DPYD links glial lipids and myelination to sleep duration

A. J. Zimmerman; S. Deal; E. Almeraya Del Valle; J. Donnelly; F. Kroll; X. Guo; T. Tsundupalli; Z. Shetty; F. Doldur-Balli; B. Keenan; S. F. Grant; J. Rihel; A. Sehgal; A. I. Pack

doi:10.64898/2026.10.31.763190

AI summary · DOI: 10.64898/2026.10.31.763190 · bioRxiv: Neuroscience

DPYD links glial lipids and myelination to sleep duration

A. J. Zimmerman, S. Deal, E. Almeraya Del Valle, J. Donnelly, F. Kroll, X. Guo, T. Tsundupalli, Z. Shetty,

and 6 more authors

F. Doldur-Balli, B. Keenan, S. F. Grant, J. Rihel, A. Sehgal, A. I. Pack

Original paper Published on 03 Nov. 2026 bioRxiv preprint License: CC BY-ND 4.0 Also in: fr

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The essentials

Across animal models, DPYD orthologs regulate sleep through glial lipid biology, and zebrafish experiments show that changing myelination can alter sleep.

Question

How does DPYD influence sleep duration, and is myelin a cause of sleep changes or merely affected by sleep loss? The authors also investigate whether DPYD’s sleep-related role reflects an ancestral glial lipid function shared across species.

Method

The authors combined mouse metabolite measurements, cell-expression analyses, and corpus-callosum electron microscopy with CRISPR-Cas9 and pharmacological manipulation of myelination in zebrafish. They also used cell-specific su(r) RNAi, sleep tracking, and lipid-droplet imaging in Drosophila, then examined human sleep-duration GWAS variants alongside oligodendrocyte regulatory data.

Findings

Result Dpyd knockout mice had thinner myelin in the corpus callosum, with no detected genotype difference in axon diameter.
See the passage in the paper
Axons from Dpyd knockout mice displayed a significantly higher g-ratio relative to sibling wild-type controls (likelihood ratio test: χ²(1) = 4.79, P = 0.029) (Fig. 1e-f), indicative of thinner myelin. Axon diameter did not differ between groups (Fig. 1g)
Result Zebrafish lacking both dpyda and dpydb had disrupted myelin and showed less active-phase sleep and more fragmented inactive-phase sleep.
See the passage in the paper
dpyda/b crispants had significantly more membranes showing myelin decompaction (22% more decompacted sheaths, P = 0.03) (Fig. 2m and Extended Data Fig. 4) and aberrant myelin features (e.g. membrane vacuolization and irregular wrapping) (20% more aberrant sheaths, P = 0.009) (Fig. 2n and Extended Data Fig. 4).
Result In zebrafish, reducing myelination reduced sleep, increasing it was associated with more sleep, and clemastine restored sleep measures in hypomyelinating mutants.
See the passage in the paper
Collectively, our data indicate hypomyelination and hypermyelination produce opposing sleep phenotypes, and the promyelinating compound clemastine can ameliorate sleep deficits in hypomyelinating mutants, including dpyda/b crispants.
Result Glial su(r) knockdown in Drosophila reduced lipid-droplet numbers and altered sleep, including reduced daytime sleep in males after pan-glial knockdown.
See the passage in the paper
We performed pan-glial knockdown of su(r) using repo-GAL4 to prevent compensation from unique glial subtypes and found this significantly reduced the number of lipid droplets in the Drosophila brain (P = 0.02 vs. repo-GAL4/+, P = 0.0006 vs. +/UAS su(r) RNAi) (Fig. 4f-g).
Authors’ interpretation The human sleep-duration-associated proxy variant was linked to reduced DPYD expression in blood and mapped to a regulatory region with oligodendrocyte chromatin features and contacts with the DPYD promoter.
See the passage in the paper
These findings importantly bridge the human GWAS variant for sleep duration to active regulation of DPYD in oligodendrocytes, implicating a cellular mechanism underlying this genetic association to sleep duration in humans and across species.

Limitations

The study did not determine whether myelin affects sleep through lipid storage, axonal conduction, or both.
See the passage in the paper
Whether myelin’s effect on sleep in vertebrates operates through this same lipid-storage function, through conduction-related properties, or both, was not directly tested here and remains an important question for future work.
The mechanism by which DPYD affects lipid synthesis or storage in the brain remains unresolved.
See the passage in the paper
Several questions remain including how DPYD specifically affects lipid synthesis and/or storage in the brain and whether its effects extend beyond myelin.
The human variant’s proposed oligodendrocyte-specific regulatory effect is inferred from association and regulatory datasets rather than directly tested in an experimental human model.

Why it matters

The authors argue that myelin is not only influenced by sleep but can itself help regulate sleep duration, supporting a bidirectional relationship. Their cross-species results identify glial lipid biology as a possible conserved link and suggest sleep disruption could signal myelin pathology.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: DPYD sleep duration myelination glia cross-species research

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Comprehensive Summary
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Original abstract

The paper investigates how DPYD, an enzyme involved in pyrimidine breakdown, influences sleep duration. Previous research found that mice lacking *Dpyd* sleep less during their active phase and experience more fragmented sleep during their inactive phase, but the underlying mechanism was unclear. The authors examined whether DPYD affects sleep through brain metabolites, glial cells, and myelin, and whether changes in myelination can themselves alter sleep. They combined experiments in mice, zebrafish, and fruit flies with analyses of human sleep genetics, using each model to investigate a different part of the proposed mechanism. In mice, brain metabolite measurements did not support the hypothesis that *Dpyd* loss alters sleep by reducing beta-alanine or related neurotransmitters. Levels of beta-alanine, GABA, glutamate, carnosine, and histidine did not differ significantly between knockout and control mice. Instead, single-cell data identified oligodendrocyte-lineage cells as an important site of *Dpyd* expression. Electron microscopy of the corpus callosum revealed thinner myelin in knockout mice, reflected by a higher g-ratio (likelihood-ratio test, *P* = 0.029), while axon diameter was unchanged. The researchers accounted for the mice’s immediate sleep and circadian context: sleep during the one- and three-hour periods before sacrifice did not differ significantly between groups. Zebrafish experiments tested whether myelin changes can influence sleep and contribute to the DPYD-related phenotype. Loss of both zebrafish DPYD copies, *dpyda* and *dpydb*, caused myelin abnormalities, including 22% more decompacted sheaths (*P* = 0.03) and 20% more aberrant sheaths (*P* = 0.009). The fish also slept 47.1 minutes less during their active phase (*P* = 0.001) and had 11.9 more sleep bouts per night (*P* = 0.0007), broadly resembling the mouse phenotype. Independent myelin manipulations provided further evidence that myelination contributes to sleep regulation. Disrupting *myrf*, which impairs myelination, reduced daytime sleep by an average of 30.3 minutes per light period (*P* = 0.04). Disrupting *fbxw7*, a manipulation associated with increased myelination, increased daytime sleep by 246.2 minutes per 14-hour light period (*P* < 0.0001). The promyelinating drug clemastine, given at 1.25 micromolar, shifted sleep and activity measures in *dpyda/b* and *myrf* mutants toward control levels. Higher doses were toxic or suppressed activity. The researchers chose the low dose partly because it preserved the fish’s arousal response to darkness. Fruit flies, which lack wrapping myelin, were used to test whether DPYD can affect sleep through glia independently of myelin. Knocking down the DPYD ortholog *su(r)* in glia reduced daytime sleep in males, particularly when the knockdown targeted ensheathing glia. Pan-glial knockdown also reduced the number of brain lipid droplets. In females, however, pan-glial knockdown increased daytime sleep by about 84–90 minutes, while other targeted knockdowns had no significant effect. These sex-dependent findings indicate that the fly response is not uniform across sexes. Finally, human genetic analyses linked a sleep-duration-associated variant near *DPYD* to reduced *DPYD* expression in blood. The analyses also identified regulatory chromatin contacts with the *DPYD* promoter in oligodendrocytes. These findings support, but do not establish, a corresponding mechanism in the human brain.

How a Metabolic Enzyme May Connect Brain Insulation and Sleep

Sleep is shaped by more than the brain’s familiar signaling chemicals. A study titled “DPYD links glial lipids and myelination to sleep duration” investigates a less obvious possibility: that the enzyme DPYD affects sleep through glial cells and the myelin that insulates nerve fibers. The research, by A. J. Zimmerman, S. Deal, E. Almeraya Del Valle, J. Donnelly, F. Kroll, X. Guo et al., brings together experiments in mice, zebrafish, and fruit flies, alongside analyses of human genetic data.

Earlier work had found that mice lacking Dpyd sleep less during their active phase and have more fragmented sleep during their inactive phase. The reason was unknown. The new study tested several possible links, including brain metabolites, glial cells, and myelin, and asked whether changing myelination could itself alter sleep.

Looking beyond the neurotransmitter hypothesis

Because DPYD helps break down pyrimidines, the researchers first considered whether its loss might change levels of beta-alanine, a metabolite connected to sleep-related neurotransmitters. Measurements in knockout and control mice did not support this explanation: beta-alanine, GABA, glutamate, carnosine, and histidine showed no significant differences.

Instead, single-cell data pointed toward oligodendrocyte-lineage cells, which produce and maintain myelin. In the corpus callosum, electron microscopy revealed thinner myelin in mice lacking Dpyd. This was reflected in a higher g-ratio, a measure of myelin thickness relative to the diameter of the nerve fiber (likelihood-ratio test, P = 0.029). Axon diameter itself was unchanged.

The researchers also checked whether the mice’s sleep just before tissue collection could explain the myelin result. Sleep during the preceding one- and three-hour periods did not differ significantly between knockout and control groups. That check helps separate the observed structural difference from an immediate difference in sleep or circadian context.

Zebrafish link myelin changes with sleep

Zebrafish offered a way to examine both myelin and sleep after disrupting DPYD. Fish missing both copies of the DPYD-related genes dpyda and dpydb showed abnormalities in their myelin sheaths: 22% more sheaths were decompacted (P = 0.03), and 20% more were classified as aberrant (P = 0.009).

The mutants also slept 47.1 minutes less during their active phase (P = 0.001) and had 11.9 more sleep bouts per night (P = 0.0007). This combination of reduced sleep and greater fragmentation broadly resembled the mouse findings.

To test whether myelination can influence sleep independently of DPYD, the researchers altered other genes. Disrupting myrf, which impairs myelination, reduced daytime sleep by an average of 30.3 minutes per light period (P = 0.04). By contrast, disrupting fbxw7, a manipulation associated with increased myelination, raised daytime sleep by 246.2 minutes over a 14-hour light period (P < 0.0001). Together, these experiments support a connection between myelin state and sleep, although they do not show that myelin is the only factor involved.

A drug test, with an important dose caveat

The team also tested clemastine, a drug with promyelinating effects. At 1.25 micromolar, it shifted sleep and activity measures in dpyda/b and myrf mutant fish toward control levels. The dose was chosen in part because it preserved the fish’s response to darkness, a sign that they could still respond to an arousal cue.

Higher doses, however, were toxic or suppressed activity. That makes the dose distinction important: the reported improvement at a low concentration should not be taken as evidence that more of the drug would produce a stronger benefit.

Fruit flies reveal a role for glia without wrapping myelin

Fruit flies do not have the wrapping myelin found in vertebrates, so they allowed the researchers to examine whether DPYD-related effects might involve glia through another route. Knocking down the DPYD ortholog su(r) in glia reduced daytime sleep in males, especially when the manipulation targeted ensheathing glia. Pan-glial knockdown also reduced the number of lipid droplets in the brain.

The results differed in females. Pan-glial knockdown increased daytime sleep by about 84–90 minutes, while other targeted knockdowns had no significant effect. This sex-dependent pattern cautions against treating the fly findings as a single, uniform response. It also suggests that DPYD’s relationship with sleep may involve glial functions beyond myelin alone.

What the human data do—and do not—show

Human genetic analyses connected a sleep-duration-associated variant near DPYD with reduced DPYD expression in blood. The study also found regulatory chromatin contacts with the DPYD promoter in oligodendrocytes. These results provide a possible link to human brain biology, but they do not establish that the same mechanism operates in people.

Overall, the study shifts attention away from a simple shortage of beta-alanine or related neurotransmitters and toward glial biology, lipid handling, and myelination. Evidence across model organisms suggests that DPYD and myelin-related processes can influence sleep, while the differing results by species and sex underline how much remains to be understood. The findings offer a promising framework for further research, not a settled explanation of human sleep duration.

Created on 09 Nov. 2026

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Weekly letter Presented in "Brain and behaviour this week" of 9 November 2026. Brain and behaviour this week: What persists when the brain changes

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DPYD links glial lipids and myelination to sleep duration

The essentials

Question

Method

Findings

Limitations

Why it matters

Read further

Definitions

How a Metabolic Enzyme May Connect Brain Insulation and Sleep

Looking beyond the neurotransmitter hypothesis

Zebrafish link myelin changes with sleep

A drug test, with an important dose caveat

Fruit flies reveal a role for glia without wrapping myelin

What the human data do—and do not—show

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