New hope for old brains seen in study of memory

The prefrontal cortex (PFC)—the front part of the brain, just behind the forehead—is the site of a dizzying array of important neurological functions. One is working memory, the short-term memory we rely on when performing simple tasks like remembering where we left our car in a parking lot. Networks of neurons in the PFC fire persistently to keep information like this in mind while we go about our business. But like other functions of the PFC, working memory declines with age: we become increasingly forgetful and distractable, and complex tasks can pose new difficulties.

Recent work by a team of School of Medicine scientists in the lab of Amy F.T. Arnsten, Ph.D., professor of neurobiology and psychology, offers new insights into age-related decline in working memory and suggests that certain drugs may lessen or reverse some of this drop-off.

Arnsten, a member of Yale’s Kavli Institute for Neuroscience, and colleagues had previously shown that elevated activity of cyclic AMP (cAMP), a chemical messenger inside cells, reduces neuronal firing in the brains of fatigued or stressed young animals by opening tiny pores in neurons known as potassium channels: when the channels open near neural connections, networks disconnect and the function of the PFC is impaired. Now, in the aging brain under normal conditions, Arnsten’s team has discovered these same physiological changes—which may increase vulnerability for age-related neurodegenerative diseases—as well as a potential way to reverse the changes.

In the new research, published July 27 in Nature, Arnsten’s team—including Min Wang, Ph.D., research scientist in the Department of Neurobiology and lead author of the study; James A. Mazer, Ph.D., associate professor of neurobiology and psychology; and Daeyeol Lee, Ph.D., associate professor of neurobiology and psychology, and member of the Kavli Institute—measured the function of PFC neurons in animals of different age groups to gauge the animals’ ability to remember spatial locations over a period of time.

The team found a marked reduction in the firing rate of working-memory cells in the PFC of middle-aged and elderly animals. But by using drugs that inhibit cAMP signaling, or that block the potassium channels regulated by cAMP , the scientists were able to significantly restore the firing of these neurons and enhance the animals’ ability to perform the task. The findings suggest that compensating for neural changes at the molecular level may aid in combating age-related deterioration of working memory.

One of the substances that enhanced neuronal firing by dampening cAMP signaling, guanfacine, is already approved for treating hypertension in adults and attention-deficit hyperactivity disorder in children, and it may now prove useful in the elderly. The School of Medicine is now enrolling elderly subjects who do not have Alzheimer’s disease or other forms of dementia in a clinical trial to test guanfacine’s ability to improve working memory and the ability to manage complex decisions and tasks.

“Age-related cognitive deficits can have a serious impact on our lives in the information age, as people often need higher cognitive functions to meet even basic needs, such as paying bills or accessing medical care,” says Arnsten. “These abilities are critical for maintaining demanding careers and being able to live independently as we grow older.”