NARSAD Distinguished Investigator Demonstrates Working Memory Can Be Restored in Elderly Primates

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Amy F. T. Arnsten, Ph.D., Yale School of Medicine
Amy F. T. Arnsten, Ph.D.

You don’t have to be a neuroscientist to know that certain of our mental faculties decline as we age. Memory is one instance or, in many people, the ability to concentrate. A NARSAD Distinguished Investigator at Yale University and her team have recently performed experiments demonstrating that age-related cognitive decline ─ as this diminution of mental capacity is called ─ is likely reversible, at least in part. Team leader Amy F. T. Arnsten, PhD, is a neurobiologist who has devoted her career to studying a part of the brain called the prefrontal cortex, or PFC, the most evolved brain area in primates, including humans.

The PFC is the seat of what scientists call working memory. When you try to remember a phone number, or recall where you left your keys, you are relying on working memory, a capacity that begins, often imperceptibly, to erode in healthy middle-aged individuals.

Dr. Arnsten’s team, as reported in the journal Nature in July, has made the first recordings of PFC nerve-cell activity in living primates ─ young, middle-aged, and elderly. The animals were trained to perform working memory tasks. Like people, healthy primates begin to develop deficits in PFC-based memory in middle age, but unlike people, they don’t suffer from age-related dementias. So their brains are particularly interesting to those like Dr. Arnsten who want to study dysfunction in the PFC that is not related to illnesses such as Alzheimer’s.

The team’s most notable discovery was that neurons in the PFC of young animals were able to maintain a high rate of firing while performing working memory tasks. In contrast, neurons in older animals showed slower firing rates. Most interesting of all, when the researchers adjusted the neurochemical environment around the PFC neurons in older monkeys to match what is typical in young monkeys, the nerve cells began to fire again at levels closer to those seen in younger animals.

According to Dr. Arnsten, the aging PFC appears to accumulate excess levels of a signaling molecule called cyclic AMP, or cAMP, which slows nerve-cell firing. Agents that either inhibited cAMP or blocked the tiny pores called ion channels that it affects enabled the scientists to restore function, including improved performance in working memory tasks. Dr. Arnsten’s colleagues at Yale’s School of Medicine have initiated a clinical trial to see whether a known compound called guanfacine can improve working memory and executive function in elderly people who don’t have Alzheimer’s.

But the work is full of other implications, says Dr. Arnsten, regarding brain and behavior disorders in which PFC function is impaired. People with schizophrenia, for instance, often have working memory deficits and abnormally low activity in the prefrontal area. There is evidence suggesting genetic changes linked with the illness, such as mutations of DISC1, dysregulate cAMP signaling. Also, the persistent neuronal firing that’s so important in working memory occurs in a layer of the PFC that is the focus of neuropathological insults in schizophrenia.

“I think our highest-order cortical circuits have evolved to have different neurochemical needs than much of the rest of the brain,” Dr. Arnsten suggests, “and therefore understanding these needs promises to reveal why they are so vulnerable.”

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