Ann M. Graybiel was born in Boston, Massachusetts, but was raised in Pensacola, Florida, where her father, a cardiologist and research scientist, was sent during the final months of World War II to work with pilots suffering from spatial disorientation. From a very early age, Graybiel developed an interest in the natural world and science, which both her parents strongly encouraged. The local school didn’t permit girls to take science classes, however. “We were required to take home economics and learn to sew,” Graybiel recalls with a laugh. “So, my parents shipped me off to a boarding school in Washington, D.C. It wasn’t very science-y, but I just loved all the music and art and history that they taught me.”
For a brief time, Graybiel thought she might become an historian, but she quickly switched her major to chemistry and then biology after enrolling at Harvard University in 1964. “I was lucky enough to go to Trinidad with [behavioral zoologist] Donald Griffin to do research on echolocation in bats,” she recalls. “It was kind of scary because we worked at night, and we had to go down these long paths in the jungle, and there were lot of snakes. But it turned out fine.” While at Harvard, Graybiel also worked in the lab of physiologist George Wald, researching oil droplets in bird retinas.
For graduate school, Graybiel chose the Massachusetts Institute of Technology (MIT), where she worked with several of the early pioneers of neuroscience, including the neuropsychologist Hans-Lukas Teuber and the neuroanatomist Walle J. H. Nauta, who was her thesis advisor. “It was an incredibly exciting time,” she recalls. “There was so much we didn’t know.” Graybiel received her PhD in 1971, and joined the MIT neuroscience faculty two years later. “I had no start-up money,” she recalls. “They gave me a room in the small place where they kept the monkeys. I used to clean the floor myself.” At that time, women working in science were rare. “It was a completely different era,” Graybiel says. “For a long time, I was the only female faculty member in a six-floor building.”
Graybiel dove eagerly into her research, however, focusing on the basal ganglia, a group of nuclei (clusters of neurons) known to be important for movement disorders, such as Parkinson’s disease and Huntington’s disease. Located deep within the forebrain, the basal ganglia were largely ignored by scientists in those pre-imaging days. Graybiel, however, developed a novel method of staining cells that enabled her to identify — in both animals and in humans — the location of different neurotransmitters, the chemicals used by neurons to communicate with each other. She then applied these stains to the striatum, the largest nucleus within the basal ganglia. This lead to a groundbreaking discovery: Rather than being a mass of homogenous cells, the striatum had a distinct and sophisticated architecture with column-like modules — dubbed striosomes by Graybiel — that distributed nearly every known neurotransmitter. Surrounding the striosomes was a matrix, which was itself modular. Four decades later, Graybiel remembers the late-night moment in her lab when she saw the striosomes for the first time. She and her team had stained some markers for the neurotransmitter acetylcholine in post-mortem human brain samples. “We looked under the microscope and suddenly saw this heterogeneity,” she recalls. “We then knew that the striatum was not primitive after all.”
In an extraordinary series of studies, Graybiel went on to demonstrate what this architecture meant functionally. She showed that striosomes and matrisomes (the modules within the matrix) are intermingled and receive different types of information and target different nearby structures in the brain. The striosomes were found to project mainly into the dopamine pathways of the substantia nigra, a basal ganglia structure that plays an important role in reward as well as in movement. This led Graybiel to wonder if the striatum acted as a “learning device.” In animal studies, Graybiel and her team discovered that dopamine-related activity in the striatum undergoes massive reorganization while the animals are learning new habits — evidence that the striatum is, indeed, linked to behavioral learning. They also found that the learning-related activity of dopamine in the striatum peaks during experiences when a reward is received and decreases when the expected reward is not forthcoming. This research then led Graybiel and her team to investigate and describe how changes in striatal neural activity during the learning of a complex motor task lead to the formation of habits, including pathological habits, such as those that characterize obsessive compulsive disorder.
After returning briefly to school to take a crash course in molecular genetics, Graybiel began to clone striatum-enriched genes. She soon discovered that different families of genes are expressed differently in striosomes and matrisomes and that some of those differences are associated with exaggerated compulsive behaviors. Then, using optogenetics — tools that use light to stimulate or shut off specific neurons in the brain in freely moving animals — Graybiel and her team discovered that they could manipulate those behaviors. Not only could they block habits already learned, but also those not yet formed — a landmark finding with potentially profound clinical applications. “We’re looking for mechanisms found in pure science that can lead to some therapeutic developments,” says Graybiel. “I deeply believe in doing just basic science, but I also believe it’s important to have a relationship between pure science and translational science. I find myself right there, at that juncture.”
Graybiel has received numerous honors and awards for her research, including membership in the National Academy of Sciences and the American Academy of Arts and Sciences. She is also a recipient of the National Medal of Science (2001) and the Kavli Prize (2012). Graybiel lives in Lincoln, Massachusetts, with her husband, astrobiologist and neuroscientist James Lackner.