Elisabeth Murray, Ph.D.

Investigating the Role of Different Brain Regions in Memory and Decision-Making

BY CLAIRE E. MCCARTHY, NCI

When you walk into Elisabeth Murray’s office, you can see a 3-D model of the brain belonging to Patient H.M. (Henry Gustav Molaison), a man well known by students in psychology and neuroscience. In 1953, surgeons removed his medial temporal lobe in an attempt to stop his epileptic seizures. Although the surgery helped, there was an unfortunate side effect: He was unable to form new memories about individuals, objects, or events. He did, however, retain most of his memories formed prior to the procedure and could carry on a normal conversation, solve math problems, and write sentences. Based on this evidence, the prevailing dogma when Murray began her postdoctoral training in 1979 with Mortimer Mishkin at the National Institute of Mental Health (NIMH) was that specific areas within the medial temporal lobe—the hippocampus and amygdala—were the seeds of memory formation for previously encountered objects and people.

But when Murray began investigating the neural substrates of this recognition memory in the 1990s, she showed that the amygdala and hippocampus were not key for object-memory formation, but that two other regions within the medial temporal lobe—the entorhinal and perirhinal cortex—were. Her studies overturned long-standing theories about neurobiology at the time.

Murray continues to challenge existing theories and explore new frontiers in neuroscience. During this year’s Anita B. Roberts Lecture held on May 17, 2018, she described her current research examining the role of the orbitofrontal cortex (OFC, the area of the brain directly above the eyes), which is important for learning and decision-making. In one set of studies with macaque monkeys (Macaca mulatta), she tested and rejected the established theory that the OFC itself plays a role in cognitive flexibility (the ability to adapt one’s thinking to changing circumstances). Instead, she and her team were surprised to find that a fiber bundle connecting the temporal lobe to the frontal lobe—passing near the OFC—was involved.

In other studies, she is attempting to gain a deeper understanding of how the OFC and the adjacent ventrolateral prefrontal cortex (VLPFC) work to guide behavior. For example, she and her lab have investigated the OFC’s role in the devaluation of rewards (when the value of something is reduced in a person’s mind and influences their actions). In her talk, Murray used the example of the hardboiled-egg-eating contest in the 1967 movie Cool Hand Luke. Luke, played by Paul Newman, sets out to win an impromptu bet that he could eat 50 eggs in an hour. Although he succeeds—the scene is agonizing to watch—he goes from valuing (liking) eggs to devaluing (hating) them. The eggs became devalued because he didn’t want to eat any ever again.

Similar to Luke, monkeys will typically devalue a food if they eat as much of it as they can during one sitting. Normally in behavioral tests, the monkeys would choose objects that would reward them with a more desirable food, avoiding objects yielding the devalued food. But Murray found that OFC-damaged monkeys continued to choose objects that rewarded them with devalued food. This research showed that the OFC is involved in decision-making based on desirability.

Murray also explored the impact of the OFC and the VLPFC on credit assignment, the ability to link an outcome with the choice or action that produced it. In monkeys, this behavior can be tested by having them press images on a touch-sensitive screen to receive a piece of food. The monkeys learn to touch the images yielding the most rewards, all while the “best” image is changing over the test session. Murray and her team discovered that damage to the VLPFC—not damage to the OFC as expected—impaired credit-assignment and the ability of monkeys to track the best image. The VLPFC, therefore, is important for determining the value of an outcome based on the probability of reward and credit assignment. Thus, unlike OFC, the VLPFC guides decision-making based on the history of rewards, which relates to availability.

To further tease out how the OFC functions, Murray’s lab used a drug that temporarily inactivated parts of it. They determined that the loss of neural activity in the back of the OFC impaired the monkeys’ value-updating abilities; loss of activity in the front interfered with goal selection (linking knowledge of outcome value to image choice).

Overall, Murray has improved the understanding of brain-behavior relationships by showing that the OFC contains distinct functional regions for determining the value of things and selecting goals. Her research may lead to new insights about neuropsychiatric and mood disorders that are associated with OFC dysfunction.

In addition to conducting research, Murray strives to be a good mentor—just as Anita Roberts was—by helping junior scientists. “I have been the beneficiary of many efforts of the NIH Women Scientist Advisors (WSA) and received good advice from a handful of female role models who were able to mentor me in my own career development,” she said during the lecture. Now, she passes on the lessons she has learned by supporting trainees in her lab, participating in the WSA, and having discussions with young tenure-track scientists at NIH to help them navigate the complexities of NIH while they work toward achieving tenure.

The “Anita B. Roberts Lecture Series: Distinguished Women Scientists at NIH” honors the research contributions Roberts and other female scientists have made. Roberts, who spent 30 years at NCI before her death in 2006, was known for her groundbreaking work on transforming growth factor–beta. To watch a videocast of Murray’s lecture, “Specializations for Decision-Making in Primate Prefrontal Cortex,” held on May 17, 2018, go tohttps://videocast.nih.gov/launch.asp?23894.

ELISABETH MURRAY, PH.D.

Senior Investigator and Chief, Section on Neurobiology of Learning and Memory, and Chief, Laboratory of Neuropsychology, National Institute of Mental Health

Born and grew up: In Syracuse, New York

Research Interests: Understanding the neural basis of learning, memory, emotion, and decision-making. Her laboratory has pioneered the use of MRI-guided stereotaxic surgery, a method that has for the first time allowed the examination of the selective mnemonic contributions of various medial temporal lobe structures.

Education: Bucknell University, Lewisburg, Pa. (B.S. in biology); University of Texas Medical Branch, Galveston, Texas (Ph.D. in physiology)

Training: Postdoctoral training in NIMH’s Laboratory of Neuropsychology with Mortimer Mishkin

Came to NIH: In 1979 for training in neuropsychology and behavior; became a NIMH staff fellow in 1982 and was promoted to senior staff fellow in 1984; became a research physiologist in 1989, chief of the Section on the Neurobiology of Learning and Memory in 1996, and chief of the Laboratory of Neuropsychology in 2015

What excites her about research: “There’s something new every day and often it is something unexpected.”

Outside interests: Hiking and birding

Little known fact: “When I was applying to graduate school, I wanted to study dolphins. I was fascinated with the work of John Lilly, who was studying communication between man and dolphins.”

Interesting fact about her family: “I recently learned that my great-aunt was one of the early female graduates of the Columbia University College of Physicians (New York). Childhood psychotherapy was her specialty and she practiced in Ithaca, New York.”

Website: https://irp.nih.gov/pi/elisabeth-murray