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A noninvasive method for deep brain stimulation

Anne Trafton |

Delivering an electrical current to a part of the brain involved in movement control has proven successful in treating many Parkinson’s disease patients. This approach, known as deep brain stimulation, requires implanting electrodes in the brain — a complex procedure that carries some risk to the patient.

Now, MIT researchers, collaborating with investigators at Beth Israel Deaconess Medical Center (BIDMC) and the IT’IS Foundation, have come up with a way to stimulate regions deep within the brain using electrodes placed on the scalp. This approach could make deep brain stimulation noninvasive, less risky, less expensive, and more accessible to patients.

“Traditional deep brain stimulation requires opening the skull and implanting an electrode, which can have complications. Secondly, only a small number of people can do this kind of neurosurgery,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, and the senior author of the study, which appears in the June 1 issue of Cell.

Doctors also use deep brain stimulation to treat some patients with obsessive compulsive disorder, epilepsy, and depression, and are exploring the possibility of using it to treat other conditions such as autism. The new, noninvasive approach could make it easier to adapt deep brain stimulation to treat additional disorders, the researchers say.

“With the ability to stimulate brain structures noninvasively, we hope that we may help discover new targets for treating brain disorders,” says the paper’s lead author, Nir Grossman, a former Wellcome Trust-MIT postdoc working at MIT and BIDMC, who is now a research fellow at Imperial College London.

Deep locations

Electrodes for treating Parkinson’s disease are usually placed in the subthalamic nucleus, a lens-shaped structure located below the thalamus, deep within the brain. For many Parkinson’s patients, delivering electrical impulses in this brain region can improve symptoms, but the surgery to implant the electrodes carries risks, including brain hemorrhage and infection.

Other researchers have tried to noninvasively stimulate the brain using techniques such as transcranial magnetic stimulation (TMS), which is FDA-approved for treating depression. Since TMS is noninvasive, it has also been used in normal human subjects to study the basic science of cognition, emotion, sensation, and movement. However, using TMS to stimulate deep brain structures can also result in surface regions being strongly stimulated, resulting in modulation of multiple brain networks.

The MIT team devised a way to deliver electrical stimulation deep within the brain, via electrodes placed on the scalp, by taking advantage of a phenomenon known as temporal interference.

This strategy requires generating two high-frequency electrical currents using electrodes placed outside the brain. These fields are too fast to drive neurons. However, these currents interfere with one another in such a way that where they intersect, deep in the brain, a small region of low-frequency current is generated inside neurons. This low-frequency current can be used to drive neurons’ electrical activity, while the high-frequency current passes through surrounding tissue with no effect.

By tuning the frequency of these currents and changing the number and location of the electrodes, the researchers can control the size and location of the brain tissue that receives the low-frequency stimulation. They can target locations deep within the brain without affecting any of the surrounding brain structures. They can also steer the location of stimulation, without moving the electrodes, by altering the currents. In this way, deep targets could be stimulated, both for therapeutic use and basic science investigations.

“You can go for deep targets and spare the overlying neurons, although the spatial resolution is not yet as good as that of deep brain stimulation,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research.

Targeted stimulation

Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, and researchers in her lab tested this technique in mice and found that they could stimulate small regions deep within the brain, including the hippocampus. They were also able to shift the site of stimulation, allowing them to activate different parts of the motor cortex and prompt the mice to move their limbs, ears, or whiskers.

“We showed that we can very precisely target a brain region to elicit not just neuronal activation but behavioral responses,” says Tsai, who is an author of the paper. “I think it’s very exciting because Parkinson’s disease and other movement disorders seem to originate from a very particular region of the brain, and if you can target that, you have the potential to reverse it.”

Significantly, in the hippocampus experiments, the technique did not activate the neurons in the cortex, the region lying between the electrodes on the skull and the target deep inside the brain. The researchers also found no harmful effects in any part of the brain.

Last year, Tsai showed that using light to visually induce brain waves of a particular frequency could substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the brains of mice. She now plans to explore whether this type of electrical stimulation could offer a new way to generate the same type of beneficial brain waves.

Other authors of the paper are MIT research scientist David Bono; former MIT postdocs Suhasa Kodandaramaiah and Andrii Rudenko; MIT postdoc Nina Dedic; MIT grad student Ho-Jun Suk; Beth Israel Deaconess Medical Center and Harvard Medical School Professor Alvaro Pascual-Leone; and IT’IS Foundation researchers Antonino Cassara, Esra Neufeld, and Niels Kuster.

The research was funded in part by the Wellcome Trust, a National Institutes of Health Director’s Pioneer Award, an NIH Director’s Transformative Research Award, the New York Stem Cell Foundation Robertson Investigator Award, the MIT Center for Brains, Minds, and Machines, Jeremy and Joyce Wertheimer, Google, a National Science Foundation Career Award, the MIT Synthetic Intelligence Project, and Harvard Catalyst: The Harvard Clinical and Translational Science Center.

Making brain implants smaller could prolong their lifespan

Anne Trafton |

Many diseases, including Parkinson’s disease, can be treated with electrical stimulation from an electrode implanted in the brain. However, the electrodes can produce scarring, which diminishes their effectiveness and can necessitate additional surgeries to replace them.

MIT researchers have now demonstrated that making these electrodes much smaller can essentially eliminate this scarring, potentially allowing the devices to remain in the brain for much longer.

“What we’re doing is changing the scale and making the procedure less invasive,” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study, which appears in the May 16 issue of Scientific Reports.

Cima and his colleagues are now designing brain implants that can not only deliver electrical stimulation but also record brain activity or deliver drugs to very targeted locations.

The paper’s lead author is former MIT graduate student Kevin Spencer. Other authors are former postdoc Jay Sy, graduate student Khalil Ramadi, Institute Professor Ann Graybiel, and David H. Koch Institute Professor Robert Langer.

Effects of size

Many Parkinson’s patients have benefited from treatment with low-frequency electrical current delivered to a part of the brain involved in movement control. The electrodes used for this deep brain stimulation are a few millimeters in diameter. After being implanted, they gradually generate scar tissue through the constant rubbing of the electrode against the surrounding brain tissue. This process, known as gliosis, contributes to the high failure rate of such devices: About half stop working within the first six months.

Previous studies have suggested that making the implants smaller or softer could reduce the amount of scarring, so the MIT team set out to measure the effects of both reducing the size of the implants and coating them with a soft polyethylene glycol (PEG) hydrogel.

The hydrogel coating was designed to have an elasticity very similar to that of the brain. The researchers could also control the thickness of the coating. They found that when coated electrodes were pushed into the brain, the soft coating would fall off, so they devised a way to apply the hydrogel and then dry it, so that it becomes a hard, thin film. After the electrode is inserted, the film soaks up water and becomes soft again.

In mice, the researchers tested both coated and uncoated glass fibers with varying diameters and found that there is a tradeoff between size and softness. Coated fibers produced much less scarring than uncoated fibers of the same diameter. However, as the electrode fibers became smaller, down to about 30 microns (0.03 millimeters) in diameter, the uncoated versions produced less scarring, because the coatings increase the diameter.

This suggests that a 30-micron, uncoated fiber is the optimal design for implantable devices in the brain.

“Before this paper, no one really knew the effects of size,” Cima says. “Softer is better, but not if it makes the electrode larger.”

New devices

The question now is whether fibers that are only 30 microns in diameter can be adapted for electrical stimulation, drug delivery, and recording electrical activity in the brain. Cima and his colleagues have had some initial success developing such devices.

“It’s one of those things that at first glance seems impossible. If you have 30-micron glass fibers, that’s slightly thicker than a piece of hair. But it is possible to do,” Cima says.
Such devices could be potentially useful for treating Parkinson’s disease or other neurological disorders. They could also be used to remove fluid from the brain to monitor whether treatments are having the intended effect, or to measure brain activity that might indicate when an epileptic seizure is about to occur.

The research was funded by the National Institutes of Health and MIT’s Institute for Soldier Nanotechnologies.

High-resolution imaging with conventional microscopes

Anne Trafton |

MIT researchers have developed a way to make extremely high-resolution images of tissue samples, at a fraction of the cost of other techniques that offer similar resolution.

The new technique relies on expanding tissue before imaging it with a conventional light microscope. Two years ago, the MIT team showed that it was possible to expand tissue volumes 100-fold, resulting in an image resolution of about 60 nanometers. Now, the researchers have shown that expanding the tissue a second time before imaging can boost the resolution to about 25 nanometers.

This level of resolution allows scientists to see, for example, the proteins that cluster together in complex patterns at brain synapses, helping neurons to communicate with each other. It could also help researchers to map neural circuits, says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT.

“We want to be able to trace the wiring of complete brain circuits,” says Boyden, the study’s senior author. “If you could reconstruct a complete brain circuit, maybe you could make a computational model of how it generates complex phenomena like decisions and emotions. Since you can map out the biomolecules that generate electrical pulses within cells and that exchange chemicals between cells, you could potentially model the dynamics of the brain.”

This approach could also be used to image other phenomena such as the interactions between cancer cells and immune cells, to detect pathogens without expensive equipment, and to map the cell types of the body.

Former MIT postdoc Jae-Byum Chang is the first author of the paper, which appears in the April 17 issue of Nature Methods.

Double expansion

To expand tissue samples, the researchers embed them in a dense, evenly generated gel made of polyacrylate, a very absorbent material that’s also used in diapers. Before the gel is formed, the researchers label the cell proteins they want to image, using antibodies that bind to specific targets. These antibodies bear “barcodes” made of DNA, which in turn are attached to cross-linking molecules that bind to the polymers that make up the expandable gel. The researchers then break down the proteins that normally hold the tissue together, allowing the DNA barcodes to expand away from each other as the gel swells.

These enlarged samples can then be labeled with fluorescent probes that bind the DNA barcodes, and imaged with commercially available confocal microscopes, whose resolution is usually limited to hundreds of nanometers.

Using that approach, the researchers were previously able to achieve a resolution of about 60 nanometers. However, “individual biomolecules are much smaller than that, say 5 nanometers or even smaller,” Boyden says. “The original versions of expansion microscopy were useful for many scientific questions but couldn’t equal the performance of the highest-resolution imaging methods such as electron microscopy.”

In their original expansion microscopy study, the researchers found that they could expand the tissue more than 100-fold in volume by reducing the number of cross-linking molecules that hold the polymer in an orderly pattern. However, this made the tissue unstable.

“If you reduce the cross-linker density, the polymers no longer retain their organization during the expansion process,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research. “You lose the information.”

Instead, in their latest study, the researchers modified their technique so that after the first tissue expansion, they can create a new gel that swells the tissue a second time — an approach they call “iterative expansion.”

Mapping circuits

Using iterative expansion, the researchers were able to image tissues with a resolution of about 25 nanometers, which is similar to that achieved by high-resolution techniques such as stochastic optical reconstruction microscopy (STORM). However, expansion microscopy is much cheaper and simpler to perform because no specialized equipment or chemicals are required, Boyden says. The method is also much faster and thus compatible with large-scale, 3-D imaging.

The resolution of expansion microscopy does not yet match that of scanning electron microscopy (about 5 nanometers) or transmission electron microscopy (about 1 nanometer). However, electron microscopes are very expensive and not widely available, and with those microscopes, it is difficult for researchers to label specific proteins.

In the Nature Methods paper, the MIT team used iterative expansion to image synapses — the connections between neurons that allow them to communicate with each other. In their original expansion microscopy study, the researchers were able to image scaffolding proteins, which help to organize the hundreds of other proteins found in synapses. With the new, enhanced resolution, the researchers were also able to see finer-scale structures, such as the location of neurotransmitter receptors located on the surfaces of the “postsynaptic” cells on the receiving side of the synapse.

“My hope is that we can, in the coming years, really start to map out the organization of these scaffolding and signaling proteins at the synapse,” Boyden says.

Combining expansion microscopy with a new tool called temporal multiplexing should help to achieve that, he believes. Currently, only a limited number of colored probes can be used to image different molecules in a tissue sample. With temporal multiplexing, researchers can label one molecule with a fluorescent probe, take an image, and then wash the probe away. This can then be repeated many times, each time using the same colors to label different molecules.

“By combining iterative expansion with temporal multiplexing, we could in principle have essentially infinite-color, nanoscale-resolution imaging over large 3-D volumes,” Boyden says. “Things are getting really exciting now that these different technologies may soon connect with each other.”

The researchers also hope to achieve a third round of expansion, which they believe could, in principle, enable resolution of about 5 nanometers. However, right now the resolution is limited by the size of the antibodies used to label molecules in the cell. These antibodies are about 10 to 20 nanometers long, so to get resolution below that, researchers would need to create smaller tags or expand the proteins away from each other first and then deliver the antibodies after expansion.

This study was funded by the National Institutes of Health Director’s Pioneer Award, the New York Stem Cell Foundation Robertson Award, the HHMI-Simons Faculty Scholars Award, and the Open Philanthropy Project.

Scientists unveil CRISPR-based diagnostic platform

Anne Trafton |

A team of scientists from the Broad Institute of MIT and Harvard, the McGovern Institute for Brain Research at MIT, the Institute for Medical Engineering and Science at MIT, and the Wyss Institute for Biologically Inspired Engineering at Harvard University has adapted a CRISPR protein that targets RNA (rather than DNA), for use as a rapid, inexpensive, highly sensitive diagnostic tool with the potential to transform research and global public health.

In a study published today in Science, Broad Institute members Feng Zhang, Jim Collins, Deb Hung, Aviv Regev, and Pardis Sabeti describe how this RNA-targeting CRISPR enzyme was harnessed as a highly sensitive detector — able to indicate the presence of as little as a single molecule of a target RNA or DNA. Co-first authors Omar Abudayyeh and Jonathan Gootenberg, graduate students at MIT and Harvard, respectively, dubbed the new tool SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing); this technology could one day be used to respond to viral and bacterial outbreaks, monitor antibiotic resistance, and detect cancer.

The scientists demonstrate the method’s versatility on a range of applications, including:

• detecting the presence of Zika virus in patient blood or urine samples within hours;
• distinguishing between the genetic sequences of African and American strains of Zika virus;
• discriminating specific types of bacteria, such as E. coli;
• detecting antibiotic resistance genes;
• identifying cancerous mutations in simulated cell-free DNA fragments; and
• rapidly reading human genetic information, such as risk of heart disease, from a saliva sample.

Because the tool can be designed for use as a paper-based test that does not require refrigeration, the researchers say it is well-suited for fast deployment and widespread use inside and outside of traditional settings — such as at a field hospital during an outbreak, or a rural clinic with limited access to advanced equipment.

“It’s exciting that the Cas13a enzyme, which was originally identified in our collaboration with Eugene Koonin to study the basic biology of bacterial immunity, can be harnessed to achieve such extraordinary sensitivity, which will be powerful for both science and clinical medicine,” says Feng Zhang, core institute member of the Broad Institute, an investigator at the McGovern Institute, and the James and Patricia Poitras ’63 Professor in Neuroscience and associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering at MIT.

In June 2016, Zhang and his colleagues first characterized the RNA-targeting CRISPR enzyme, now called Cas13a (previously known as C2c2), which can be programmed to cleave particular RNA sequences in bacterial cells. Unlike DNA-targeting CRISPR enzymes (such as Cas9 and Cpf1), Cas13a can remain active after cutting its intended RNA target and may continue to cut other nontargeted RNAs in a burst of activity that Zhang lab scientists referred to as “collateral cleavage.” In their paper and patent filing, the team described a wide range of biotechnological applications for the system, including harnessing RNA cleavage and collateral activity for basic research, diagnostics, and therapeutics.

In a paper in Nature in September 2016, Jennifer Doudna, Alexandra East-Seletsky, and their colleagues at the University of California at Berkeley employed the Cas13a collateral cleavage activity for RNA detection. That method required the presence of many millions of molecules, however, and therefore lacked the sensitivity required for many research and clinical applications.

The method reported today is a million-fold more sensitive. This increase was the result of a collaboration between Zhang and his team and Broad Institute member Jim Collins, who had been working on diagnostics for Zika virus.

Working together, the Zhang and Collins teams were able to use a different amplification process, relying on body heat, to boost the levels of DNA or RNA in their test samples. Once the level was increased, the team applied a second amplification step to convert the DNA to RNA, which enabled them to increase the sensitivity of the RNA-targeting CRISPR by a millionfold, all with a tool that can be used in nearly any setting.

“We can now effectively and readily make sensors for any nucleic acid, which is incredibly powerful when you think of diagnostics and research applications,” says Collins, the Termeer Professor of Medical Engineering and Science at MIT and core faculty member at the Wyss Institute. “This tool offers the sensitivity that could detect an extremely small amount of cancer DNA in a patient’s blood sample, for example, which would help researchers understand how cancer mutates over time. For public health, it could help researchers monitor the frequency of antibiotic-resistant bacteria in a population. The scientific possibilities get very exciting very quickly.”

One of the most urgent and obvious applications for this new diagnostic tool would be as a rapid, point-of-care diagnostic for infectious disease outbreaks in resource-poor areas.
“There is great excitement around this system,” says Deb Hung, co-author and co-director of the Broad’s Infectious Disease and Microbiome Program. “There is still much work to be done, but if SHERLOCK can be developed to its full potential it could fundamentally change the diagnosis of common and emerging infectious diseases.”

“One thing that’s especially powerful about SHERLOCK is its ability to start testing without a lot of complicated and time-consuming upstream experimental work,” says Pardis Sabeti, also a co-author in the paper. In the wake of the ongoing Zika outbreak, Sabeti and the members of her lab have been working to collect samples, rapidly sequence genomes, and share data in order to accelerate the outbreak response effort. “This ability to take raw samples and immediately start processing could transform the diagnosis of Zika and a boundless number of other infectious diseases,” she says. “This is just the beginning.”

Additional authors include Jeong Wook Lee, Patrick Essletzbichler, Aaron J. Dy, Julia Joung, Vanessa Verdine, Nina Donghia, Nichole M. Daringer, Catherine A. Freije, Cameron Myhrvold, Roby P. Bhattacharyya, Jonathan Livny, and Eugene V. Koonin.

2017 Sharp Lecture: Larry Abbott

Anne Trafton |

March 20, 2017
Phillip A. Sharp Lecture in Neural Circuits
Sponsored by Biogen Idec

“Unmarring the Perceptron: Lessons in Cerebellar Computing from Fish and Flies”
Larry Abbott, Columbia University

Precise technique tracks dopamine in the brain

Anne Trafton |

MIT researchers have devised a way to measure dopamine in the brain much more precisely than previously possible, which should allow scientists to gain insight into dopamine’s roles in learning, memory, and emotion.

Dopamine is one of the many neurotransmitters that neurons in the brain use to communicate with each other. Previous systems for measuring these neurotransmitters have been limited in how long they provide accurate readings and how much of the brain they can cover. The new MIT device, an array of tiny carbon electrodes, overcomes both of those obstacles.

“Nobody has really measured neurotransmitter behavior at this spatial scale and timescale. Having a tool like this will allow us to explore potentially any neurotransmitter-related disease,” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

Furthermore, because the array is so tiny, it has the potential to eventually be adapted for use in humans, to monitor whether therapies aimed at boosting dopamine levels are succeeding. Many human brain disorders, most notably Parkinson’s disease, are linked to dysregulation of dopamine.

“Right now deep brain stimulation is being used to treat Parkinson’s disease, and we assume that that stimulation is somehow resupplying the brain with dopamine, but no one’s really measured that,” says Helen Schwerdt, a Koch Institute postdoc and the lead author of the paper, which appears in the journal Lab on a Chip.

Studying the striatum

For this project, Cima’s lab teamed up with David H. Koch Institute Professor Robert Langer, who has a long history of drug delivery research, and Institute Professor Ann Graybiel, who has been studying dopamine’s role in the brain for decades with a particular focus on a brain region called the striatum. Dopamine-producing cells within the striatum are critical for habit formation and reward-reinforced learning.

Until now, neuroscientists have used carbon electrodes with a shaft diameter of about 100 microns to measure dopamine in the brain. However, these can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine, and other types of interfering films can also form on the electrode surface over time. Furthermore, there is only about a 50 percent chance that a single electrode will end up in a spot where there is any measurable dopamine, Schwerdt says.

The MIT team designed electrodes that are only 10 microns in diameter and combined them into arrays of eight electrodes. These delicate electrodes are then wrapped in a rigid polymer called PEG, which protects them and keeps them from deflecting as they enter the brain tissue. However, the PEG is dissolved during the insertion so it does not enter the brain.

These tiny electrodes measure dopamine in the same way that the larger versions do. The researchers apply an oscillating voltage through the electrodes, and when the voltage is at a certain point, any dopamine in the vicinity undergoes an electrochemical reaction that produces a measurable electric current. Using this technique, dopamine’s presence can be monitored at millisecond timescales.

Using these arrays, the researchers demonstrated that they could monitor dopamine levels in many parts of the striatum at once.

“What motivated us to pursue this high-density array was the fact that now we have a better chance to measure dopamine in the striatum, because now we have eight or 16 probes in the striatum, rather than just one,” Schwerdt says.

The researchers found that dopamine levels vary greatly across the striatum. This was not surprising, because they did not expect the entire region to be continuously bathed in dopamine, but this variation has been difficult to demonstrate because previous methods measured only one area at a time.

How learning happens

The researchers are now conducting tests to see how long these electrodes can continue giving a measurable signal, and so far the device has kept working for up to two months. With this kind of long-term sensing, scientists should be able to track dopamine changes over long periods of time, as habits are formed or new skills are learned.

“We and other people have struggled with getting good long-term readings,” says Graybiel, who is a member of MIT’s McGovern Institute for Brain Research. “We need to be able to find out what happens to dopamine in mouse models of brain disorders, for example, or what happens to dopamine when animals learn something.”

She also hopes to learn more about the roles of structures in the striatum known as striosomes. These clusters of cells, discovered by Graybiel many years ago, are distributed throughout the striatum. Recent work from her lab suggests that striosomes are involved in making decisions that induce anxiety.

This study is part of a larger collaboration between Cima’s and Graybiel’s labs that also includes efforts to develop injectable drug-delivery devices to treat brain disorders.

“What links all these studies together is we’re trying to find a way to chemically interface with the brain,” Schwerdt says. “If we can communicate chemically with the brain, it makes our treatment or our measurement a lot more focused and selective, and we can better understand what’s going on.”

Other authors of the paper are McGovern Institute research scientists Minjung Kim, Satoko Amemori, and Hideki Shimazu; McGovern Institute postdoc Daigo Homma; McGovern Institute technical associate Tomoko Yoshida; and undergraduates Harshita Yerramreddy and Ekin Karasan.

The research was funded by the National Institutes of Health, the National Institute of Biomedical Imaging and Bioengineering, and the National Institute of Neurological Disorders and Stroke.

McGovern Institute awards 2017 Scolnick Prize to Catherine Dulac

by Charles Jennings |

The McGovern Institute for Brain Research at MIT announced today that Catherine Dulac of Harvard University is the winner of the 2017 Edward M. Scolnick Prize in Neuroscience. She was awarded the prize for her contributions to the understanding of how pheromones control brain function and behavior and the characterization of neuronal circuits underlying sex-specific behaviors. The Scolnick Prize is awarded annually by the McGovern Institute to recognize outstanding advances in any field of neuroscience.

Dulac is the Higgins Professor in the Department of Molecular and Cellular Biology at Harvard University, where she served as Department Chair from 2007-2013. She is also an investigator of the Howard Hughes Medical Institute. She received her PhD from Pierre and Marie Curie University in Paris, where she studied mechanisms of neural crest development with Nicole le Douarin at the College de France. She moved to the US in 1992 as a postdoctoral fellow in the laboratory of Richard Axel at Columbia University, and joined the Harvard faculty in 1996.

Catherine DulacDulac is best known for her discovery of pheromone receptors and downstream brain circuits controlling sex-specific behaviors. Pheromones are volatile chemical signals that play a major role in controlling mammalian behaviors, in particular social and sexual behaviors such as aggression and reproduction. Unlike odorants, which give rise to the perception of smell, and which can be learned and flexibly associated with different stimuli, the responses to pheromones are fixed and stereotypic. Pheromone responses were known to require the vomeronasal organ (VNO), a specialized part of the olfactory epithelium within the nose, but until Dulac’s work, the molecular identity of the receptors and the neuronal circuits that underlie pheromone-evoked responses had been elusive.

In work that began while she was a postdoc, Dulac set out to identify these receptors, developing novel methods for analyzing RNA from individual sensory neurons. This pioneering work not only led her to the discovery of a large family of pheromone receptor genes, but also demonstrated the feasibility of analyzing the transcriptomes of individual neurons, an approach that is now widely used to study the brain’s extraordinary complexity.

Soon after starting her own lab at Harvard, Dulac discovered a second family of pheromone receptors. Both families are distinct from odorant receptors and are expressed in characteristic spatial patterns within the VNO. Dulac went on to study the mechanism of pheromone action, identifying the ion channel TRPC2 as an essential player in the response of VNO neurons to pheromone signaling. By genetically manipulating this signaling pathway in mice, Dulac was able to show that inputs from the VNO are necessary for gender identification and for the sex-specificity of social behaviors, including mating, aggression and parenting. She was also able to trace the connections from the VNO to the brain systems that control these behaviors, and to characterize specific neuronal populations that are necessary and sufficient for specific social behaviors. In one study, for example, she identified a population of neurons within the hypothalamus that induce parenting behaviors while suppressing aggression toward the offspring that would otherwise be triggered in males by signals from the VNO.

In another recent line of work, Dulac has studied genomic imprinting, an epigenetic phenomenon by which certain genes are differentially expressed depending on whether they were inherited from the mother or the father. Dulac’s work has revealed that imprinting of brain genes is much more common than previously realized, with important implications for basic biology and for the epidemiology of brain disorders.
Among her many honors and awards, Dulac is a fellow of the American Academy of Arts and Sciences, a Chevalier de la Legion d’Honneur, a member of the French Academy of Sciences, and a member of the US National Academy of Sciences.

The McGovern Institute will award the Scolnick Prize to Dr. Dulac on Monday March 13. At 4:00pm she will deliver a lecture entitled “The Neurobiology of Social Behavior Circuits,” to be followed by a reception, at the McGovern Institute in the Brain and Cognitive Sciences Complex, 43 Vassar Street (building 46, room 3002) in Cambridge. The event is free and open to the public.