The Relationship Between Sleep, Circadian Rhythms, and Neuronal Myelination
Post by Meredith McCarty
The takeaway
Myelination is pivotal for neuronal function and is altered in many neurodegenerative disorders including multiple sclerosis (MS). In this study, the authors find that myelination development and maintenance are dependent on the circadian transcription factor Bmal1.
What's the science?
Myelination is the process by which neurons are encased in a myelin sheath, providing metabolic support and increased signaling efficiency of the neuron. Myelination is maintained by oligodendrocyte cells, which produce myelin sheaths for neurons throughout the central nervous system. Oligodendrocyte precursor cells (OPCs) are the precursor for oligodendrocytes, yet not much is known about their development and regulation.
Bmal1 is a transcription factor involved in circadian rhythm regulation, and recent research has found the disruption of Bmal1 to be correlated with changes in OPC function. This week in Neuron, Rojo and colleagues investigate the role of Bmal1 in myelination processes, and how these dynamics are related to sleep disruption and circadian cycles.
How did they do it?
To study the relationship between circadian rhythms, Bmal1 dynamics, and myelination throughout development, the authors conducted several genetic and behavioral experiments in mouse models.
The mouse models used in this study were wild-type (i.e., normal) mice and mice that had the Bmal1 transcription factor knocked out from the OPC cells specifically (OPC-specific Bmal1 knockout mice). To quantify changes in OPC proliferation at different experimental time points, the authors injected a tag to measure DNA proliferation called EdU. To understand the role of Bmal1 in OPC regulation, the authors performed RNA-sequencing and circadian rhythmicity assessment on OPC cells from mice at varying experimental time points. The authors then quantified physical changes in myelination throughout the central nervous system using transmission electron microscopy (TEM) as well as tests of the integrity of the blood-brain barrier in wild-type and mice without Bmal1.
To quantify changes in mouse behavior, the authors used measures of gait, stride length, and working memory. To study the role of sleep deprivation in Bmal1 function, the authors altered the mouse sleep/wake cycles and recorded during wake and sleep from implanted EEG electrodes. To probe the regulation of remyelination during adulthood, the authors quantified morphological complexity in older mice and performed a focal demyelination procedure in wild-type mice and mice without Bmal1. Lastly, the authors analyzed human genetic data to study the relationship between the risk of MS and sleep fragmentation.
What did they find?
The authors found changes in OPC proliferation depending on the circadian rhythm. Additionally, mice without Bmal1 exhibited decreased OPC density and physical complexity in the corpus callosum (the white matter connecting the left and right hemispheres of the brain), but not in other brain regions. The authors also found a significant reduction in OPCs throughout cortical and subcortical brain regions in the developing brains of mice without Bmal1, suggesting reduced OPC migration in these mice. The authors next used RNA sequencing to compare genes expressed in OPCs at different time points in the circadian cycle and found that 10% of genes were rhythmically expressed in OPCs. This suggests that Bmal1 regulates OPC dynamics in specific brain regions at specific points in development and during the circadian rhythm.
When measuring changes in myelination using transmission electron microscopy (TEM), the authors found the corpus callosum to have thinner myelination in mice without Bmal1 relative to wild-type mice. The authors found no differences in the integrity of the blood-brain barrier in mice without Bmal1-KO. Next, when the authors used a novel object recognition task to assess whether these changes in myelination altered the behavior of mice without Bmal1, they found deficits in working memory, stride length, and gait. suggesting that Bmal1 disruption and altered myelination results in behavioral and cognitive effects.
EEG recordings during sleep deprivation experiments revealed mice without Bmal1 exhibited disrupted sleep and altered recovery from sleep deprivation relative to wild-type mice. The authors next compared the effect of Bmal1 disruption in early versus later developmental time points, quantifying changes in OPC morphology and migration. They found that Bmal1 knockout in adolescence led to significant disruption of OPC density and complexity. Interestingly, Bmal1 knockout in adulthood led to disrupted remyelination, but no changes in OPC density.
What's the impact?
In this study, the authors find that Bmal1 regulation is tightly linked with circadian rhythms and the maintenance of myelination throughout specific regions of the mouse central nervous system. Interestingly, the authors note that since sleep disruption is associated with an increased risk of MS in humans, this novel evidence has implications for the treatment of demyelinating disorders like MS. Future research is necessary to clarify the relationship between MS and sleep in human studies.