Chronotherapy to reinforce circadian rhythms improves poststroke outcomes and glymphatic function in mice
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
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Research Article Cell biology Neuroscience

Chronotherapy to reinforce circadian rhythms improves poststroke outcomes and glymphatic function in mice

Abstract

Stroke remains a leading cause of morbidity and mortality worldwide, with few effective interventions to promote recovery. Targeting circadian timing and glymphatic function may represent viable therapeutic strategies. Here, we show that the small-molecule clock modulator, KL001; high-dose melatonin; acute light pulses; and active-phase time-restricted feeding were each sufficient to enhance glymphatic function in mice. Moreover, initiating treatment with either KL001 or active-phase time-restricted feeding 3 days after preclinical models of stroke improved motor outcomes, reduced lesion volume, increased glymphatic flow, and lowered poststroke brain cytokine burden. These findings suggest that reinforcing normal daily rhythmicity after stroke can markedly enhance neurological recovery, even when interventions are initiated several days after stroke onset.

Authors

Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz

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Figure 1

Circadian interventions boost glymphatic flow in healthy mice.

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Circadian interventions boost glymphatic flow in healthy mice. (A) Exper...
(A) Experimental design of acute KL001 administration. (B and C) Box plots of mean pixel intensity (MPI) of glymphatic influx and representative coronal sections for experiments done at Zeitgeber time 4 (ZT4, lights on at ZT0) (B) or ZT16 (C). (D) Experimental design of KL001 treatment and diurnal behavioral monitoring. (E) Representative single-plotted actograms of mice receiving vehicle (gray) or KL001 (green) for 8 days. Each treatment is indicated by a colored dot; black tick marks denote general cage activity; white represents lights off; tan indicates lights on. (F) Box plot of χ2 periodogram calculated rhythmicity amplitude at 24 hours. (G) Experimental design of high-dose melatonin administration. (H and I) Box plots of MPI of glymphatic influx and representative coronal sections for experiments done at ZT0 (H) or ZT10 (I). (J) Experimental design of time-restricted feeding (TRF). (K) Representative coronal brain sections for glymphatic influx analysis (left). The region within the dotted box is shown at ×2.5 magnification to the right. (L) Box plot of MPI of glymphatic influx. For all box plots, median and quartiles are shown by box-and-whisker plots, with individual mice shown as colored dots. *P < 0.05, **P < 0.01. B, C, F, and H: unpaired 2-tailed t tests. I: unpaired 2-tailed t test with Welch’s correction. L: 1-way ANOVA test with Tukey’s HSD post hoc comparisons. All statistics are shown in Supplemental Table 1.