Researcher: Ann Graybiel

Obama hosts Dresselhaus, Graybiel and Luu in Oval Office

Anne Trafton |

President Barack Obama met Thursday, March 28, in the Oval Office with the six U.S. recipients of the 2012 Kavli Prizes — including MIT’s Mildred S. Dresselhaus, Ann M. Graybiel and Jane X. Luu. Obama and his science and technology advisor, John P. Holdren, received the scientists to recognize their landmark contributions in nanoscience, neuroscience and astrophysics, respectively. [watch video]

“American scientists, engineers and innovators strengthen our nation every day and in countless ways, but the all-stars honored by the Kavli Foundation deserve special praise for the scale of their advances in some of the most important and exciting research disciplines today,” said Holdren, who also serves as director of the White House Office of Science and Technology Policy. “I am grateful not only for their profound accomplishments, but for the inspiration they are providing to a new generation of doers, makers and discoverers.”

The researchers received their Kavli Prizes for making fundamental contributions to our understanding of the outer solar system; of the differences in material properties at nano- and larger scales; and of how the brain receives and responds to sensations such as sight, sound and touch.

The 2012 Kavli Prize in Astrophysics was awarded to Luu, David C. Jewitt of the University of California at Los Angeles, and Michael E. Brown of the California Institute of Technology for discovering and characterizing the Kuiper Belt and its largest members, work that led to a major advance in the understanding of the history of our planetary system. The Kuiper Belt lies beyond the orbit of Neptune and is a disk of more than 70,000 small bodies made of rock and ice, and orbiting the sun. Jewitt and Luu discovered the Kuiper Belt, and Brown discovered and characterized many of its largest members.

The 2012 Kavli Prize in Nanoscience was awarded to Dresselhaus for her work explaining why the properties of materials structured at the nanoscale can vary so much from those of the same materials at larger dimensions. Her early work provided the foundation for later discoveries concerning the famous C60 buckyball, carbon nanotubes and graphene. Dresselhaus received the Kavli Prize for her research into uniform oscillations of elastic arrangements of atoms or molecules called phonons; phonon-electron interactions; and heat conductivity in nanostructures.

The 2012 Kavli Prize in Neuroscience was awarded to Graybiel, Cornelia Isabella Bargmann of Rockefeller University, and Winfried Denk of the Max Planck Institute for Medical Research, who have pioneered the study of how sensory signals pass from the point of sensation — whether the eye, the foot or the nose — to the brain, and how decisions are made to respond. Each working on different parts of the brain, and using different techniques and models, they have combined precise neuroanatomy with sophisticated functional studies to gain understanding of their chosen systems.

Breaking down the Parkinson’s pathway

Anne Trafton |

The key hallmark of Parkinson’s disease is a slowdown of movement caused by a cutoff in the supply of dopamine to the brain region responsible for coordinating movement. While scientists have understood this general process for many years, the exact details of how this happens are still murky.

“We know the neurotransmitter, we know roughly the pathways in the brain that are being affected, but when you come right down to it and ask what exactly is the sequence of events that occurs in the brain, that gets a little tougher,” says Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research.

A new study from Graybiel’s lab offers insight into some of the precise impairments caused by the loss of dopamine in brain cells affected by Parkinson’s disease. The findings, which appear in the March 12 online edition of the Journal of Neuroscience, could help researchers not only better understand the disease, but also develop more targeted treatments.

Lead author of the paper is Ledia Hernandez, a former MIT postdoc. Other authors are McGovern Institute research scientists Yasuo Kubota and Dan Hu, former MIT graduate student Mark Howe and graduate student Nuné Lemaire.

Cutting off dopamine

The neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources — the neocortex and a tiny region known as the substantia nigra. The cortex relays sensory information as well as plans for future action, while the substantia nigra sends dopamine that helps to coordinate all of the cortical input.

“This dopamine somehow modulates the circuit interactions in such a way that we don’t move too much, we don’t move too little, we don’t move too fast or too slow, and we don’t get overly repetitive in the movements that we make. We’re just right,” Graybiel says.

Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum die, cutting off a critical dopamine source; in a process that is not entirely understood, too little dopamine translates to difficulty initiating movement. Most Parkinson’s patients receive L-dopa, which can substitute for the lost dopamine. However, the effects usually wear off after five to 10 years, and complications appear.

To study exactly how dopamine loss affects the striatum, the researchers disabled dopamine-releasing cells on one side of the striatum, in rats. This mimics what usually happens in the early stages of Parkinson’s disease, when dopamine input is cut off on only one side of the brain.

As the rats learned to run a T-shaped maze, the researchers recorded electrical activity in many individual neurons. The rats were rewarded for correctly choosing to run left or right as they approached the T, depending on the cue that they heard.

The researchers focused on two types of neurons: projection neurons, which send messages from the striatum to the neocortex to initiate or halt movement, and fast-spiking interneurons, which enable local communication within the striatum. Among the projection neurons, the researchers identified two subtypes — those that were active just before the rats began running, and those that were active during the run.

In the dopamine-depleted striatum, the researchers found, to their surprise, that the projection neurons still developed relatively normal activity patterns. However, they became even more active during the time when they were usually active (before or during the run). These hyper-drive effects were related to whether the rats had learned the maze task or not.

The interneurons, however, never developed the firing patterns seen in normal interneurons during learning, even after the rats had learned to run the maze. The local circuits were disabled.

Restoring neuron function

When the researchers then treated the rats with L-dopa, the drug restored normal activity in the projection neurons, but did not bring back normal activity in the interneurons. A possible reason for that is that those cells become disconnected by the loss of dopamine, so even when L-dopa is given, they can no longer shape the local circuits to respond to it.

This is the first study to show that the effects of dopamine loss depend not only on the type of neuron, but also on the phase of task behavior and how well the task has been learned, according to the researchers. To glean even more detail, Graybiel’s lab is now working on measuring dopamine levels in different parts of the brain as the dopamine-depleted rats learn new behaviors.

The lab is also seeking ways to restore function to the striatal interneurons that don’t respond to L-dopa treatment. The findings underscore the need for therapies that target specific deficiencies, says Joshua Goldberg, a senior lecturer in medical neurobiology at the Hebrew University of Jerusalem.

The new study “refines our appreciation of the complexity of [Parkinson’s],” says Goldberg, who was not part of the research team. “Graybiel’s team drives home the message that dopamine depletion, and dopamine replacement therapy, do not affect brain dynamics or behavior in a uniform fashion. Instead, their effect is highly context-dependent and differentially affects various populations of neurons.”

The research was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the National Parkinson Foundation, the Stanley H. and Sheila G. Sydney Fund, a Parkinson’s Disease Foundation Fellowship and a Fulbright Fellowship.

How the brain controls our habits

Anne Trafton |

Habits are behaviors wired so deeply in our brains that we perform them automatically. This allows you to follow the same route to work every day without thinking about it, liberating your brain to ponder other things, such as what to make for dinner.

However, the brain’s executive command center does not completely relinquish control of habitual behavior. A new study from MIT neuroscientists has found that a small region of the brain’s prefrontal cortex, where most thought and planning occurs, is responsible for moment-by-moment control of which habits are switched on at a given time.

“We’ve always thought – and I still do – that the value of a habit is you don’t have to think about it. It frees up your brain to do other things,” says Institute Professor Ann Graybiel, a member of the McGovern Institute for Brain Research at MIT. “However, it doesn’t free up all of it. There’s some piece of your cortex that are still devoted to that control.”

The new study offers hope for those trying to kick bad habits, says Graybiel, senior author of the new study, which appears this week in the Proceedings of the National Academy of Sciences. It shows that though habits may be deeply ingrained, the brain’s planning centers can shut them off. It also raises the possibility of intervening in that brain region to treat people who suffer from disorders involving overly habitual behavior, such as obsessive-compulsive disorder.

Lead author of the paper is Kyle Smith, a McGovern Institute research scientist. Other authors are recent MIT graduate Arti Virkud and Karl Deisseroth, a professor of psychiatry and behavioral sciences at Stanford University.

Old habits die hard

Habits often become so ingrained that we keep doing them even though we’re no longer benefiting from them. The MIT team experimentally simulated this situation with rats trained to run a T-shaped maze. As the rats approached the decision point, they heard a tone indicating whether they should turn left or right. When they chose correctly, they received a reward – chocolate milk (for turning left) or sugar water (for turning right).

To show that the behavior was habitual, the researchers eventually stopped giving the trained rats any rewards, and found that they continued running the maze correctly. The researchers then went a step further, offering the rats chocolate milk in their cages but mixing it with lithium chloride, which causes light nausea. The rats still continued to run left when cued to do so, although they stopped drinking the chocolate milk.

Once they had shown that the habit was fully ingrained, the researchers wanted to see if they could break it by interfering with a part of the prefrontal cortex known as the infralimbic (IL) cortex. Although the neural pathways that encode habitual behavior appear to be located in deep brain structures known as the basal ganglia, it has been shown that the IL cortex is also necessary for such behaviors to develop.

Using optogenetics, a technique that allows researchers to inhibit specific cells with light, the researchers turned off IL cortex activity for several seconds as the rats approached the point in the maze where they had to decide which way to turn.

Almost instantly, the rats dropped the habit of running to the left (the side with the now-distasteful reward). This suggests that turning off the IL cortex switches the rats’ brains from an “automatic, reflexive mode to a mode that’s more cognitive or engaged in the goal of processing what exactly it is that they’re running for,” Smith says.

Once broken of the habit of running left, the rats soon formed a new habit, running to the right side every time, even when cued to run left. The researchers showed that they could break this new habit by once again inhibiting the IL cortex with light. To their surprise, they found that these rats immediately regained their original habit of running left when cued to do so.

“This habit was never really forgotten,” Smith says. “It’s lurking there somewhere, and we’ve unmasked it by turning off the new one that had been overwritten.”

Online control

The findings suggest that the IL cortex is responsible for determining, moment-by-moment, which habitual behaviors will be expressed. “To us, what’s really stunning is that habit representation still must be totally intact and retrievable in an instant, and there’s an online monitoring system controlling that,” Graybiel says.

The study also raises interesting ideas concerning how automatic habitual behaviors really are, says Jane Taylor, a professor of psychiatry and psychology at Yale University. “We’ve always thought of habits as being inflexible, but this suggests you can have flexible habits, in some sense,” says Taylor, who was not part of the research team.

It also appears that the IL cortex favors new habits over old ones, consistent with previous studies showing that when habits are broken they are not forgotten, but replaced with new ones.

Although it would be too invasive to use optogenetic interventions to break habits in humans, Graybiel says it is possible the technology will evolve to the point where it might be a feasible option for treating disorders involving overly repetitive or addictive behavior.

In follow-up studies, the researchers are trying to pinpoint exactly when during a maze run the IL cortex selects the appropriate habit. They are also planning to specifically inhibit different cell types within the IL cortex, to see which ones are most involved in habit control.

The research was funded by the National Institutes of Health, the Stanley H. and Sheila G. Sydney Fund, R. Pourian and Julia Madadi, the Defense Advanced Research Projects Agency, and the Gatsby Foundation.

Ann Graybiel wins Kavli Prize in Neuroscience

Anne Trafton |

Three MIT researchers including Ann Graybiel  are among seven pioneering scientists worldwide named today as this year’s recipients of the Kavli Prizes.

These prizes recognize scientists for their seminal advances in astrophysics, nanoscience and neuroscience, and include a cash award of $1 million in each field. This year’s laureates were selected for their fundamental contributions to our understanding of the outer solar system; the differences in material properties at the nanoscale and at larger scales; and how the brain receives and responds to sensations such as sight, sound and touch.

The Kavli Prizes, awarded biennially since 2008, are a partnership between the Norwegian Academy of Science and Letters, the Kavli Foundation and the Norwegian Ministry of Education and Research. Today’s announcement was made by Nils Christian Stenseth, president of the Norwegian Academy of Science and Letters, and transmitted live at the opening event of the World Science Festival in New York.

King Harald of Norway will present the Kavli Prizes to the laureates at an award ceremony in Oslo on Sept. 4. The ceremony will be hosted by Ã…se Kleveland, former minister of culture for Norway, and Alan Alda, the actor, director, writer and longtime supporter of science.

The Kavli Prize in Astrophysics

The 2012 Kavli Prize in Astrophysics is shared by Jane X. Luu, a technical staff member at MIT’s Lincoln Laboratory, along with David C. Jewitt of the University of California at Los Angeles and Michael E. Brown of the California Institute of Technology. They received the prize “for discovering and characterizing the Kuiper Belt and its largest members, work that led to a major advance in the understanding of the history of our planetary system.”

In 1992, Luu and Jewitt spotted the first known object in the Kuiper Belt, a region beyond Neptune’s orbit that is more than 30 times Earth’s distance from the sun. Since then, they and others have identified more than 1,000 Kuiper Belt objects. Astronomers are particularly interested in these objects because their composition may resemble the primordial material that coalesced around the sun during the formation of our solar system.

Brown followed in Luu and Jewitt’s footsteps by searching the Kuiper Belt for planet-sized bodies. In 2005, he found Eris, an object about the same size as Pluto but with 27 percent more mass. As a result, astronomers revisited the definition of planets; Pluto was subsequently relegated to “dwarf planet” status.

The Kavli Prize in Nanoscience

The 2012 Kavli Prize in Nanoscience is given to Mildred S. Dresselhaus, Institute Professor Emerita of Physics and Computer Science and Engineering at MIT, “for her pioneering contributions to the study of phonons, electron-phonon interactions, and thermal transport in nanostructures.”

Over five decades, Dresselhaus has made multiple advances explaining how the nanoscale properties of materials can vary from those of the same materials at larger dimensions. Her early work on carbon fibers and on compounds made up of different chemical species sandwiched between graphite layers — known as graphite intercalation compounds — laid the groundwork for later discoveries concerning buckyballs, carbon nanotubes and graphene.

The Kavli Prize in Neuroscience

The Kavli Prize in Neuroscience is shared by Ann M. Graybiel, Institute Professor in MIT’s Department of Brain and Cognitive Science, along with Cornelia Isabella Bargmann of Rockefeller University and Winfried Denk of the Max Planck Institute for Medical Research. They received the prize “for elucidating basic neuronal mechanisms underlying perception and decision.”

Graybiel, of MIT’s McGovern Institute for Brain Research, has identified and traced neural loops connecting the outer layer of the brain to a region called the striatum, revealing that these form the basis for linking sensory cues to actions involved in habitual behaviors. Her work has provided a deeper understanding of human ability to make or break habits, and of what goes wrong in disorders involving movement and repetitive behaviors.

Bargmann has used nematode worms to provide insights into the molecular controls of animal behavior, yielding important advances including the discovery of the first evidence that odor response is governed by neurons; of the intracellular signaling pathways between odorant receptors and sensory neurons; and of specific neurons, receptors and neurotransmitters involved in behavior adaption following experience.

Two techniques developed by Denk have answered major questions about how information is transmitted from the eye to the brain: His invention of two-photon laser scanning fluorescence microscopy allowed imaging of living tissue at greater depths and with less unwanted background fluorescence, and his development of serial block-face electron microscopy allowed detailed 3-D imaging of minute structures within tissue.

About the Kavli Prizes

Kavli Prize recipients are chosen biennially by committees of distinguished international scientists recommended by the Chinese Academy of Sciences, the French Academy of Sciences, the Max Planck Society, the National Academy of Sciences and the Royal Society. The recommendations of these prize committees are then confirmed by the Norwegian Academy of Science and Letters.

The Kavli Prizes were initiated by and named after Fred Kavli, founder and chairman of the Kavli Foundation, which is dedicated to advancing science for the benefit of humanity, promoting public understanding of scientific research, and supporting scientists and their work.

For more detailed information on each of the prizes including a video of the 2012 award ceremony, see the Kavli Prize website.