Researcher: Ann Graybiel

How our gray matter tackles gray areas

by Gina Vitale | MIT News correspondent |

When Katie O’Nell’s high school biology teacher showed a NOVA video on epigenetics after the AP exam, he was mostly trying to fill time. But for O’Nell, the video sparked a whole new area of curiosity.

She was fascinated by the idea that certain genes could be turned on and off, controlling what traits or processes were expressed without actually editing the genetic code itself. She was further excited about what this process could mean for the human mind.

But upon starting at MIT, she realized that she was less interested in the cellular level of neuroscience and more fascinated by bigger questions, such as, what makes certain people generous toward certain others? What’s the neuroscience behind morality?

“College is a time you can learn about anything you want, and what I want to know is why humans are really, really wacky,” she says. “We’re dumb, we make super irrational decisions, it makes no sense. Sometimes it’s beautiful, sometimes it’s awful.”

O’Nell, a senior majoring in brain and cognitive sciences, is one of five MIT students to have received a Marshall Scholarship this year. Her quest to understand the intricacies of the wacky human brain will not be limited to any one continent. She will be using the funding to earn her master’s in experimental psychology at Oxford University.

Chocolate milk and the mouse brain

O’Nell’s first neuroscience-related research experience at MIT took place during her sophomore and junior year, in the lab of Institute Professor Ann Graybiel at the McGovern Institute.

The research studied the neurological components of risk-vs-reward decision making, using a key ingredient: chocolate milk. In the experiments, mice were given two options — they could go toward the richer, sweeter chocolate milk, but they would also have to endure a brighter light. Or, they could go toward a more watered-down chocolate milk, with the benefit of a softer light. All the while, a fluorescence microscope tracked when certain cell types were being activated.

“I think that’s probably the closest thing I’ve ever had to a spiritual experience … watching this mouse in this maze deciding what to do, and watching the cells light up on the screen. You can see single-cell evidence of cognition going on. That’s just the coolest thing.”

In her junior spring, O’Nell delved even deeper into questions of morality in the lab of Professor Rebecca Saxe. Her research there centers on how the human brain parses people’s identities and emotional states from their faces alone, and how those computations are related to each other. Part of what interests O’Nell is the fact that we are constantly making decisions, about ourselves and others, with limited information.

“We’re always solving under uncertainty,” she says. “And our brain does it so well, in so many ways.”

International intrigue

Outside of class, O’Nell has no shortage of things to do. For starters, she has been serving as an associate advisor for a first-year seminar since the fall of her sophomore year.

“Basically it’s my job to sit in on a seminar and bully them into not taking seven classes at a time, and reminding them that yes, your first 8.01 exam is tomorrow,” she says with a laugh.

She has also continued an activity she was passionate about in high school — Model United Nations. One of the most fun parts for her is serving on the Historical Crisis Committee, in which delegates must try to figure out a way to solve a real historical problem, like the Cuban Missile Crisis or the French and Indian War.

“This year they failed and the world was a nuclear wasteland,” she says. “Last year, I don’t entirely know how this happened, but France decided that they wanted to abandon the North American theater entirely and just took over all of Britain’s holdings in India.”

She’s also part of an MIT program called the Addir Interfaith Fellowship, in which a small group of people meet each week and discuss a topic related to religion and spirituality. Before joining, she didn’t think it was something she’d be interested in — but after being placed in a first-year class about science and spirituality, she has found discussing religion to be really stimulating. She’s been a part of the group ever since.

O’Nell has also been heavily involved in writing and producing a Mystery Dinner Theater for Campus Preview Weekend, on behalf of her living group J Entry, in MacGregor House. The plot, generally, is MIT-themed — a physics professor might get killed by a swarm of CRISPR nanobots, for instance. When she’s not cooking up murder mysteries, she might be running SAT classes for high school students, playing piano, reading, or spending time with friends. Or, when she needs to go grocery shopping, she’ll be stopping by the Trader Joe’s on Boylston Avenue, as an excuse to visit the Boston Public Library across the street.

Quite excited for the future

O’Nell is excited that the Marshall Scholarship will enable her to live in the country that produced so many of the books she cherished as a kid, like “The Hobbit.” She’s also thrilled to further her research there. However, she jokes that she still needs to get some of the lingo down.

“I need to learn how to use the word ‘quite’ correctly. Because I overuse it in the American way,” she says.

Her master’s research will largely expand on the principles she’s been examining in the Saxe lab. Questions of morality, processing, and social interaction are where she aims to focus her attention.

“My master’s project is going to be basically taking a look at whether how difficult it is for you to determine someone else’s facial expression changes how generous you are with people,” she explains.

After that, she hopes to follow the standard research track of earning a PhD, doing postdoctoral research, and then entering academia as a professor and researcher. Teaching and researching, she says, are two of her favorite things — she’s excited to have the chance to do both at the same time. But that’s a few years ahead. Right now, she hopes to use her time in England to learn all she can about the deeper functions of the brain, with or without chocolate milk.

Ann Graybiel

Probing the Deep Brain

Ann Graybiel studies the basal ganglia, forebrain structures that are profoundly important for normal brain function. Dysfunction in these regions is implicated in neurologic and neuropsychiatric disorders ranging from Parkinson’s disease and Huntington’s disease to obsessive-compulsive disorder, anxiety and depression, and addiction. Graybiel’s laboratory is uncovering circuits underlying both the neural deficits related to these disorders, as well as the role that the basal ganglia play in guiding normal learning, motivation, and behavior.

Is it worth the risk?

by Shannon Fischer |

During the Klondike Gold Rush, thousands of prospectors climbed Alaska’s dangerous Chilkoot Pass in search of riches. McGovern scientists are exploring how a once-overlooked part of the brain might be at the root of cost-benefit decisions like these. McGovern researchers are studying how the brain balances risk and reward to make decisions.

Is it worth speeding up on the highway to save a few minutes’ time? How about accepting a job that pays more, but requires longer hours in the office?

Scientists call these types of real-life situations cost-benefit conflicts. Choosing well is an essential survival ability—consider the animal that must decide when to expose itself to predation to gather more food.

Now, McGovern researchers are discovering that this fundamental capacity to make decisions may originate in the basal ganglia—a brain region once considered unimportant to the human
experience—and that circuits associated with this structure may play a critical role in determining our state of mind.

Anatomy of decision-making

A few years back, McGovern investigator Ann Graybiel noticed that in the brain imaging literature, a specific part of the cortex called the pregenual anterior cingulate cortex or pACC, was implicated in certain psychiatric disorders as well as tasks involving cost-benefit decisions. Thanks to her now classic neuroanatomical work defining the complex anatomy and function of the basal ganglia, Graybiel knew that the pACC projected back into the basal ganglia—including its largest cluster of neurons, the striatum.

The striatum sits beneath the cortex, with a mouse-like main body and curving tail. It seems to serve as a critical way-station, communicating with both the brain’s sensory and motor areas above, and the limbic system (linked to emotion and memory) below. Running through the striatum are striosomes, column-like neurochemical compartments. They wire down to a small, but important part of the brain called the substantia nigra, which houses the huge majority of the brain’s dopamine neurons—a key neurochemical heavily involved, much like the basal ganglia as a whole, in reward, learning, and movement. The pACC region related to mood control targeted these striosomes, setting up a communication line from the neocortex to the dopamine neurons.

Graybiel discovered these striosomes early in her career, and understood them to have distinct wiring from other compartments in the striatum, but picking out these small, hard-to-find striosomes posed a technological challenge—so it was exciting to have this intriguing link to the pACC and mood disorders.

Working with Ken-ichi Amemori, then a research scientist in her lab, she adapted a common human cost-benefit conflict test for macaque monkeys. The monkeys could elect to receive a food treat, but the treat would always be accompanied by an annoying puff of air to the eyes. Before they decided, a visual cue told them exactly how much treat they could get, and exactly how strong the air puff would be, so they could choose if the treat was worth it.

Normal monkeys varied their choices in a fairly rational manner, rejecting the treat whenever it seemed like the air puff was too strong, or the treat too small to be worth it—and this corresponded with activity in the pACC neurons. Interestingly, they found that some pACC neurons respond more when animals approach the combined offers, while other pACC neurons
fire more when the animals avoid the offers. “It is as though there are two opposing armies. And the one that wins, controls the state of the animal.” Moreover, when Graybiel’s team electrically stimulated these pACC neurons, the animals begin to avoid the offers, even offers that they normally would approach. “It is as though when the stimulation is on, they think the future is worse than it really is,” Graybiel says.

Intriguingly, this effect only worked in situations where the animal had to weigh the value of a cost against a benefit. It had no effect on a decision between two negatives or two positives, like two different sizes of treats. The anxiety drug diazepam also reversed the stimulatory effect, but again, only on cost-benefit choices. “This particular kind of mood-influenced cost-benefit
decision-making occurs not only under conflict conditions but in our regular day to day lives. For example: I know that if I eat too much chocolate, I might get fat, but I love it, I want it.”

Glass half empty

Over the next few years, Graybiel, with another research scientist in her lab, Alexander Friedman, unraveled the circuit behind the macaques’ choices. They adapted the test for rats and mice,
so that they could more easily combine the cellular and molecular technologies needed to study striosomes, such as optogenetics and mouse engineering.

They found that the cortex (specifically, the pre-limbic region of the prefrontal cortex in rodents) wires onto both striosomes and fast-acting interneurons that also target the striosomes. In a
healthy circuit, these interneurons keep the striosomes in check by firing off fast inhibitory signals, hitting the brakes before the striosome can get started. But if the researchers broke that corticalstriatal connection with optogenetics or chronic stress, the animals became reckless, going for the high-risk, high-reward arm of the maze like a gambler throwing caution to the wind. If they amplified this inhibitory interneuron activity, they saw the opposite effect. With these techniques, they could block the effects of prior chronic stress.

This summer, Graybiel and Amemori published another paper furthering the story and returning to macaques. It was still too difficult to hit striosomes, and the researchers could only stimulate the striatum more generally. However, they replicated the effects in past studies.

Many electrodes had no effect, a small number made the monkeys choose the reward more often. Nearly a quarter though made the monkeys more avoidant—and this effect correlated with a change in the macaques’ brainwaves in a manner reminiscent of patients with depression.

But the surprise came when the avoidant-producing stimulation was turned off, the effects lasted unexpectedly long, only returning to normal on the third day.

Graybiel was stunned. “This is very important, because changes in the brain can get set off and have a life of their own,” she says. “This is true for some individuals who have had a terrible experience, and then live with the aftermath, even to the point of suffering from post-traumatic stress disorder.”

She suspects that this persistent state may actually be a form of affect, or mood. “When we change this decision boundary, we’re changing the mood, such that the animal overestimates cost, relative to benefit,” she explains. “This might be like a proxy state for pessimistic decision-making experienced during anxiety and depression, but may also occur, in a milder form, in you and me.”

Graybiel theorizes that this may tie back into the dopamine neurons that the striosomes project to: if this avoidance behavior is akin to avoidance observed in rodents, then they are stimulating a circuit that ultimately projects to dopamine neurons of the substantia nigra. There, she believes, they could act to suppress these dopamine neurons, which in turn project to the rest of the brain, creating some sort of long-term change in their neural activity. Or, put more simply, stimulation of these circuits creates a depressive funk.

Bottom up

Three floors below the Graybiel lab, postdoc Will Menegas is in the early stages of his own work untangling the role of dopamine and the striatum in decision-making. He joined Guoping Feng’s lab this summer after exploring the understudied “tail of the striatum” at Harvard University.

While dopamine pathways influence many parts of the brain, examination of connections to the striatum have largely focused on the frontmost part of the striatum, associated with valuations.

But as Menegas showed while at Harvard, dopamine neurons that project to the rear of the striatum are different. Those neurons get their input from parts of the brain associated with general arousal and sensation—and instead of responding to rewards, they respond to novelty and intense stimuli, like air puffs and loud noises.

In a new study published in Nature Neuroscience, Menegas used a neurotoxin to disrupt the dopamine projection from the substantia nigra to the posterior striatum to see how this circuit influences behavior. Normal mice approach novel items cautiously and back away after sniffing at them, but the mice in Menegas’ study failed to back away. They stopped avoiding a port that gave an air puff to the face and they didn’t behave like normal mice when Menegas dropped a strange or new object—say, a lego—into their cage. Disrupting the nigral-posterior striatum
seemed to turn off their avoidance habit.

“These neurons reinforce avoidance the same way that canonical dopamine neurons reinforce approach,” Menegas explains. It’s a new role for dopamine, suggesting that there may be two different and distinct systems of reinforcement, led by the same neuromodulator in different parts of the striatum.

This research, and Graybiel’s discoveries on cost-benefit decision circuits, share clear parallels, though the precise links between the two phenomena are yet to be fully determined. Menegas plans to extend this line of research into social behavior and related disorders like autism in marmoset monkeys.

“Will wants to learn the methods that we use in our lab to work on marmosets,” Graybiel says. “I think that working together, this could become a wonderful story, because it would involve social interactions.”

“This a very new angle, and it could really change our views of how the reward system works,” Feng says. “And we have very little understanding of social circuits so far and especially in higher organisms, so I think this would be very exciting. Whatever we learn, it’s going to be new.”

Human choices

Based on their preexisting work, Graybiel’s and Menegas’ projects are well-developed—but they are far from the only McGovern-based explorations into ways this brain region taps into our behaviors. Maiya Geddes, a visiting scientist in John Gabrieli’s lab, has recently published a paper exploring the little-known ways that aging affects the dopamine-based nigral-striatum-hippocampus learning and memory systems.

In Rebecca Saxe’s lab, postdoc Livia Tomova just kicked off a new pilot project using brain imaging to uncover dopamine-striatal circuitry behind social craving in humans and the urge to rejoin peers. “Could there be a craving response similar to hunger?” Tomova wonders. “No one has looked yet at the neural mechanisms of this.”

Graybiel also hopes to translate her findings into humans, beginning with collaborations at the Pizzagalli lab at McLean Hospital in Belmont. They are using fMRI to study whether patients
with anxiety and depression show some of the same dysfunctions in the cortico-striatal circuitry that she discovered in her macaques.

If she’s right about tapping into mood states and affect, it would be an expanded role for the striatum—and one with significant potential therapeutic benefits. “Affect state” colors many psychological functions and disorders, from memory and perception, to depression, chronic stress, obsessive-compulsive disorder, and PTSD.

For a region of the brain once dismissed as inconsequential, McGovern researchers have shown the basal ganglia to influence not only our choices but our state of mind—suggesting that this “primitive” brain region may actually be at the heart of the human experience.

 

 

New sensors track dopamine in the brain for more than a year

Anne Trafton |

Dopamine, a signaling molecule used throughout the brain, plays a major role in regulating our mood, as well as controlling movement. Many disorders, including Parkinson’s disease, depression, and schizophrenia, are linked to dopamine deficiencies.

MIT neuroscientists have now devised a way to measure dopamine in the brain for more than a year, which they believe will help them to learn much more about its role in both healthy and diseased brains.

“Despite all that is known about dopamine as a crucial signaling molecule in the brain, implicated in neurologic and neuropsychiatric conditions as well as our ability to learn, it has been impossible to monitor changes in the online release of dopamine over time periods long enough to relate these to clinical conditions,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and one of the senior authors of the study.

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, and Rober Langer, the David H. Koch Institute Professor and a member of the Koch Institute, are also senior authors of the study. MIT postdoc Helen Schwerdt is the lead author of the paper, which appears in the Sept. 12 issue of Communications Biology.

Long-term sensing

Dopamine is one of many neurotransmitters that neurons in the brain use to communicate with each other. Traditional systems for measuring dopamine — carbon electrodes with a shaft diameter of about 100 microns — can only be used reliably for about a day because they produce scar tissue that interferes with the electrodes’ ability to interact with dopamine.

In 2015, the MIT team demonstrated that tiny microfabricated sensors could be used to measure dopamine levels in a part of the brain called the striatum, which contains dopamine-producing cells that are critical for habit formation and reward-reinforced learning.

Because these probes are so small (about 10 microns in diameter), the researchers could implant up to 16 of them to measure dopamine levels in different parts of the striatum. In the new study, the researchers wanted to test whether they could use these sensors for long-term dopamine tracking.

“Our fundamental goal from the very beginning was to make the sensors work over a long period of time and produce accurate readings from day to day,” Schwerdt says. “This is necessary if you want to understand how these signals mediate specific diseases or conditions.”

To develop a sensor that can be accurate over long periods of time, the researchers had to make sure that it would not provoke an immune reaction, to avoid the scar tissue that interferes with the accuracy of the readings.

The MIT team found that their tiny sensors were nearly invisible to the immune system, even over extended periods of time. After the sensors were implanted, populations of microglia (immune cells that respond to short-term damage), and astrocytes, which respond over longer periods, were the same as those in brain tissue that did not have the probes inserted.

In this study, the researchers implanted three to five sensors per animal, about 5 millimeters deep, in the striatum. They took readings every few weeks, after stimulating dopamine release from the brainstem, which travels to the striatum. They found that the measurements remained consistent for up to 393 days.

“This is the first time that anyone’s shown that these sensors work for more than a few months. That gives us a lot of confidence that these kinds of sensors might be feasible for human use someday,” Schwerdt says.

Paul Glimcher, a professor of physiology and neuroscience at New York University, says the new sensors should enable more researchers to perform long-term studies of dopamine, which is essential for studying phenomena such as learning, which occurs over long time periods.

“This is a really solid engineering accomplishment that moves the field forward,” says Glimcher, who was not involved in the research. “This dramatically improves the technology in a way that makes it accessible to a lot of labs.”

Monitoring Parkinson’s

If developed for use in humans, these sensors could be useful for monitoring Parkinson’s patients who receive deep brain stimulation, the researchers say. This treatment involves implanting an electrode that delivers electrical impulses to a structure deep within the brain. Using a sensor to monitor dopamine levels could help doctors deliver the stimulation more selectively, only when it is needed.

The researchers are now looking into adapting the sensors to measure other neurotransmitters in the brain, and to measure electrical signals, which can also be disrupted in Parkinson’s and other diseases.

“Understanding those relationships between chemical and electrical activity will be really important to understanding all of the issues that you see in Parkinson’s,” Schwerdt says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, the Army Research Office, the Saks Kavanaugh Foundation, the Nancy Lurie Marks Family Foundation, and Dr. Tenley Albright.

Constructing the striatum

by Sabbi Lall |

The striatum, the largest nucleus of the basal ganglia in the vertebrate brain, was historically thought to be a homogeneous group of cells. This view was overturned in a classic series of papers from MIT Institute Professor, Ann Graybiel. In previous work, Graybiel, who is also an investigator at MIT’s McGovern Institute, found that the striatum is highly organized, both structurally and functionally and in terms of connectivity. Graybiel has now collaborated with Z. Josh Huang’s lab at Cold Spring Harbor Laboratory to map the developmental lineage of cells that give rise to this complex architecture. The authors found that different functions of the striatum, such as execution of actions as opposed to evaluation of outcomes, are defined early on as part of the blueprint that constructs this brain region, rather than sculpted through a later mechanism.

Graybiel and colleagues tracked what is happening early in development by driving cell-specific fluorescent markers that allowed them to follow the progenitors that give rise to cells in the striatum. The striatum is known, thanks to Graybiel’s early work, to be organized into compartments called striosomes and the matrix. These have distinct connections to other brain regions. Broadly speaking, while striosomes are linked to value-based decision-making and reinforcement-based behaviors, the matrix has been linked to action execution. These regions are further subdivided into direct and indirect pathways. The direct pathway neurons are involved in releasing inhibition in other regions of the basal ganglia and thus actively promote action. Neurons projecting into the indirect pathway, instead inhibit “unwanted” actions that are not part of the current “cortical plan.” Based on their tracking, Graybiel and colleagues were indeed able to build a “fate map” that told them when the cells that build these different regions of the striatum commit to a functional path during development.

“It was already well known that individual neurons have lineages that can be traced back to early development, and many such lineages are now being traced,” says Graybiel. “What is so striking in what we have found with the Huang lab is that the earliest specification of lineages we find—at least with the markers that we have used—corresponds to what later become the two major neurochemically distinct compartments of the striatum, rather than many other divisions that might have been specified first. If this is so, then the fundamental developmental ground plan of the striatum is expressed later by these two distinct compartments of the striatum.”

Building the striatum turns out to be a symphony of organization embedded in lateral ganglion eminence cells, the source of cells during development that will end up in the striatum. Progenitors made early in development are somewhat committed: they can only generate spiny projection neurons (SPNs) that are striosomal. Following this in time, cells that will give rise to matrix SPNs appear. There is then a second mechanism laid over this initial ground plan that is switched on in both striosomal and matrisomal neurons and independently gives rise to neurons that will connect into direct as opposed to indirect pathways. This latter specification of direct-indirect pathway neurons is less rigid, but there is an overarching tendency for neurons expressing a certain neurotransmitter, dopamine, to appear earlier in developmental time. In short, progenitors move through an orchestrated process where they generate spiny projection neurons that can first sit in any area of the striatum, then where the ultimate fate of cells is more restricted at the level of striosome or matrix, and finally choices are made in both regions regarding indirect-direct pathway circuitry. Remarkably, these results suggest that even at the very earliest development of the striatum, its ultimate organization is already laid down in a way that distinguishes value-related circuit from movement-related circuits.

“What is thrilling,” says Graybiel, “is that there are lineage progressions— the step by step laying out of the brain’s organization— the turn out to match the striosome-matrix architecture of the striatum the were not even known to exist 40 years ago!”

The striatum is a hub regulating movement, emotion, motivation, evaluation, and learning, and linked to disorders such as Parkinson’s Disease and persistent negative valuations. This means that understanding its construction has important implications, perhaps even, one day, for rebuilding a striatum affected by neurodegeneration. That said, the findings have broader implications. Consider the worm, specifically, C. elegans. The complete lineage of cells that make up this organism is known, including where each neuron comes from, what it connects to, and its function and phenotype. There’s a clear relationship between lineage and function in this relatively simple organism with its highly stereotyped nervous system. Graybiel’s work suggests that in the big picture, early development in the forebrain is also providing a game plan. In this case, however, this groundwork underpins for circuits that underlie extremely complex behaviors, those that come to support the volitional and habitual behaviors that make up part of who we are as individuals.

 

Neuroscientists get at the roots of pessimism

Anne Trafton |

Many patients with neuropsychiatric disorders such as anxiety or depression experience negative moods that lead them to focus on the possible downside of a given situation more than the potential benefit.

MIT neuroscientists have now pinpointed a brain region that can generate this type of pessimistic mood. In tests in animals, they showed that stimulating this region, known as the caudate nucleus, induced animals to make more negative decisions: They gave far more weight to the anticipated drawback of a situation than its benefit, compared to when the region was not stimulated. This pessimistic decision-making could continue through the day after the original stimulation.

The findings could help scientists better understand how some of the crippling effects of depression and anxiety arise, and guide them in developing new treatments.

“We feel we were seeing a proxy for anxiety, or depression, or some mix of the two,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and the senior author of the study, which appears in the Aug. 9 issue of Neuron. “These psychiatric problems are still so very difficult to treat for many individuals suffering from them.”

The paper’s lead authors are McGovern Institute research affiliates Ken-ichi Amemori and Satoko Amemori, who perfected the tasks and have been studying emotion and how it is controlled by the brain. McGovern Institute researcher Daniel Gibson, an expert in data analysis, is also an author of the paper.

Emotional decisions

Graybiel’s laboratory has previously identified a neural circuit that underlies a specific kind of decision-making known as approach-avoidance conflict. These types of decisions, which require weighing options with both positive and negative elements, tend to provoke a great deal of anxiety. Her lab has also shown that chronic stress dramatically affects this kind of decision-making: More stress usually leads animals to choose high-risk, high-payoff options.

In the new study, the researchers wanted to see if they could reproduce an effect that is often seen in people with depression, anxiety, or obsessive-compulsive disorder. These patients tend to engage in ritualistic behaviors designed to combat negative thoughts, and to place more weight on the potential negative outcome of a given situation. This kind of negative thinking, the researchers suspected, could influence approach-avoidance decision-making.

To test this hypothesis, the researchers stimulated the caudate nucleus, a brain region linked to emotional decision-making, with a small electrical current as animals were offered a reward (juice) paired with an unpleasant stimulus (a puff of air to the face). In each trial, the ratio of reward to aversive stimuli was different, and the animals could choose whether to accept or not.

This kind of decision-making requires cost-benefit analysis. If the reward is high enough to balance out the puff of air, the animals will choose to accept it, but when that ratio is too low, they reject it. When the researchers stimulated the caudate nucleus, the cost-benefit calculation became skewed, and the animals began to avoid combinations that they previously would have accepted. This continued even after the stimulation ended, and could also be seen the following day, after which point it gradually disappeared.

This result suggests that the animals began to devalue the reward that they previously wanted, and focused more on the cost of the aversive stimulus. “This state we’ve mimicked has an overestimation of cost relative to benefit,” Graybiel says.

The study provides valuable insight into the role of the basal ganglia (a region that includes the caudate nucleus) in this type of decision-making, says Scott Grafton, a professor of neuroscience at the University of California at Santa Barbara, who was not involved in the research.

“We know that the frontal cortex and the basal ganglia are involved, but the relative contributions of the basal ganglia have not been well understood,” Grafton says. “This is a nice paper because it puts some of the decision-making process in the basal ganglia as well.”

A delicate balance

The researchers also found that brainwave activity in the caudate nucleus was altered when decision-making patterns changed. This change, discovered by Amemori, is in the beta frequency and might serve as a biomarker to monitor whether animals or patients respond to drug treatment, Graybiel says.

Graybiel is now working with psychiatrists at McLean Hospital to study patients who suffer from depression and anxiety, to see if their brains show abnormal activity in the neocortex and caudate nucleus during approach-avoidance decision-making. Magnetic resonance imaging (MRI) studies have shown abnormal activity in two regions of the medial prefrontal cortex that connect with the caudate nucleus.

The caudate nucleus has within it regions that are connected with the limbic system, which regulates mood, and it sends input to motor areas of the brain as well as dopamine-producing regions. Graybiel and Amemori believe that the abnormal activity seen in the caudate nucleus in this study could be somehow disrupting dopamine activity.

“There must be many circuits involved,” she says. “But apparently we are so delicately balanced that just throwing the system off a little bit can rapidly change behavior.”

The research was funded by the National Institutes of Health, the CHDI Foundation, the U.S. Office of Naval Research, the U.S. Army Research Office, MEXT KAKENHI, the Simons Center for the Social Brain, the Naito Foundation, the Uehara Memorial Foundation, Robert Buxton, Amy Sommer, and Judy Goldberg.

Chronic neural implants modulate microstructures in the brain with pinpoint accuracy

Anne Trafton |

Post by Windy Pham

The diversity of structures and functions of the brain is becoming increasingly realized in research today. Key structures exist in the brain that regulate emotion, anxiety, happiness, memory, and mobility. These structures can come in a huge variety of shapes and sizes and can all be physically near one another. Dysfunction of these structures and circuits linking them are common causes of many neurologic and neuropsychiatric diseases. For example, the substantia nigra is only a few millimeters in size yet is crucial for movement and coordination. Destruction of substantia nigra neurons is what causes motor symptoms in Parkinson’s disease.

New technologies such as optogenetics have allowed us to identify similar microstructures in the brain. However, these techniques rely on liquid infusions into the brain, which prepare the regions to be studied to respond to light. These infusions are done with large needles, which do not have the fine control to target specific regions. Clinical therapy has also lagged behind. New drug therapies aimed at treating these conditions are delivered orally, which results in drug distribution throughout the brain, or through large needle-cannulas, which do not have the fine control to accurately dose specific regions. As a result, patients of neurologic and psychiatric disorders frequently fail to respond to therapies due to poor drug delivery to diseased regions.

A new study addressing this problem has been published in Proceedings of the National Academy of Sciences. The lead author is Khalil Ramadi, a medical engineering and medical physics (MEMP) PhD candidate in the Harvard-MIT Program in Health Sciences and Technology (HST). For this study, Khalil and his thesis advisor, Michael Cima, the David H. Koch Professor of Engineering within the Department of Materials Science and Engineering and the Koch Institute for Integrative Cancer Research, and associate dean of innovation in the School of Engineering, collaborated with Institute Professors Robert Langer and Ann Graybiel, an Investigator at the McGovern Institute of Brain Research to tackle this issue.

The team developed tools to enable targeted delivery of nanoliters of drugs to deep brain structures through chronically implanted microprobes. They also developed nuclear imaging techniques using positron emission tomography (PET) to measure the volume of the brain region targeted with each infusion. “Drugs for disorders of the central nervous system are nonspecific and get distributed throughout the brain,” Cima says. “Our animal studies show that volume is a critical factor when delivering drugs to the brain, as important as the total dose delivered. Using microcannulas and microPET imaging, we can control the area of brain exposed to these drugs, improving targeting accuracy double time comparing to the traditional methods used today.”

The researchers were also able to design cannulas that are MRI-compatible and implanted up to one year in rats. Implanting these cannulas with micropumps allowed the researchers to remotely control the behavior of animals. Significantly, they found that varying the volume infused alone had a profound effect on behavior induced, even if the total drug dose delivered stayed constant. These results show that regulation of volume delivery to brain region is extremely important in influencing brain activity. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more effective treatment in human patients.

 

 

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.

Distinctive brain pattern helps habits form

Anne Trafton |

Our daily lives include hundreds of routine habits. Brushing our teeth, driving to work, or putting away the dishes are just a few of the tasks that our brains have automated to the point that we hardly need to think about them.

Although we may think of each of these routines as a single task, they are usually made up of many smaller actions, such as picking up our toothbrush, squeezing toothpaste onto it, and then lifting the brush to our mouth. This process of grouping behaviors together into a single routine is known as “chunking,” but little is known about how the brain groups these behaviors together.

MIT neuroscientists have now found that certain neurons in the brain are responsible for marking the beginning and end of these chunked units of behavior. These neurons, located in a brain region highly involved in habit formation, fire at the outset of a learned routine, go quiet while it is carried out, then fire again once the routine has ended.

This task-bracketing appears to be important for initiating a routine and then notifying the brain once it is complete, says Ann Graybiel, an Institute Professor at MIT, a member of the McGovern Institute for Brain Research, and the senior author of the study.

Nuné Martiros, a recent MIT PhD recipient who is now a postdoc at Harvard University, is the lead author of the paper, which appears in the Feb. 8 issue of Current Biology. Alexandra Burgess, a recent MIT graduate and technical associate at the McGovern Institute, is also an author of the paper.

Routine activation

Graybiel has previously shown that a part of the brain called the striatum, which is found in the basal ganglia, plays a major role in habit formation. Several years ago, she and her group found that neuron firing patterns in the striatum change as animals learn a new habit, such as turning to the right or left in a maze upon hearing a certain tone.

When the animal is just starting to learn the maze, these neurons fire continuously throughout the task. However, as the animal becomes better at making the correct turn to receive a reward, the firing becomes clustered at the very beginning of the task and at the very end. Once these patterns form, it becomes extremely difficult to break the habit.

However, these previous studies did not rule out other explanations for the pattern, including the possibility that it might be related to the motor commands required for the maze-running behavior. In the new study, Martiros and Graybiel set out to determine whether this firing pattern could be conclusively linked with the chunking of habitual behavior.

The researchers trained rats to press two levers in a particular sequence, for example, 1-2-2 or 2-1-2. The rats had to figure out what the correct sequence was, and if they did, they received a chocolate milk reward. It took several weeks for them to learn the task, and as they became more accurate, the researchers saw the same beginning-and-end firing patterns develop in the striatum that they had seen in their previous habit studies.

Because each rat learned a different sequence, the researchers could rule out the possibility that the patterns correspond to the motor input required to preform a particular series of movements. This offers strong evidence that the firing pattern corresponds specifically to the initiation and termination of a learned routine, the researchers say.

“I think this more or less proves that the development of bracketing patterns serves to package up a behavior that the brain — and the animals — consider valuable and worth keeping in their repertoire. It really is a high-level signal that helps to release that habit, and we think the end signal says the routine has been done,” Graybiel says.

Distinctive patterns

The researchers also discovered a distinct pattern in a set of inhibitory neurons in the striatum. Activity in these neurons, known as interneurons, displayed a strong inverse relationship with the activity of the excitatory neurons that produce the bracketing pattern.

“The interneurons were activated during the time when the rats were in the middle of performing the learned sequence, and could possibly be preventing the principal neurons from initiating another routine until the current one was finished. The discovery of this opposite activity by the interneurons also gets us one step closer to understanding how brain circuits can actually produce this pattern of activity,” Martiros says.

Graybiel’s lab is now investigating further how the interaction between these two groups of neurons helps to encode habitual behavior in the striatum.

The research was funded by the National Institutes of Health/National Institute of Mental Health, the Office of Naval Research, and a McGovern Institute Mark Gorenberg Fellowship.

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.