From NIH Research Matters

Exercise provides many health benefits, including protection from many diseases. Some people seem to enjoy physical activity more than others. But the mechanisms affecting people’s motivation to exercise are not well understood.

Researcher swabbing a petri dish with bacteria to study the microbiome of mice.

An NIH-funded team of researchers, led by Dr. Christoph Thaiss at the University of Pennsylvania, set out to identify factors affecting exercise performance in mice. Their study appeared in Nature on Dec. 14, 2022.

The researchers first measured how long mice running on a treadmill took to exhaust themselves and how much the mice voluntarily ran on a wheel. They found that the makeup of the gut microbiome — the trillions of microbes living in the gut — predicted these values better than genetic, metabolic, or behavioral traits. When the researchers used antibiotics to eliminate gut microbes, the mice got exhausted earlier and ran less on the wheel.

Motivation is controlled in part by a region of the brain known as the striatum. Neurons in the striatum are activated by the neurotransmitter dopamine. Dopamine activation provides a feeling of reward. The team found that dopamine levels in the striatum increased after exercise in normal mice, but not in microbiome-depleted mice. Treating mice with a drug that blocks dopamine signaling had the same effect on exercise as depleting the microbiome. Conversely, a drug that activates dopamine signaling restored exercise capacity in microbiome-depleted mice.

Activating certain sensory neurons in the gut restored exercise capacity in the microbiome-depleted mice. But when dopamine signaling was blocked, so was the effect of these neurons. The researchers then tested mice engineered to lack these same sensory neurons. They found that the mice had impaired exercise capacity like that of microbiome-depleted mice.

Next, the team screened various compounds produced by gut microbes to see which ones could stimulate gut sensory neurons. They identified a class of compounds called fatty acid amides (FAAs). Supplementing the diets of microbiome-depleted mice with FAAs restored their exercise capacity.

Several FAAs are known to activate a receptor on sensory neurons called cannabinoid receptor 1 (CB1). The team found that blocking CB1 had the same effect on exercise as microbiome depletion. When CB1 was blocked, dietary FAA supplementation did not restore exercise capacity. But activation of dopamine receptors still restored exercise capacity even when CB1 was blocked.

These results suggest that microbiome-produced FAAs in the gut stimulate sensory neurons. Signals from these sensory neurons lead to increased dopamine levels in the striatum during exercise. Dopamine, in turn, enhances the desire for exercise. The findings suggest that the motivation to exercise — or lack thereof — might depend on the state of the gut microbiome. The motivation for exercise, then, might be enhanced by stimulating this sensory pathway.

“If we can confirm the presence of a similar pathway in humans, it could offer an effective way to boost people’s levels of exercise to improve public health generally,” Thaiss says.

by Brian Doctrow, Ph.D.

This research was supported in part by NIA grant DP2AG067492.

In recent years, Koronyo-Hamaoui, Ph.D., M.S. (a professor in the Cedars-Sinai Department of Neurosurgery) and her colleagues have discovered the first evidence of the specific diagnostic signs of Alzheimer’s disease-related amyloid beta protein plaques in retinas from Alzheimer’s and mild cognitive impairment patients. In a series of several NIA-funded innovative studies, her team found increased retinal amyloid plaques and associated retina blood vessel and nerve cell degeneration in patients compared to age and sex-matched cognitively healthy individuals.

Her team also created a low-cost, noninvasive technique to detect Alzheimer’s protein plaques at a very high resolution in the retinas of living patients. Additionally, they developed a modified version of a powerful eye imaging tool — the scanning laser ophthalmoscope — that includes a wider look at previously overlooked peripheral regions in the retina. They combine this scan with giving research participants an oral dose of curcumin, a natural compound that lends zest and orange color to Indian spices such as curry and turmeric. Curcumin is naturally drawn to amyloid beta, the protein that comprises Alzheimer’s disease plaques in the brain, making it easier for the researchers to spot.

“You can look at the retina and see things at the molecular, cellular, and vascular levels, like protein aggregates and vascular abnormalities,” said Koronyo-Hamaoui. Her team is exploring if optical retinal imaging with curcumin could be a cost-effective test to identify Alzheimer’s pathology, including in people with mild cognitive impairment. “We uncovered parallels between the effects of Alzheimer’s disease in the retina and brain, and that specific changes in the retinal regions mimic changes in the brain and cognitive status,” she added.

Koronyo-Hamaoui’s team is collaborating with neuropathology experts across the United States, Europe, and Australia to expand their studies into Alzheimer’s retinopathy and visual deficits to see if a similar test can detect buildup of the protein tau, another hallmark of the disease, in the retina. Their hope is to develop affordable, accessible retina-based scanning technology that might someday be used in combination with routine cognitive and brain imaging for the earlier detection of Alzheimer’s and related dementias, Parkinson’s disease, and stroke.

Untreated vision loss can be especially devastating. Using data from the Health and Retirement Study, NIA-funded scientists recently made the case for including vision impairment as a risk factor for dementia, estimating that nearly 100,000 dementia cases in the U.S. could possibly have been prevented with existing vision treatments.

Older adults stop driving, they stop going out, they have difficulty reading, and they don’t exercise as much because they’re afraid of falling. Untreated vision problems really reduce social interaction, emotional well-being, and physical activity, which are all risk factors for cognitive decline.