A new study shows that some chemicals given to rhesus macaques blocked a brain molecule that slows the firing of the brain's nerve cells, or neurons, as they age—prompting those nerve cells to act young again.
“It's our first glimpse of what's going on physiologically that's causing age-related cognitive decline,” said study leader Amy Arnsten, a neurobiologist at Yale University. She added, “We all assumed, given there's a lot of architectural changes in aged brains ... that we were stuck with it.” But with the new results, “the hopeful thing is that the neurochemical environment still makes a big difference, and we might be able to remediate some of these things.”
It is known that as the brain gets older, the prefrontal cortex begins to decline quickly. This part of the brain is responsible for many high-order functions, including maintaining working memories—the ability to keep things on a “mental sketch pad” in the absence of stimuli from an action-based task. But when people get into their 40s and 50s, that part of the brain begins to accumulate too much of a signaling molecule called cAMP, which can stop the cells from firing as efficiently—leading to forgetfulness and distractedness.
For their study, Arnsten and colleagues spent years training six rhesus macaques of various ages how to play simple video games that require the use of working memory. During this trial electrical recordings were being made from about 50 neurons in the prefrontal cortex (the brain region holding spatial working memory) of each monkey. Two of the monkeys were young (seven and nine years), two were middle-aged (12 and 13 years) and two were old (17 and 21 years). The light could appear in one of eight different positions, assigned randomly. If, after a brief delay, the monkeys remembered the most recent position of the flashing light correctly, they earned a reward of their favorite juice.
“The youngsters do it great for a long time—they're just like humans,” she said. Once the monkeys had mastered the task, the team made recordings of single neurons firing using a tiny fiber inserted painlessly into the brain—a first in any elderly living animal. Not surprisingly, the team found that the younger animals' neurons fired often during periods when there were no stimuli. Neurons in the older animals tended to be less active during the same periods, according to the study.
But when the team administered certain drugs to the older animals via the fibers—including a chemical called guanfacine—the chemicals blocked the cAMP pathways and revved up neural activity. Guanfacine is currently an ingredient in a drug used to treat high-blood pressure in adults. The chemical is also in separate clinical trials to see if it improves working memory in the elderly.
Arnsten added that she and her team led previous studies showing that the drug improved working memory in monkeys, and those results have been repeated by other groups in both monkeys and humans. She cautions that even if the drug is approved as a brain booster, it's too early to say how much memory improvement a person could expect—“we can't say it [would] bring you back to being a 30-year-old,” she said.
According to neuroscientist James L. McGaugh a fellow at the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, who was not part of the study team, the previous studies “did not, as I understand it, provide evidence that the enhanced performance was directly associated with 'restored firing' of the neurons. That was an implication.”
Associate Professor Sharon Naismith of the Brain and Mind Research Institute at the University of Sydney looks for interventions that can improve cognitive function in the elderly. She said the study is valuable because it identifies changes in the delay neurons. “It's also nice that they've applied an intervention…As people age they just can't hold as much in their working memory, and taking in conversations and things they see on the news becomes difficult. You even need working memory for things like cooking.” This paper tackles the basic science, said Naismith. “Of course, we have to understand normal ageing first before we can really target diseases like Alzheimer's,” she said.
Paul Aisen, a neuroscientist and director of the Alzheimer's Disease Cooperative Study at the University of California, San Diego, said the study is “another incremental advance” from a strong group of scientists, but it's “uncertain whether this will have implications for treatment for humans.” That's because “measuring ... firing at the level of a single cell, a neuron, is difficult to extend to human behavior, which is highly complex.” “It's not so much that a monkey is not a human—it's that this kind of single-cell recording is a very isolated aspect of brain function,” he said.
Aisen added that the big question is whether age-related memory decline really needs drug treatment. “In the absence of a disease such as Alzheimer's, people [compensate] quite well despite the decline in memory,” he said. For example, some elderly people combat forgetfulness by simply writing things down. But study leader Arnsten argues that the fight against cognitive decline is still crucial for many otherwise healthy people. “These abilities are critical for managing one's finances, for being able to manage one's medical treatment, and [to] live independently.”
The study, which was supported by a grant from the National Institute on Aging, was published today (July 27) in the journal Nature.
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