Brain Disorder: Parkinson’s Disease

Ann Graybiel wins 2018 Gruber Neuroscience Prize

Anne Trafton |

Institute Professor Ann Graybiel, a professor in the Department of Brain and Cognitive Sciences and member of MIT’s McGovern Institute for Brain Research, is being recognized by the Gruber Foundation for her work on the structure, organization, and function of the once-mysterious basal ganglia. She was awarded the prize alongside Okihide Hikosaka of the National Institute of Health’s National Eye Institute and Wolfram Schultz of the University of Cambridge in the U.K.

The basal ganglia have long been known to play a role in movement, and the work of Graybiel and others helped to extend their roles to cognition and emotion. Dysfunction in the basal ganglia has been linked to a host of disorders including Parkinson’s disease, Huntington’s disease, obsessive-compulsive disorder and attention-deficit hyperactivity disorder, and to depression and anxiety disorders. Graybiel’s research focuses on the circuits thought to underlie these disorders, and on how these circuits act to help us form habits in everyday life.

“We are delighted that Ann has been honored with the Gruber Neuroscience Prize,” says Robert Desimone, director of the McGovern Institute. “Ann’s work has truly elucidated the complexity and functional importance of these forebrain structures. Her work has driven the field forward in a fundamental fashion, and continues to do so.’

Graybiel’s research focuses broadly on the striatum, a hub in basal ganglia-based circuits that is linked to goal-directed actions and habits. Prior to her work, the striatum was considered to be a primitive forebrain region. Graybiel found that the striatum instead has a complex architecture consisting of specialized zones: striosomes and the surrounding matrix. Her group went on to relate these zones to function, finding that striosomes and matrix differentially influence behavior. Among other important findings, Graybiel has shown that striosomes are focal points in circuits that link mood-related cortical regions with the dopamine-containing neurons of the midbrain, which are implicated in learning and motivation and which undergo degeneration in Parkinson’s disorder and other clinical conditions. She and her group have shown that these regions are activated by drugs of abuse, and that they influence decision-making, including decisions that require weighing of costs and benefits.

Graybiel continues to drive the field forward, finding that striatal neurons spike in an accentuated fashion and ‘bookend’ the beginning and end of behavioral sequences in rodents and primates. This activity pattern suggests that the striatum demarcates useful behavioral sequences such, in the case of rodents, pressing levers or running down mazes to receive a reward. Additionally, she and her group worked on miniaturized tools for chemical sensing and delivery as part of a continued drive toward therapeutic intervention in collaboration with the laboratories of Robert Langer in the Department of Chemical Engineering and Michael Cima, in the Department of Materials Science and Engineering.

“My first thought was of our lab, and how fortunate I am to work with such talented and wonderful people,” says Graybiel.  “I am deeply honored to be recognized by this prestigious award on behalf of our lab.”

The Gruber Foundation’s international prize program recognizes researchers in the areas of cosmology, neuroscience and genetics, and includes a cash award of $500,000 in each field. The medal given to award recipients also outlines the general mission of the foundation, “for the fundamental expansion of human knowledge,” and the prizes specifically honor those whose groundbreaking work fits into this paradigm.

Graybiel, a member of the MIT Class of 1971, has also previously been honored with the National Medal of Science, the Kavli Award, the James R. Killian Faculty Achievement Award at MIT, Woman Leader of Parkinson’s Science award from the Parkinson’s Disease Foundation, and has been recognized by the National Parkinson Foundation for her contributions to the understanding and treatment of Parkinson’s disease. Graybiel is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences.

The Gruber Neuroscience Prize will be presented in a ceremony at the annual meeting of the Society for Neuroscience in San Diego this coming November.

Ultrathin needle can deliver drugs directly to the brain

Anne Trafton |

MIT researchers have devised a miniaturized system that can deliver tiny quantities of medicine to brain regions as small as 1 cubic millimeter. This type of targeted dosing could make it possible to treat diseases that affect very specific brain circuits, without interfering with the normal function of the rest of the brain, the researchers say.

Using this device, which consists of several tubes contained within a needle about as thin as a human hair, the researchers can deliver one or more drugs deep within the brain, with very precise control over how much drug is given and where it goes. In a study of rats, they found that they could deliver targeted doses of a drug that affects the animals’ motor function.

“We can infuse very small amounts of multiple drugs compared to what we can do intravenously or orally, and also manipulate behavioral changes through drug infusion,” says Canan Dagdeviren, the LG Electronics Career Development Assistant Professor of Media Arts and Sciences and the lead author of the paper, which appears in the Jan. 24 issue of Science Translational Medicine.

“We believe this tiny microfabricated device could have tremendous impact in understanding brain diseases, as well as providing new ways of delivering biopharmaceuticals and performing biosensing in the brain,” says Robert Langer, the David H. Koch Institute Professor at MIT and one of the paper’s senior authors.

Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, is also a senior author of the paper.

Targeted action

Drugs used to treat brain disorders often interact with brain chemicals called neurotransmitters or the cell receptors that interact with neurotransmitters. Examples include l-dopa, a dopamine precursor used to treat Parkinson’s disease, and Prozac, used to boost serotonin levels in patients with depression. However, these drugs can have side effects because they act throughout the brain.

“One of the problems with central nervous system drugs is that they’re not specific, and if you’re taking them orally they go everywhere. The only way we can limit the exposure is to just deliver to a cubic millimeter of the brain, and in order to do that, you have to have extremely small cannulas,” Cima says.

The MIT team set out to develop a miniaturized cannula (a thin tube used to deliver medicine) that could target very small areas. Using microfabrication techniques, the researchers constructed tubes with diameters of about 30 micrometers and lengths up to 10 centimeters. These tubes are contained within a stainless steel needle with a diameter of about 150 microns. “The device is very stable and robust, and you can place it anywhere that you are interested,” Dagdeviren says.

The researchers connected the cannulas to small pumps that can be implanted under the skin. Using these pumps, the researchers showed that they could deliver tiny doses (hundreds of nanoliters) into the brains of rats. In one experiment, they delivered a drug called muscimol to a brain region called the substantia nigra, which is located deep within the brain and helps to control movement.

Previous studies have shown that muscimol induces symptoms similar to those seen in Parkinson’s disease. The researchers were able to generate those effects, which include stimulating the rats to continually turn in a clockwise direction, using their miniaturized delivery needle. They also showed that they could halt the Parkinsonian behavior by delivering a dose of saline through a different channel, to wash the drug away.

“Since the device can be customizable, in the future we can have different channels for different chemicals, or for light, to target tumors or neurological disorders such as Parkinson’s disease or Alzheimer’s,” Dagdeviren says.

This device could also make it easier to deliver potential new treatments for behavioral neurological disorders such as addiction or obsessive compulsive disorder, which may be caused by specific disruptions in how different parts of the brain communicate with each other.

“Even if scientists and clinicians can identify a therapeutic molecule to treat neural disorders, there remains the formidable problem of how to delivery the therapy to the right cells — those most affected in the disorder. Because the brain is so structurally complex, new accurate ways to deliver drugs or related therapeutic agents locally are urgently needed,” says Ann Graybiel, an MIT Institute Professor and a member of MIT’s McGovern Institute for Brain Research, who is also an author of the paper.

Measuring drug response

The researchers also showed that they could incorporate an electrode into the tip of the cannula, which can be used to monitor how neurons’ electrical activity changes after drug treatment. They are now working on adapting the device so it can also be used to measure chemical or mechanical changes that occur in the brain following drug treatment.

The cannulas can be fabricated in nearly any length or thickness, making it possible to adapt them for use in brains of different sizes, including the human brain, the researchers say.

“This study provides proof-of-concept experiments, in large animal models, that a small, miniaturized device can be safely implanted in the brain and provide miniaturized control of the electrical activity and function of single neurons or small groups of neurons. The impact of this could be significant in focal diseases of the brain, such as Parkinson’s disease,” says Antonio Chiocca, neurosurgeon-in-chief and chairman of the Department of Neurosurgery at Brigham and Women’s Hospital, who was not involved in the research.

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

Researchers engineer CRISPR to edit single RNA letters in human cells

Anne Trafton |

The Broad Institute and MIT scientists who first harnessed CRISPR for mammalian genome editing have engineered a new molecular system for efficiently editing RNA in human cells. RNA editing, which can alter gene products without making changes to the genome, has profound potential as a tool for both research and disease treatment.

In a paper published today in Science, senior author Feng Zhang and his team describe the new CRISPR-based system, called RNA Editing for Programmable A to I Replacement, or “REPAIR.” The system can change single RNA nucleotides in mammalian cells in a programmable and precise fashion. REPAIR has the ability to reverse disease-causing mutations at the RNA level, as well as other potential therapeutic and basic science applications.

“The ability to correct disease-causing mutations is one of the primary goals of genome editing,” says Zhang, a 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. “So far, we’ve gotten very good at inactivating genes, but actually recovering lost protein function is much more challenging. This new ability to edit RNA opens up more potential opportunities to recover that function and treat many diseases, in almost any kind of cell.”

REPAIR has the ability to target individual RNA letters, or nucleosides, switching adenosines to inosines (read as guanosines by the cell). These letters are involved in single-base changes known to regularly cause disease in humans. In human disease, a mutation from G to A is extremely common; these alterations have been implicated in, for example, cases of focal epilepsy, Duchenne muscular dystrophy, and Parkinson’s disease. REPAIR has the ability to reverse the impact of any pathogenic G-to-A mutation regardless of its surrounding nucleotide sequence, with the potential to operate in any cell type.

Unlike the permanent changes to the genome required for DNA editing, RNA editing offers a safer, more flexible way to make corrections in the cell. “REPAIR can fix mutations without tampering with the genome, and because RNA naturally degrades, it’s a potentially reversible fix,” explains co-first author David Cox, a graduate student in Zhang’s lab.

To create REPAIR, the researchers systematically profiled the CRISPR-Cas13 enzyme family for potential “editor” candidates (unlike Cas9, the Cas13 proteins target and cut RNA). They selected an enzyme from Prevotella bacteria, called PspCas13b, which was the most effective at inactivating RNA. The team engineered a deactivated variant of PspCas13b that still binds to specific stretches of RNA but lacks its “scissor-like” activity, and fused it to a protein called ADAR2, which changes the letters A to I in RNA transcripts.

In REPAIR, the deactivated Cas13b enzyme seeks out a target sequence of RNA, and the ADAR2 element performs the base conversion without cutting the transcript or relying on any of the cell’s native machinery.

The team further modified the editing system to improve its specificity, reducing detectable off-target edits from 18,385 to only 20 in the whole transcriptome. The upgraded incarnation, REPAIRv2, consistently achieved the desired edit in 20 to 40 percent — and up to 51 percent — of a targeted RNA without signs of significant off-target activity. “The success we had engineering this system is encouraging, and there are clear signs REPAIRv2 can be evolved even further for more robust activity while still maintaining specificity,” says Omar Abudayyeh, co-first author and a graduate student in Zhang’s lab. Cox and Abudayyeh are both students in the Harvard-MIT Program in Health Sciences and Technology.

To demonstrate REPAIR’s therapeutic potential, the team synthesized the pathogenic mutations that cause Fanconi anemia and X-linked nephrogenic diabetes insipidus, introduced them into human cells, and successfully corrected these mutations at the RNA level. To push the therapeutic prospects further, the team plans to improve REPAIRv2’s efficiency and to package it into a delivery system appropriate for introducing REPAIRv2 into specific tissues in animal models.

The researchers are also working on additional tools for other types of nucleotide conversions. “There’s immense natural diversity in these enzymes,” says co-first author Jonathan Gootenberg, a graduate student in both Zhang’s lab and the lab of Broad core institute member Aviv Regev. “We’re always looking to harness the power of nature to carry out these changes.”

Zhang, along with the Broad Institute and MIT, plans to share the REPAIR system widely. As with earlier CRISPR tools, the groups will make this technology freely available for academic research via the Zhang lab’s page on the plasmid-sharing website Addgene, through which the Zhang lab has already shared reagents more than 42,000 times with researchers at more than 2,200 labs in 61 countries, accelerating research around the world.

This research was funded, in part, by the National Institutes of Health and the Poitras Center for Affective Disorders Research.

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.

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.

Newly discovered neural connections may be linked to emotional decision-making

Anne Trafton |

MIT neuroscientists have discovered connections deep within the brain that appear to form a communication pathway between areas that control emotion, decision-making, and movement. The researchers suspect that these connections, which they call striosome-dendron bouquets, may be involved in controlling how the brain makes decisions that are influenced by emotion or anxiety.

This circuit may also be one of the targets of the neural degeneration seen in Parkinson’s disease, says Ann Graybiel, an Institute Professor at MIT, member of the McGovern Institute for Brain Research, and the senior author of the study.

Graybiel and her colleagues were able to find these connections using a technique developed at MIT known as expansion microscopy, which enables scientists to expand brain tissue before imaging it. This produces much higher-resolution images than would otherwise be possible with conventional microscopes.

That technique was developed in the lab of Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences at the MIT Media Lab, who is also an author of this study. Jill Crittenden, a research scientist at the McGovern Institute, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Sept. 19.

Tracing a circuit

In this study, the researchers focused on a small region of the brain known as the striatum, which is part of the basal ganglia — a cluster of brain centers associated with habit formation, control of voluntary movement, emotion, and addiction. Malfunctions of the basal ganglia have been associated with Parkinson’s and Huntington’s diseases, as well as autism, obsessive-compulsive disorder, and Tourette’s syndrome.

Much of the striatum is uncharted territory, but Graybiel’s lab has previously identified clusters of cells there known as striosomes. She also found that these clusters receive very specific input from parts of the brain’s prefrontal cortex involved in processing emotions, and showed that this communication pathway is necessary for making decisions that require an anxiety-provoking cost-benefit analysis, such as choosing whether to take a job that pays more but forces a move away from family and friends.

Her studies also suggested that striosomes relay information to cells within a region called the substantia nigra, one of the brain’s main dopamine-producing centers. Dopamine has many functions in the brain, including roles in initiating movement and regulating mood.

To figure out how these regions might be communicating, Graybiel, Crittenden, and their colleagues used expansion microscopy to image the striosomes and discovered extensive connections between those clusters of cells and dopamine-producing cells of the substantia nigra. The dopamine-producing cells send down many tiny extensions known as dendrites that become entwined with axons that come up to meet them from the striosomes, forming a bouquet-like structure.

“With expansion microscopy, we could finally see direct connections between these cells by unraveling their unusual rope-like bundles of axons and dendrites,” Crittenden says. “What’s really exciting to us is we can see that it’s small discrete clusters of dopamine cells with bundles that are being targeted.”

Hard decisions

This finding expands the known decision-making circuit so that it encompasses the prefrontal cortex, striosomes, and a subset of dopamine-producing cells. Together, the striosomes may be acting as a gatekeeper that absorbs sensory and emotional information coming from the cortex and integrates it to produce a decision on how to react, which is initiated by the dopamine-producing cells, the researchers say.

To explore that possibility, the researchers plan to study mice in which they can selectively activate or shut down the striosome-dendron bouquet as the mice are prompted to make decisions requiring a cost-benefit analysis.

The researchers also plan to investigate whether these connections are disrupted in mouse models of Parkinson’s disease. MRI studies and postmortem analysis of brains of Parkinson’s patients have shown that death of dopamine cells in the substantia nigra is strongly correlated with the disease, but more work is needed to determine if this subset overlaps with the dopamine cells that form the striosome-dendron bouquets.

Genome Editing with CRISPR – Cas9

Anne Trafton |

This animation depicts the CRISPR-Cas9 method for genome editing – a powerful new technology with many applications in biomedical research, including the potential to treat human genetic disease. Feng Zhang, a leader in the development of this technology, is a faculty member at MIT, an investigator at the McGovern Institute for Brain Research, and a core member of the Broad Institute.

 

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.

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.