Resetting the body clock could help the brain recover after stroke

Published in the Journal of Clinical Investigation, the study showed that interventions designed to reinforce circadian rhythms improved recovery in mouse models of stroke. These improvements were accompanied by stronger activity in the glymphatic system, the brain's waste-clearing network, along with lower levels of inflammatory molecules that can persist after a stroke.

How the Brain Clears Waste

The findings build on more than a decade of research led by URochester Medicine neuroscientist Maiken Nedergaard, MD, DMSc. Her laboratory discovered the glymphatic system in 2012.

This system moves cerebrospinal fluid through the brain, helping remove waste products and other debris. Later studies found that glymphatic activity is especially strong during sleep and plays an important role in maintaining brain health.

Neuroscientist Lauren Hablitz, PhD, later helped show that glymphatic activity is influenced 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 demonstrated that glymphatic function follows daily cycles even independently of sleep, establishing a direct link between circadian biology and the brain's waste-clearing system.

Stroke May Disrupt the Brain's Timing

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

Scientists have long known that strokes tend to follow distinct time-of-day patterns. They occur more often during the morning and are frequently more severe near the end of the sleep period.

After a stroke, many patients also develop disrupted sleep-wake cycles. Those disturbances have been linked with worse recovery, depression, and reduced 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?"

When the Brain's Cleanup System Slows Down

In a healthy brain, the glymphatic system carries cerebrospinal fluid along blood vessels and through brain tissue. This process delivers nutrients while helping remove waste products and inflammatory signals.

Earlier research has shown that glymphatic function becomes impaired after stroke. That disruption may reduce the brain's ability to clear harmful molecules that accumulate during recovery.

Stroke research has traditionally focused on separating beneficial inflammation from harmful inflammation and finding ways to suppress the damaging forms. Hablitz and her colleagues suggest that another part of the problem may be that the brain is no longer clearing inflammatory signals effectively.

"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."

Under this model, stroke damages both brain tissue and the pathways responsible for removing inflammatory signals. As those molecules accumulate, they may contribute to continued damage and slower recovery.

Resetting the Body Clock

To test whether stronger circadian rhythms could improve recovery, the researchers examined several interventions known to affect the body's internal clock. These included timed light exposure, melatonin, a clock-targeting drug called KL001, and time-restricted feeding.

The team first showed that each of these interventions could improve glymphatic function in healthy animals. They then selected the most promising strategies, KL001 and time-restricted feeding, and tested them in mouse models of stroke.

Treatment did not begin until three days after the stroke, far beyond the narrow window used for clot-busting drugs and other acute stroke treatments.

Even with that delay, mice that received either intervention showed better motor recovery, smaller lesion volumes, improved 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 Strategy That Could Be Easier to Use

One of the most promising approaches was time-restricted feeding, a behavioral intervention that is already being investigated for obesity, diabetes, cardiovascular disease, and other conditions.

That could make the findings especially relevant for stroke rehabilitation because such an approach might eventually be easier to use outside specialized medical settings.

"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.

What Researchers Need to Test Next

The researchers emphasize that the findings so far are limited to animal models. More studies will be needed to determine exactly how circadian rhythms, glymphatic function, and inflammation influence one another after stroke.

Future work will also examine whether improved glymphatic flow directly causes better recovery and whether circadian-based interventions can eventually be tested in clinical trials.

More broadly, the study reflects a growing view in neuroscience that sleep, circadian rhythms, and fluid movement through the brain are central to brain health.

By learning more about how the brain's internal clock regulates the glymphatic system, researchers hope to uncover new ways to improve recovery not only after stroke, but also in other neurological conditions involving inflammation and poor 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."