How memory is lost — and found

Yale University researchers can’t tell you where you left your car keys — but they can tell you why you can’t find them.

A new study published July 27 in the journal Nature shows that the neural networks in the brains of the middle-aged and elderly have weaker connections and fire less robustly than in youthful ones. Intriguingly, note the scientists, the research suggests that this condition is reversible.

“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 Amy Arnsten, professor of neurobiology and psychology and a member of the Kavli Institute for Neuroscience. “These abilities are critical for maintaining demanding careers and being able to live independently as we grow older.”

As people age, they tend to forget things, are more easily distracted and have greater difficulty with executive functions. These age-related deficits have been known for years but the cellular basis for these common cognitive difficulties has not been understood. The new study examined for the first time age-related changes in the activity of neurons in the prefrontal cortex (PFC), the area of the brain that is responsible for higher cognitive and executive functions.

Networks of neurons in the prefrontal cortex generate persistent firing to keep information “in mind” even in the absence of cues from the environment. This process is called “working memory,” which allows us to recall information, such as where the car keys were left, even when that information must be constantly updated. This ability is the basis for abstract thought and reasoning, and is often called the “Mental Sketch Pad.” It is also essential for executive functions, such as multi-tasking, organizing, and inhibiting inappropriate thoughts and actions.

Arnsten and her team studied the firing of prefrontal cortical neurons in young, middle-aged and old animals as they performed a working memory task. Neurons in the prefrontal cortex of the young animals were able to maintain firing at a high rate during working memory, while neurons in older animals showed slower firing rates. However, when the researchers adjusted the neurochemical environment around the neurons to be more similar to that of a younger subject, the neuronal firing rates were restored to more youthful levels.

Arnsten says that the aging prefrontal cortex appears to accumulate excessive levels of a signaling molecule called cAMP, which can open ion channels and weaken prefrontal neuronal firing. Agents that either inhibited cAMP or blocked cAMP-sensitive ion channels were able to restore more youthful firing patterns in the aged neurons. One of the compounds that enhanced neuronal firing was guanfacine, a medication that is already approved for treating hypertension in adults and prefrontal deficits in children, suggesting that it may be helpful in the elderly as well, note the researchers.

Arnsten’s finding is already moving to the clinical setting. Christopher vn Dyck of the Yale School of Medicine is enrolling subjects in a clinical trial testing guanfacine’s ability to improve working memory and executive functions in elderly subjects who do not have Alzheimer’s disease or other dementias. Information about the clinical trial can be found online, or by contacting Nicole Barcelos at 203-764-8100.

Other Yale authors are lead author Min Wang, Nao J. Gamo, Yang Yang, Xiao-jing Wang, Mark Laubach, James A. Mazer, Daeyeol Lee and Lu E. Jin.

Disclosure: Yale University and Arnsten receive royalties from the sale of extended release guanfacine (Intuniv), which is used for the treatment of Attention Deficit Hyperactivity Disorder in children and adolescents. Royalties are not received from the sale of the immediate-release form of guanfacine, which is the form used in Arnsten’s studies and is the test compound in Yale’s clinical trial of elderly subjects.

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