Reinforcing daily rhythms helps the brain recover after stroke

A new study from scientists at the University of Rochester Medicine suggests that reinforcing the body's natural daily rhythms to improve sleep could help the brain recover after a stroke, pointing to a potential new strategy to improve brain waste clearance and outcomes long after the initial injury.

The research, which was published in the Journal of Clinical Investigation, found that interventions designed to reinforce the body's natural circadian rhythms improved recovery in mouse models of stroke. The benefits were accompanied by improvements in the glymphatic system-the brain's waste-clearing network-and reductions in inflammatory molecules that can linger in the brain after a stroke.

The findings build upon more than a decade of pioneering research led by URochester Medicine neuroscientist Maiken Nedergaard, MD, DMSc, whose laboratory discovered the glymphatic system in 2012. The system circulates cerebrospinal fluid through the brain, helping clear waste products and other debris. Subsequent research revealed that glymphatic activity is most robust during sleep and plays an important role in maintaining brain health.

Building on that discovery, neuroscientist Lauren Hablitz, PhD, helped demonstrate that glymphatic activity is governed not only by sleep but also by circadian rhythms-the body's internal 24-hour clock. In a landmark 2020 study, Hablitz, Nedergaard, and colleagues showed that glymphatic function follows daily rhythms independent of sleep itself, helping establish a direct connection between the brain's waste-clearing system and circadian biology.

Stroke as a disorder of timing

Lauren Hablitz, PhD, lead author of the new studyThe discussion of stroke recovery really starts with the idea that stroke is not just a vascular event, but also a disorder of timing."

Researchers have long known that strokes follow predictable time-of-day patterns. They are more likely to occur in the morning hours and are often more severe near the end of the sleep period. At the same time, many stroke patients experience disrupted sleep-wake cycles after their injury, and those disruptions are associated with poorer recovery, depression, and lower quality of life.

"That led us to ask a simple question," said Hablitz. "If timing is broken after a stroke, can we improve recovery by reinforcing the biological clock?"

The brain's cleaning system

Under healthy conditions, the glymphatic system moves cerebrospinal fluid along blood vessels and through brain tissue, delivering nutrients and helping remove waste products and inflammatory signals. Previous studies showed that glymphatic function becomes impaired after stroke, potentially limiting the brain's ability to clear harmful molecules that accumulate during recovery.

Traditionally, stroke researchers have focused on distinguishing beneficial inflammation from harmful inflammation and finding ways to suppress the latter. Hablitz and her colleagues propose that impaired clearance may be part of the problem.

"We think part of the problem may be a failure of cleaning," she said. "If the system responsible for clearing signaling molecules isn't working properly, everything builds up."

In this model, stroke damages not only brain tissue but also the pathways that normally help clear inflammatory signals. As those molecules accumulate, they may contribute to ongoing injury and impaired recovery.

Reinforcing the clock

To test whether restoring circadian rhythms could improve recovery, the researchers evaluated several interventions known to influence the body's internal clock, including timed light exposure, melatonin, a clock-targeting drug called KL001, and time-restricted feeding.

The team first demonstrated that each intervention could enhance glymphatic function in healthy animals. They then tested the most promising approaches-KL001 and time-restricted feeding-in mouse models of stroke.

Importantly, treatment began three days after stroke, well beyond the narrow treatment window for clot-busting drugs and other acute interventions. Despite the delay, the animals receiving either intervention showed improved motor recovery, smaller lesion volumes, enhanced glymphatic flow, and lower levels of inflammatory cytokines in the brain.

"All of the cytokines moved in the same direction," Hablitz said. "That suggests we may not be targeting one specific inflammatory pathway. Instead, we may be helping the brain clear inflammatory signals more effectively."

A potentially accessible therapy

Because the most promising intervention involved time-restricted feeding-a behavioral approach already being studied for obesity, diabetes, cardiovascular disease, and other conditions-the findings could have practical implications for stroke rehabilitation.

"One of the exciting aspects of this work is that we're studying interventions that could potentially be implemented not only in hospitals but also at home," Hablitz said.

Looking ahead

The researchers caution that the findings are currently limited to animal models and that more work is needed to understand exactly how circadian rhythms, glymphatic function, and inflammation interact after stroke.

Future studies will seek to determine whether improved glymphatic flow directly drives recovery and whether circadian-based interventions can be translated into clinical trials.

More broadly, the work reflects a growing shift in neuroscience that views sleep, circadian rhythms, and fluid transport as fundamental drivers of brain health. By uncovering how the brain's internal clock influences the glymphatic system, researchers hope to identify new ways to enhance recovery not only after stroke, but also in other neurological disorders marked by inflammation and impaired waste clearance.

"Understanding how circadian regulation shapes glymphatic clearance will help us develop more targeted therapies," said Hablitz. "Ultimately, our goal is to find ways to improve the brain's ability to clear waste, reduce inflammation, and recover after injury."

Source:

University of Rochester Medical Center

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