Champalimaud Center for the Unknown
Dr. Carey is a group leader in the Neuroscience Program at the Champalimaud Center for the Unknown, Lisbon, Portugal.
The Cerebellar Circuit: From Synapse to Behavior
Megan Carey vividly remembers the first time she heard the brain in action. As an undergraduate at Wesleyan University in Connecticut, she visited the lab of neuroscientist David Bodznick. He and his colleagues had inserted electrodes in the brains of skates—bottom-dwelling relatives of sharks—and were eavesdropping on chattering neurons, playing the recordings through speakers. “I was hooked,” Carey says.
Having cultivated an early interest in science, she had considered becoming a physicist until the first day of college, when she found that the physics and biology classes conflicted. In biology, she knew, she could study the brain. Her experience in Bodznick’s lab cemented that decision, and she went on to complete undergraduate and master’s projects there.
Skates locate food by detecting electrical fields emanating from their prey. But the animals’ own movements, even their breathing, produce electrical interference that can swamp signals from potential meals. Observing the fish, Carey was intrigued by how animals predict the consequences of their own movement and, specifically, how skates recognize and filter out their own electrical signals. By listening to and stimulating neurons, she identified the ones in the skate’s brain that dispatch a “cancellation signal,” enabling the animal to tune out its own noise.
Later, as a Ph.D. student at the University of California, San Francisco, Carey identified brain neurons that guide learning in a more complex model organism—rhesus monkeys. Working in the lab of neuroscientist and HHMI investigator Stephen Lisberger, she looked at how the brain controls smooth pursuit eye movements, in which eyes track an object in motion. If the object suddenly changes direction, the eyes follow, but only after a short delay. However, if an animal sees the same redirection again and again, its eye movements begin to anticipate the course change. Carey pinpointed neurons in the brains of monkeys that teach the eyes where to look. As she and her colleagues found, applying a current to these neurons has the same effect as changing an object’s direction, training the monkeys to gaze skyward, for example. “It was really exciting—by stimulating the neurons we were able to produce learned changes in behavior,” she says.
Carey soon became interested in understanding how individual neural circuits control behaviors and realized she needed to learn more about the workings of neurons and their connections, called synapses. That led her to a postdoctoral fellowship with neurobiologist Wade Regehr at Harvard Medical School in Boston. During a five-year stint in his lab, she investigated the factors that influence synaptic plasticity, changes in the strength of synapses that researchers think are crucial for memory and learning.
For one study, she and her coworkers clarified the role of a type of cannabinoid receptor. These receptors are best known for their response to marijuana, but they also interact with endocannabinoid molecules released by neurons.
Carey and other researchers have been interested in these receptors because they are known to play a role in short- and long-term synaptic plasticity. For their study, Carey and her colleagues genetically deleted the receptors from certain neurons in the cerebellum of the mouse brain. Their findings, reported in a 2010 Journal of Neurophysiology paper, suggest that the receptors promote long-term synaptic plasticity through an unexpected mechanism. Carey plans to follow up on this discovery to determine whether the receptors underlie the ability to learn specific behaviors that involve the cerebellum, which plays an important role in motor control.
During her postdoc, Carey gave birth to her two children, a son who is now five and a daughter who is now two. Toward the end of her postdoc, she received a job offer from the Champalimaud Center for the Unknown, a new institute in Lisbon, Portugal, that fosters research in a variety of biomedical fields, including neuroscience and cancer. A native of Philadelphia, Pennsylvania, Carey says it was “terrifying deciding to move to a new country, where I didn’t even speak the language, with two young children.” But, she adds, “it was an unmissable opportunity to be a part of an exciting new neuroscience institute from the very beginning.”
Her lab is gearing up to determine how specific neurons and synapses control the activities of the cerebellum. She will use transgenic mice to modify how neurons and synapses work, asking questions such as how mice coordinate their limb movements while scampering on a treadmill and use their limbs and tail to balance on a narrow beam like gymnasts.
The work is in the early stages, Carey says. Meanwhile, she and her family are taking advantage of synaptic plasticity to learn Portuguese.