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doi: 10.1097/01.NT.0000407899.71777.c5
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Investigators Restore Working Memory in Aged Monkeys

Talan, Jamie

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ARTICLE IN BRIEF

In experiments with rhesus monkeys of different ages, investigators observed that the persistent firing of neurons in the prefrontal cortex — the neural basis for our higest order cognitive functions — was reduced with advancing age; moreover, a drug known to improve working memory in animals restored normal firing, showing that some age-related synaptic deficits are reversible.

DR. AMY F. ARNSTEN P...
DR. AMY F. ARNSTEN P...
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What does memory loss due to normal aging look like physiologically? And can it be reversed? While investigators have gained a clearer understanding of the pathophysiological cascade leading to dementia in recent years, far less is known about the molecular changes associated with normal age-related memory loss.

In the July 27 edition of Nature, a research team at Yale provide insight into the cellular underpinnings of that process through in vivo recordings of neuronal activity of animals engaged in a task of working memory — defined as the temporary retention of information that was recently obtained or that was recently retrieved from long-term memory but no longer exists in the external environment.

In experiments with rhesus monkeys of different ages, the investigators observed that the persistent firing of neurons in the prefrontal cortex (PFC) — the neural basis for our higest order cognitive functions — was reduced with advancing age; moreover, a drug known to improve working memory in animals restored normal firing, showing that some age-related synaptic deficits are reversible.

The investigators contend that the the cells that keep information on tap while attention may temporarily be called to other things are vulnerable to damage but are also resilient enough to respond to certain therapies.

“People have often assumed that there is not much you can do to undo the effects of aging,” said Amy F. Arnsten, PhD, professor of neurobiology and psychology at Yale University. “We were able to restore memory-related firing to more youthful levels by correcting the neurochemical environment.”

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STUDY METHODS

In the experiment, the investigators had six monkeys — two young (7- and 9-year-old males), two middle-aged (12- and 13-year-old males), and two elders (a 17-year-old male and 21-year-old female) learn to perform a task involving working memory. The monkeys had to remember where a flashing light had most recently appeared on a computer screen during a short period without the cue or stimulus (delay) and then had to respond with a saccade to the remembered location. If, after a brief delay, the monkeys remembered the most recent position of the flashing light, they were rewarded with juice. The investigators made in vivo recordings of the firing rate of neurons in their dorsolateral PFC while they performed the task with brief time delays between training periods.

The researchers observed that the firing rates from the recorded neurons in the PFC remained sustained over the delay period when the animal performed correctly — that is, they remembered where the flashing light had been — and the firing rate was reduced when errors occurred. Some neurons fired only when the monkeys saw the cue — they refer to these as the cue cells — whereas most neurons fired during the delay period — referred to as delay cells — when a memory is retained.

DR. YAAKOV STERN The...
DR. YAAKOV STERN The...
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But there were age-related differences in the response of delay neurons in the monkeys. The older and middle-aged monkeys made more errors than the younger animals and there was a linear decline in network neuronal firing with advancing age, similar to what has previously seen in behavioral studies of cognitive changes with age. When the delay periods between performing the task were increased, the older animals performed worse than the younger and middle-aged animals.

In a subsequent testing session, the investigators used a small electrical charge, through a process called iontophoresis, to move small amounts of guanfacine directly onto the neurons in the PFC; in earlier studies, the drug improved working memory in aged monkeys.

When the monkeys repeated the task, the firing pattern in the older monkeys returned to its youthful vigor — similar to the patterns of the younger monkeys.

Dr. Arnsten noted that the FDA approved guanfacine for the treatment of attention deficit disorder in 2009. The medicine was initially developed two decades ago to treat high blood pressure, she said, but it is now being used for conditions that affect the PFC, including Tourette syndrome, strokes that cause attentional neglect, and traumatic brain injury to the frontal lobe.

“Our studies showed that medicines could potentially restore the normal neurochemical environment,” said Dr. Arnsten. “And this could help maintain strong prefrontal cortex physiology into advancing age.”

The Yale investigators are now trying to determine which changes in the aging brain are responsible for the dysregulation of cAMP signaling that leads to loss of neuronal firing, and whether these changes increase vulnerability to neurodegeneration.

A clinical trial is also under way at Yale School of Medicine to test guanfacine's effects on enhancing executive function and memory in people over 75 who do not have dementia or mild cognitive impairment. This trial is being led by Christopher H. van Dyck, MD, director of the Yale Alzheimer's Disease Research Unit. The study will attempt to determine whether beneficial effects seen in younger people with prefrontal deficits can extend to the elderly, as suggested by the data from aged monkeys.

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EXPERTS WEIGH IN

Elkhonon Goldberg, PhD, clinical professor of neurology at New York University School of Medicine, called the results “intriguing.” “These findings are important because they suggest that parts of the aging process may be reversible,” he said.

Another expert questioned that conclusion, however. “It's an interesting study, “ said Yaakov Stern, PhD, professor of clinical neuropsychology and director of the Cognitive Neuroscience Division in the department of neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University College of Physicians and Surgeons. But, he added, it's too early to say whether it suggests that age-related memory loss can be reversed.

Dr. Stern said the model is intriguing because it allows scientists to go right into the brain to figure out what mediates memory over the adult lifespan.”The findings are exciting but it is a proof of concept,” he continued. “By no means does it suggest that this could be used to reverse memory changes associated with aging.”

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GUANFACINE FOR WORKING MEMORY

What is happening during the memory loss and why would guanfacine be effective? Lead study author Amy Arnsten, PhD, professor of neurobiology and psychology at Yale University, explained that the aging PFC appears to accumulate excessive levels of a signaling molecule called cAMP, which can open potassium channels. When these potassium channels open, they gate the network input, weakening the prefrontal neuronal firing.

In young brains, enzymes are on hand to chew up cAMP. It is a tightly regulated system but can be altered by stress and fatigue. With age, there is a dramatic change in the network signaling as cAMP stays around longer, opening ion channels that reduce memory-related firing and the communication between these neurons.

Agents that either inhibit cAMP or block cAMP-sensitive potassium channels are able to restore more youthful firing patterns in the aged neurons. Guanfacine mimics norepinephrine's actions at alpha-2A receptors, Dr. Arnsten explained. These receptors are situated next to potassium channels that are opened by cAMP signaling. When guanfacine engages alpha-2A receptors on prefrontal neurons, it inhibits cAMP production in the dendritic spine, which in turn closes the nearby potassium channels. This strengthens the prefrontal cortical network connection, increasing network firing and improving performance.

—Jamie Talan

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REFERENCE:

Wang M, Gamo N, Arnsten AF, et al. Neuronal basis of age-related working memory decline. Nature 2011; 476:210–213.

Wang M, Ramos BP, Arnsten AF, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007; 129:397–410.

Arnsten AF, Paspalas CD, Wang M, et al. Dynamic network connectivity: A new form of neuroplasticity. Trends Cogn Sci 2010; 14: 365–75.
Malhotra PA, Parton AD, Husain M, et al. Noradrenergic modulation of space exploration in visual neglect. Ann Neurol 2006; 59: 186–90.

McAllister TW, McDonald BC, Saykin AJ, et al. Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: Altered working memory and BOLD response. Int J Psychophysiol 2011; E-pub 2011 Jul 19.

©2011 American Academy of Neurology

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