Much of our health and happiness is rooted in our own behaviors: whether we exercise and eat right, whether we make choices as optimists or as pessimists, whether we stay motivated to reach our goals or stick to the status quo. But even the best conscious intentions don’t always translate into the behavior we want. Increasingly, neuroscientists are starting to see—and even manipulate—the brain activity responsible for turning thoughts and feelings into actions. This work raises the tantalizing possibility that we could find more precise therapies for conditions like mood disorders and anxiety, compulsive behaviors, and addiction.
Institute Professor Ann Graybiel, PhD ’71, is at the forefront of this research, having devoted much of a career now in its fifth decade to understanding a seemingly humble set of brain structures called the basal ganglia. Once known only for helping to control movement, this region deep within the brain is now believed to play fundamental roles in how we learn, process emotions, make decisions, and adopt habits. And that shift in thinking is due in no small part to the research done in Graybiel’s lab.
Her work has already yielded insights into patterns of brain activity associated with movement disorders and psychiatric diseases. Recent studies using light to control individual brain cells, for instance, show how shutting off some of this activity can control habit formation or pessimistic decision-making. Although this technique, known as optogenetics, is still just a research tool, she is convinced that such technological advances hold therapeutic promise—and that learning about these deep patterns in the brain will also be important for everyone who wonders: What makes me do what I do?
“This is truly important for everyday life, and it’s truly important at a social and societal level,” says Graybiel, an investigator at MIT’s McGovern Institute for Brain Research and a member of the Department of Brain and Cognitive Sciences. “We human beings need to understand this stuff about ourselves.”
A new brain architecture
The study of the brain has long been stymied by the meagerness of the techniques available to address grand questions about the nature of thoughts, memories, and decisions. Today, the field is enjoying a renaissance driven by technologies that offer new ways to study patterns of communication between cells and regions of the brain. It’s yielding some stunning breakthroughs in the ability to manipulate complex behaviors. Graybiel’s early fundamental insights into the basic architecture of the brain were among those that laid the groundwork for these breakthroughs.
Graybiel was born in Boston in 1942 but raised in Pensacola, Florida, where ninth-grade girls of her era studied sewing but not science. After boarding school in Washington, D.C., she studied chemistry and biology at Harvard and headed to MIT, whose psychology department, led by Hans-Lukas Teuber, was a magnet for pioneers in the field of neuroscience.
By then—the late 1960s—scientists were performing landmark experiments that began to map out how the systems governing vision and touch were organized in the brain. “There were so few techniques to study the brain,” Graybiel says, “but it was a very exciting time.” Scientists were beginning to measure electrical signals in animals’ brain cells to map the organization of the neocortex, the folded outer rind of the brain that is the seat of higher functions like perception and conscious thought.
When she joined the MIT faculty two years after receiving her PhD in 1971, Graybiel specialized in studying the brain’s anatomy. She was well equipped for that task by her training under the great neuroanatomist Walle Nauta, who developed special stains that could be applied to human or animal brain tissue to trace how brain fibers were connected. It was “aesthetically pleasing work,” she says. “The brain just happens to be very beautiful. It doesn’t need to be, but it’s just extraordinarily beautiful.”
Most stains were designed to show the physical properties of cells, but Graybiel developed novel stains that revealed the locations of chemicals that cells use to communicate, creating a map of chemical activity.
This strategy turned out to be useful in exposing the organization of the brain. In some areas that organization had been easy to see: the neocortex was fascinating, for instance, because it held a layer cake of precisely ordered neurons that hinted at the complexity of its functions. But other regions seemed chaotic at first glance. “It’s just fabulous,” Graybiel says of the neocortex. “Then you look underneath that, and there’s this huge ball of neurons that aren’t elegantly organized apparently; it’s very humble-looking, but it’s huge.” This giant glop of brain tissue was the striatum, part of the basal ganglia, which was seen as a more primitive area of the brain.
When she applied her chemical stains to the seemingly homogeneous mass of the striatum, however, an organizing principle suddenly came into view. The striatum’s cells were arranged into chemically distinct compartments, which Graybiel dubbed striosomes. This insight revealed a new way to understand the brain’s anatomy: through chemistry rather than the shape or orientation of cells. Paul Glimcher, a neurobiologist at New York University who has been inspired by her work, calls Graybiel’s exploration of the striatum’s structure “the last of the heroic neuroanatomical projects” in classical brain anatomy.
Deciphering a mosaic
The striatum turned out to be much more interesting than people thought, and Graybiel has spent her career seeking to understand it and the neural circuits for which it serves as a hub. When she began her research, the striatum was known to be involved in movement disorders like Parkinson’s disease, which is caused by the death of brain cells that supply dopamine to that part of the brain. Since then, it has been linked to a fascinating array of brain functions, including motivation, reward, habit formation, and decision-making.
For Graybiel, the organization that she uncovered in the striatum is the key to understanding how it works. “If you could imagine the most beautiful mosaic … that’s the way the striatum is,” she says, “only it’s in 3-D.” The “tiles” of this mosaic are chemically distinct striosomes. Individual striosomes and their surrounding matrices of cells seem to make up separate groups of tiles or modules connected to distinct parts of the brain.
It’s clear that the striatum contains information hubs connecting areas located above it, in the neocortex, with regions lying under it, which govern emotion and mood. In recent years Graybiel’s lab has produced key findings that illuminate the communication between these regions and the role this communication plays in determining behavior. The striatum’s modular architecture, she believes, is a very different way of organizing information from the one seen in the layered cortex. She has come to see it as a learning device: it gathers information from other brain regions so that we can learn to quickly choose which behaviors to carry out, eventually acting instinctively.
Some parts of the striatum are involved in learning, planning, anticipating rewards, and making value judgments about whether something is positive or negative. Other parts allow us to form habits. These seem to involve a different kind of brain functioning, in which we’re not actively anticipating and judging but automatically playing out a previously learned script.
Studies in Graybiel’s lab explore both of these processes and how they interact. One, led by research scientist Ken-ichi Amemori, investigated an area of the cortex that appears to communicate with the striatum and is associated with anxiety and depression. When animals faced a task that produced combinations of negative and positive results (an annoying puff of air and a food reward), stimulating that area made them more likely to avoid the negative outcome even if it meant missing out on the reward, reflecting a tendency to make pessimistic decisions. The researchers were able to block this tendency with an antianxiety drug. Amemori’s research suggests that an independent brain circuit governs this pessimistic decision-making, and he is now investigating a different circuit that may control decisions made on the assumption of a positive outcome, challenging the conventional view that assessing costs and benefits is a single unified process.
Graybiel thinks such findings could identify brain circuits that handle highly emotional decisions hinging on judgments about whether an outcome will be good or bad. “A lot of our emotional lives are very rich, but we have to make decisions that are sometimes ‘feel it in your gut’ decisions,” she says. In other words, the complex emotions and perceptions must coalesce into a simple yes or no. She wants to understand what motivates this decision-making, and why this emotional evaluation goes awry in certain psychiatric disorders.
Another study revealed the role dopamine plays in anticipating how far we are from distant rewards. By examining rats running a maze, grad student Mark Howe, PhD ’13, found that the amount of dopamine released in the striatum slowly rose as the rats approached their goal. These dopamine “ramps” were steeper when a larger reward was expected or when the goal was farther away; they may help maintain motivation to reach a goal.
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