Keeping the brain in balance

Amy F. T. Arnsten, Ph.D., is one of those lucky souls who discover at a fairly young age what their life’s work will be. While a student at Columbia High School in Maplewood, N.J., in the early 1970s, Arnsten spent summers working with children with mental illness, an interest that was “crystallized,” she says, when she volunteered at the Greystone Park Psychiatric Hospital in nearby Morris Plains. At Greystone, only two psychiatrists served a population of 2,000 patients, many of whom, in an age of limited legal rights for psychiatric patients and relatively crude medications, had been institutionalized for their entire adult lives. “It was like we were still in the Middle Ages,” she says, “and I knew this was an area where one could make — and needed to make — a huge difference.”

As an undergraduate at Brown University, Arnsten largely designed her own course of study in the “irresistibly fascinating” field of neuroscience. Having noted at Greystone that even mild stress could greatly worsen patients’ symptoms, Arnsten devoted her doctoral research at the University of California, San Diego (UCSD), to norepinephrine (NE), a brain chemical released in response to stress. She had ARRAnged a postdoctoral fellowship at the University of Cambridge to continue this work, but a seminar given at UCSD by the late Patricia Goldman-Rakic, Ph.D., a scientist visiting from Yale, changed her plan, and altered the course of her scientific career. “She talked about her research on the development of the prefrontal cortex,” Arnsten recalls, “and I said to myself, ‘That’s what I have to know.’”

In 1982, Arnsten began postdoctoral studies at Yale. Under Goldman-Rakic’s tutelage, she began the exploration of the neurochemistry of the prefrontal cortex (PFC) that has captivated her ever since.

The PFC is a region at the front of the brain that is crucial to so-called executive functions — decision-making, planning, predicting, and suppressing distracting thoughts or socially unacceptable behaviors. For such an important structure, there is remarkably little room for error in the PFC, says Arnsten, who has playfully dubbed it the brain’s Goldilocks: it functions best “when everything is just right.” When we are fatigued or stressed, which can happen many times over the course of a single day, the relative levels of PFC neurotransmitters fluctuate, and its function declines. In extreme situations, or as a result of genetic factors, mental illness can result, and the list of psychiatric disorders associated with PFC dysfunction — post-traumatic stress disorder (PTSD), schizophrenia, obsessive-compulsive disorder, bipolar disorder, attention-deficit hyperactivity disorder (ADHD), anxiety disorders, and many more — is long and varied.

Arnsten has seen her research bear fruit in medications that meet the PFC’s “molecular needs.” Based on work in her lab, the generic compound prazosin is now used to treat PTSD. And last September, for ADHD, the Food and Drug Administration approved Intuniv, a new formulation of a compound that was inspired by Arnsten’s research. Arnsten is now working with Yale’s Office of Cooperative Research to develop a plant-derived compound that has shown promise for treating schizophrenia, bipolar disorder, PTSD, and related conditions.

“This is a tremendously collaborative environment,” says Arnsten. “We are at a point of revolution in psychiatry and neuroscience, and Yale is a place where a lot of that is happening.”