulse. This effect is nearly instantaneous and easily reversible.

Using this approach, researchers can selectively turn a population of cells on or off and observe what happens in the brain. However, until now, they could activate only one population at a time, because the only opsins that responded to red light also responded to blue light, so they couldn’t be paired with other opsins to control two different cell populations.

To seek additional useful opsins, the MIT researchers worked with Wong’s team at the University of Alberta, which is sequencing the transcriptomes of 1,000 plants, including some algae. (The transcriptome is similar to the genome but includes only the genes that are expressed by a cell, not the entirety of its genetic material.)

Once the team obtained genetic sequences that appeared to code for opsins, Klapoetke tested their light-responsiveness in mammalian brain tissue, working with Martha Constantine-Paton, a professor of brain and cognitive sciences and of biology, a member of the McGovern Institute for Brain Research at MIT, and also an author of the paper. The red-light-sensitive opsin, which the researchers named Chrimson, can mediate neural activity in response to light with a 735-nanometer
wavelength.

The researchers also discovered a blue-light-driven opsin that has two highly desirable traits: It operates at high speed, and it is sensitive to very dim light. This opsin, called Chronos, can be stimulated with levels of blue light that are too weak to activate Chrimson.

“You can use short pulses of dim blue light to drive the blue one, and you can use strong red light to drive Chrimson, and that allows you to do true two-color, zero-cross-talk activation in intact brain tissue,” says Boyden, who is a member of MIT’s Media Lab and an associate professor of biological engineering and brain and cognitive sciences at MIT.

Researchers had previously tried to modify naturally occurring opsins to make them respond faster and react to dimmer light, but trying to optimize one feature often made other features worse.

“It was apparent that when trying to engineer traits like color, light sensitivity, and kinetics, there are always tradeoffs,” Klapoetke says. “We’re very lucky that something natural actually was more than several times faster and also five or six times more light-sensitive than anything else.”

Selective control

These new opsins lend themselves to several types of studies that were not possible before, Boyden says. For one, scientists could not only manipulate activity of a cell population of interest, but also control upstream cells that influence the target population by secreting neurotransmitters.

Pairing Chrimson and Chronos could also allow scientists to study the functions of different types of cells in the same microcircuit within the brain. Such cells are usually located very close together, but with the new opsins they can be controlled independently with two different colors of light.

“I think the tools described in this excellent paper represent a major advance for both basic and translational neuroscience,” says Botond Roska, a senior group leader at the Friedrich Miescher Institute for Biomedical Research in Switzerland, who was not part of the research team. “Optogenetic tools that are shifted towards the infrared range, such as Chrimson described in this paper, are much better than the more blue-shifted variants since these are less toxic, activate less the pupillary reflex, and activate less the remaining photoreceptors of patients.”

Most optogenetic studies thus far have been done in mice, but Chrimson could be used for optogenetic studies of fruit flies, a commonly used experimental organism. Researchers have had trouble using blue-light-sensitive opsins in fruit flies because the light can get into the flies’ eyes and startle them, interfering with the behavior being studied.

Vivek Jayaraman, a research group leader at Janelia Farms and an author of the paper, was able to show that this startle response does not occur when red light is used to stimulate Chrimson in fruit flies.

Because red light is less damaging to tissue than blue light, Chrimson also holds potential for eventual therapeutic use in humans, Boyden says. Animal studies with other opsins have shown promise in helping to restore vision after the loss of photoreceptor cells in the retina.

The researchers are now trying to modify Chrimson to respond to light in the infrared range. They are also working on making both Chrimson and Chronos faster and more light sensitive.

MIT’s portion of the project was funded by the National Institutes of Health, the MIT Media Lab, the National Science Foundation, the Wallace H. Coulter Foundation, the Alfred P. Sloan Foundation, a NARSAD Young Investigator Grant, the Human Frontiers Science Program, an NYSCF Robertson Neuroscience Investigator Award, the IET A.F. Harvey Prize, Janet and Sheldon Razin ’59, and the Skolkovo Institute of Science and Technology.

Controlling genes with light

Anne Trafton |

Although human cells have an estimated 20,000 genes, only a fraction of those are turned on at any given time, depending on the cell’s needs — which can change by the minute or hour. To find out what those genes are doing, researchers need tools that can manipulate their status on similarly short timescales.

That is now possible, thanks to a new technology developed at MIT and the Broad Institute that can rapidly start or halt the expression of any gene of interest simply by shining light on the cells.

The work is based on a technique known as optogenetics, which uses proteins that change their function in response to light. In this case, the researchers adapted the light-sensitive proteins to either stimulate or suppress the expression of a specific target gene almost immediately after the light comes on.

“Cells have very dynamic gene expression happening on a fairly short timescale, but so far the methods that are used to perturb gene expression don’t even get close to those dynamics. To understand the functional impact of those gene-expression changes better, we have to be able to match the naturally occurring dynamics as closely as possible,” says Silvana Konermann, an MIT graduate student in brain and cognitive sciences.

The ability to precisely control the timing and duration of gene expression should make it much easier to figure out the roles of particular genes, especially those involved in learning and memory. The new system can also be used to study epigenetic modifications — chemical alterations of the proteins that surround DNA — which are also believed to play an important role in learning and memory.

Konermann and Mark Brigham, a graduate student at Harvard University, are the lead authors of a paper describing the technique in the July 22 online edition of Nature. The paper’s senior author is Feng Zhang, the W. M. Keck Career Development Professor in Biomedical Engineering at MIT and a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.

Shining light on genes

The new system consists of several components that interact with each other to control the copying of DNA into messenger RNA (mRNA), which carries genetic instructions to the rest of the cell. The first is a DNA-binding protein known as a transcription activator-like effector (TALE). TALEs are modular proteins that can be strung together in a customized way to bind any DNA sequence.

Fused to the TALE protein is a light-sensitive protein called CRY2 that is naturally found in Arabidopsis thaliana, a small flowering plant. When light hits CRY2, it changes shape and binds to its natural partner protein, known as CIB1. To take advantage of this, the researchers engineered a form of CIB1 that is fused to another protein that can either activate or suppress gene copying.

After the genes for these components are delivered to a cell, the TALE protein finds its target DNA and wraps around it. When light shines on the cells, the CRY2 protein binds to CIB1, which is floating in the cell. CIB1 brings along a gene activator, which initiates transcription, or the copying of DNA into mRNA. Alternatively, CIB1 could carry a repressor, which shuts off the process.

A single pulse of light is enough to stimulate the protein binding and initiate DNA copying.

The researchers found that pulses of light delivered every minute or so are the most effective way to achieve continuous transcription for the desired period of time. Within 30 minutes of light delivery, the researchers detected an uptick in the amount of mRNA being produced from the target gene. Once the pulses stop, the mRNA starts to degrade within about 30 minutes.

In this study, the researchers tried targeting nearly 30 different genes, both in neurons grown in the lab and in living animals. Depending on the gene targeted and how much it is normally expressed, the researchers were able to boost transcription by a factor of two to 200.




Epigenetic modifications



An important element of gene-expression control is epigenetic modification. One major class of epigenetic effectors is chemical modification of the proteins, known as histones, that anchor chromosomal DNA and control access to the underlying genes. The researchers showed that they can also alter these epigenetic modifications by fusing TALE proteins with histone modifiers.

Epigenetic modifications are thought to play a key role in learning and forming memories, but this has not been very well explored because there are no good ways to disrupt the modifications, short of blocking histone modification of the entire genome. The new technique offers a much more precise way to interfere with modifications of individual genes.

“We want to allow people to prove the causal role of specific epigenetic modifications in the genome,” Zhang says.

So far, the researchers have demonstrated that some of the histone effector domains can be tethered to light-sensitive proteins; they are now trying to expand the types of histone modifiers they can incorporate into the system.

“It would be really useful to expand the number of epigenetic marks that we can control. At the moment we have a successful set of histone modifications, but there are a good deal more of them that we and others are going to want to be able to use this technology for,” Brigham says.

The research was funded by a Hubert Schoemaker Fellowship; a National Institutes of Health Transformative R01 Award; an NIH Director’s Pioneer Award; the Keck, McKnight, Vallee, Damon Runyon, Searle Scholars, Klingenstein and Simons foundations; and Bob Metcalfe and Jane Pauley.

Ed Boyden to share prestigious brain prize

Anne Trafton |

Ed Boyden, a faculty member in the MIT Media Lab and the McGovern Institute for Brain Research, was today named a recipient of the 2013 Grete Lundbeck European Brain Research Prize. The 1 million Euro prize is awarded for the development of optogenetics, a technology that makes it possible to control brain activity using light.

The Brain Prize is awarded annually by the Denmark-based Lundbeck Foundation for outstanding contributions to European neuroscience. Boyden is recognized for work done in collaboration with Karl Deisseroth at Stanford University, which builds on earlier discoveries by four European researchers: Ernst Bamberg, Georg Nagel and Peter Hegemann in Germany, and Gero Miesenböck, now in Oxford, U.K. The prize will be shared equally between all six researchers.

The idea of using light to control brain activity was suggested by Francis Crick in 1999, and Miesenbock performed a proof of concept demonstration in 2002, showing that light-sensitive proteins obtained from the eyes of fruit-flies could be used to activate mammalian neurons. A further breakthrough was enabled by the discovery of channelrhodopsin-2 (ChR2), a light-activated ion channel from a common pond algal species that had been characterized by Hegemann in Martinsried and by Nagel and Bamberg in Frankfurt.

The application of ChR2 to neuroscience was pioneered by Boyden and Deisseroth at Stanford University, where Deisseroth is now a faculty member. In a collaboration that began when Boyden was a graduate student and Deisseroth a postdoctoral fellow, they obtained the ChR2 gene from Nagel and Bamberg, expressed it in cultured neurons, and pulsed the dish with blue light to see whether it could trigger neural activity. The first experiment was performed in August 2004, and it worked first time; as Boyden recounted in a recent historical article, “serendipity had struck — the molecule was good enough in its wild-type form to be used in neurons right away.”

They reported this result in 2005, in a landmark paper in Nature Neuroscience that has now been cited more than 600 times. Their method, later dubbed “optogenetics,” is now used by hundreds of labs worldwide and is also being explored for a wide range of potential therapeutic applications. In announcing the Brain Prize, the chairman of the selection committee, Professor Colin Blakemore, described optogenetics as “arguably the most important technical advance in neuroscience in the past 40 years.”

Boyden joined the MIT faculty in 2006, where he is now the Benesse Career Development Professor in the Media Lab, with joint appointments at the McGovern Institute for Brain Research and in the Departments of Biological Engineering and Brain and Cognitive Sciences. His contributions have been recognized by numerous awards and honors, including the inaugural AF Harvey Prize and the 2011 Perl/UNC prize (shared with Karl Deisseroth and with Feng Zhang, also at MIT). He continues to develop novel optogenetic tools, along with many other technologies for understanding and manipulating neural circuits within the living brain.

Boyden’s work was supported by the Fannie and John Hertz Foundation, the Helen Hay Whitney Foundation, the McKnight Foundation, Jerry and Marge Burnett, DARPA and the Department of Defense, Google, Harvard/MIT Joint Grants Program in Basic Neuroscience, Human Frontiers Science Program, IET A. F. Harvey Prize, MIT McGovern Institute and MIT Media Lab, NARSAD, New York Stem Cell Foundation-Robertson Investigator Award, NIH, NSF, Paul Allen Distinguished Investigator in Neuroscience Award, Shelly Razin, SkTech, Alfred P. Sloan Foundation, the Society for Neuroscience Research Award for Innovation in Neuroscience (RAIN), and the Wallace H. Coulter Foundation.

Precisely engineering 3-D brain tissues

Anne Trafton |

Borrowing from microfabrication techniques used in the semiconductor industry, MIT and Harvard Medical School (HMS) engineers have developed a simple and inexpensive way to create three-dimensional brain tissues in a lab dish.

The new technique yields tissue constructs that closely mimic the cellular composition of those in the living brain, allowing scientists to study how neurons form connections and to predict how cells from individual patients might respond to different drugs. The work also paves the way for developing bioengineered implants to replace damaged tissue for organ systems, according to the researchers.

“We think that by bringing this kind of control and manipulation into neurobiology, we can investigate many different directions,” says Utkan Demirci, an assistant professor in the Harvard-MIT Division of Health Sciences and Technology (HST).

Demirci and Ed Boyden, associate professor of biological engineering and brain and cognitive sciences at MIT’s Media Lab and McGovern Institute,  are senior authors of a paper describing the new technique, which appears in the Nov. 27 online edition of the journal Advanced Materials. The paper’s lead author is Umut Gurkan, a postdoc at HST, Harvard Medical School and Brigham and Women’s Hospital.

‘Unique challenges’

Although researchers have had some success growing artificial tissues such as liver or kidney, “the brain presents some unique challenges,” Boyden says. “One of the challenges is the incredible spatial heterogeneity. There are so many kinds of cells, and they have such intricate wiring.”

Brain tissue includes many types of neurons, including inhibitory and excitatory neurons, as well as supportive cells such as glial cells. All of these cells occur at specific ratios and in specific locations.

To mimic this architectural complexity in their engineered tissues, the researchers embedded a mixture of brain cells taken from the primary cortex of rats into sheets of hydrogel. They also included components of the extracellular matrix, which provides structural support and helps regulate cell behavior.

Those sheets were then stacked in layers, which can be sealed together using light to crosslink hydrogels. By covering layers of gels with plastic photomasks of varying shapes, the researchers could control how much of the gel was exposed to light, thus controlling the 3-D shape of the multilayer tissue construct.

This type of photolithography is also used to build integrated circuits onto semiconductors — a process that requires a photomask aligner machine, which costs tens of thousands of dollars. However, the team developed a much less expensive way to assemble tissues using masks made from sheets of plastic, similar to overhead transparencies, held in place with alignment pins.

The tissue cubes can be made with a precision of 10 microns, comparable to the size of a single cell body. At the other end of the spectrum, the researchers are aiming to create a cubic millimeter of brain tissue with 100,000 cells and 900 million connections.

The new system is the first that includes all of the necessary features for building useful 3-D tissues: It is inexpensive, precise, and allows complex patterns to be generated, says Metin Sitti, a professor of mechanical engineering at Carnegie Mellon University. “Many people could easily use this method for creating heterogeneous, complex gel structures,” says Sitti, who was not part of the research team.

Answering fundamental questions

Because the tissues include a diverse repertoire of brain cells, occurring in the same ratios as they do in natural brain tissue, they could be used to study how neurons form the connections that allow them to communicate with each other.

“In the short term, there’s a lot of fundamental questions you can answer about how cells interact with each other and respond to environmental cues,” Boyden says.

As a first step, the researchers used these tissue constructs to study how a neuron’s environment might constrain its growth. To do this, they placed single neurons in gel cubes of different sizes, then measured the cells’ neurites, long extensions that neurons use to communicate with other cells. It turns out that under these conditions, neurons get “claustrophobic,” Demirci says. “In small gels, they don’t necessarily send out as long neurites as they would in a five-times-larger gel.”

In the long term, the researchers hope to gain a better understanding of how to design tissue implants that could be used to replace damaged tissue in patients. Much research has been done in this area, but it has been difficult to figure out whether the new tissues are correctly wiring up with existing tissue and exchanging the right kinds of information.

Another long-term goal is using the tissues for personalized medicine. One day, doctors may be able to take cells from a patient with a neurological disorder and transform them into induced pluripotent stem cells, then induce these constructs to grow into neurons in a lab dish. By exposing these tissues to many possible drugs, “you might be able to figure out if a drug would benefit that person without having to spend years giving them lots of different drugs,” Boyden says.

Other authors of the paper are Yantao Fan, a visiting graduate student at HMS and HST; Feng Xu and Emel Sokullu Urkac, postdocs at HMS and HST; Gunes Parlakgul, a visiting medical student at HMS and HST; MIT graduate students Jacob Bernstein and Burcu Erkmen; and Wangli Xing, a professor at Tsinghua University.

The research was funded by the National Science Foundation, the Paul Allen Family Foundation, the New York Stem Cell Foundation, the National Institutes of Health, the Institute of Engineering and Technology A.F. Harvey Prize, and MIT Lincoln Laboratory.

Optogenetics: A Light Switch for Neurons

by Julie Pryor |

This animation illustrates optogenetics — a radical new technology for controlling brain activity with light. Ed Boyden, the co-inventor of this technology, continues to develop new technologies for controlling brain activity.

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