Discovering what is normal as memory slips with age

Carol Barnes has been shaking up brain-related research for nearly 30 years, and she has lots more on her agenda. When she jumped into the neuroscience field—or was drawn in, actually—in 1971, it was much smaller, attracted a fraction of the billions in current annual funding and lacked the new sense of national urgency.

Alzheimer’s disease alone costs $150 billion a year globally and threatens to bankrupt the U.S. health care system. Yet Barnes, who directs the Evelyn F. McKnight Brain Institute, is a Regents’ Professor of Psychology and Neurology, and is the associate director of the BIO5 Institute, says the research may be skipping one vital step.

“First we need to understand how the normal brain ages,” she said, “to know the symptoms that most of us will experience. I don’t believe you can understand diseases, such as Alzheimer’s, until you understand the normally aging brain.”

Far too little is known, she says, about the most basic mechanisms of how we remember things, or fail to as we age. For her part, Barnes studies the brain’s main center for learning and memory, the hippocampus. She is one of a handful of scholars who study aging and the hippocampus with her innovative methods.

She has been filling in the gaps for almost 20 years at the UA.

At her labs in the Division of Neural Systems, Memory and Aging in the Arizona Research Laboratories, Barnes conducts animal behavioral studies. In some, animals learn to swim to a target in a water tank or learn to solve a maze for a food reward, as Barnes charts brain cell activity, noting differences between young and old animals.

One major breakthrough has been recording impulses in hundreds of brain cells at once in a freely behaving animal, producing a giant mural of memory in action. That map shows exactly which cells fall down on the job during aging.

She is one of the most frequently cited scholars on the ability to create memories at synapses, a phenomenon called long-term potentiation, or LTP. When functioning well, LTP can stabilize brain circuits and prevent one from getting disoriented or lost on the street.

As we age, all of us will see some circuits misfire. Neuroscientists used to think that all brains aged similarly, in a generalized march into dementia, disease or senility. Not so, says Barnes. Successful brain aging shows a distinctly different pattern of brain change from those who age abnormally.

Her focus is the hippocampus, the brain’s “save” function, which moves a memory into long-term storage. It helps the brain keep track of up to 1,000 gigabytes of data, running on about 10 watts of power, just enough for a small light bulb. A thimble-sized chunk of it, or a cubic centimeter, would hold 50 million neurons, hundreds of miles of wiring, and a trillion or so connections, or synapses. Our three-pound brain would equal about a thousand such thimbles.

Barnes’ early experiments provided the first concrete evidence to explain the connection between LTP and memory, still one of the hottest topics in memory science. “When the hippocampus of an older rat pulls up the wrong map, that’s a retrieval error, and the rat is disoriented in space,” she said. “That may explain why older animals, including us, become lost more frequently.”

This is all part of normal aging. Understanding these glitches in the ordinary aging brain—which means about 80 to 90 percent of us—may one day show biomedicine how to fight Alzheimer’s disease among the 10 to 20 percent of us who age abnormally. It may also lead to breakthroughs in optimizing memory in healthy older adults.

In her own life, Barnes was drawn into a normal case of aging – her grandfather. When she was in graduate school in 1971, her mother called to say he was wandering off during walks and did she have advice? Barnes wondered, “How do you draw the line between normal aging and an illness worth worrying about?” She continued her studies, for her doctorate at Carleton University, in Canada, in 1977, and on into a career in brain studies. She joined the UA in 1990 and has become a world leader in understanding memory and aging, and the roles of molecules, genes and brain circuits.

In postdoctoral study at the Institute of Neurophysiology in Oslo in 1979, Barnes provided some of the first evidence that age-linked deterioration in the normal brain was quite different at cellular and neural levels from those with disease. “It was amazing how little we knew about memory, learning and aging, at that time.”

The McKnight Institute, only the fourth of its kind at U.S. universities, began in 2006 with a $5 million McKnight Brain Research Foundation gift that was matched through funds from the Arizona Research Laboratories, College of Medicine, Social and Behavioral Sciences, the Technology Research Infrastructure Fund( TRIF), and the Arizona Alzheimer’s Consortium.

“With new kinds of methods to target specific cells in the brain, we are on the verge of therapeutics like never before,” Barnes said. Drugs that can help fix memory loss in one area, like the medial temporal lobe, can sometimes be harmful in the frontal lobe, she says. But her lab is finding ways to direct a drug into just the right area of the brain.

Finding ways to use the newest technologies in memory study fulfills a dream, she says. “We are learning how to triangulate, to identify single cells and their roles in behavior. It is still theoretical; but since our first papers in the late 1970s, we have spent the subsequent decades deepening our understanding of memory and narrowing the gap between the laboratory bench and meaningful clinical application.”

In therapy, she says, her findings may help older adults in many ways. “If you know you are going down a path that is a precursor to Alzheimer’s disease, you could get to a clinic and see if early treatment can help you. If you are having normal age-related changes, this knowledge will reduce your anxiety to know that it’s to be expected.”

After several decades, she muses, “Being a scientist I can’t think about when it will be done. It will never be done. You just ask, ‘What can I contribute?’ ”

Collaborations

Carol Barnes collaborates closely on understanding memory in the aging brain with the McKnight Institute’s Scientific Advisory Board, including psychology professors Lynn Nadel, Elizabeth Glisky, Alfred Kaszniak, Gene Alexander and Lee Ryan; neurology professor Geoffrey Ahern; and neuropathology professor Naomi Rance.

Barnes has studied the molecular basis of altered persistence of memory during aging with Paul Worley at The Johns Hopkins University and David Sweatt at the University of Alabama to pinpoint defects in signaling pathways that may be responsible for hippocampal-dependent, age-related memory impairment.

Accomplishments

Barnes’ research provided the first concrete evidence that durability of long-term potentiation, or LTP, correlates with memory persistence behaviorally, in both young and old animals.

Barnes has been president of the 37,000-member Society for Neuroscience, the organization of scientists who the study the brain, and was an associate editor of the Society’s journal.

She served four years as a member of the National Advisory Council on Aging at the National Institute on Aging, and four years as a member of the Board of Scientific Counselors at the National Institute of Mental Health.

Barnes co-founded the Arizona Research Laboratories Division of Neural Systems, Memory and Aging along with Bruce McNaughton. This division studies brain mechanisms of learning and their changes with age.

Her lab has pinpointed the specific gene that is activated when animals are engaged in a particular experience or memory. “We can actually identify all the cells in a brain used in a particular experience, at a specific time,” she said. “We can look across the entire brain to reconstruct the contributions that different brain circuits make to an experience.”

Barnes’ team is taking major steps forward in understanding how differences in the physiology of different brain regions may predict successful aging. “It’s an exciting new approach,” she said. “It’s an amazing challenge for us. Our memories reveal changes across a lifespan, showing how some of us may be vulnerable to other disorders affecting memory. We may get to know the brain well enough to adjust things, by some kind of intervention, either behavioral or pharmaceutical.”