CoChat
Sign Up
Cited by 149Cerebrospinal fluid and hydrocephalusSleep and Wakefulness ResearchTraumatic Brain Injury and Neurovascular Disturbances

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport

Open access
Bojarskaite, Laura, Vallet, Alexandra, Bjørnstad, Daniel M., Gullestad Binder, Kristin M., Cunen, Céline, Heuser, Kjell, Kuchta, Miroslav, Mardal, Kent-Andre, Enger, Rune·2023·Nature Communications
DOI 10.1038/s41467-023-36643-5PMC PMC9941497
Open this paper in CoChat — free accountOpen PDF

Abstract

Perivascular spaces are important highways for fluid and solute transport in the brain enabling efficient waste clearance during sleep. However, the underlying mechanisms augmenting perivascular flow in sleep are unknown. Using two-photon imaging of naturally sleeping male mice we demonstrate sleep cycle-dependent vascular dynamics of pial arteries and penetrating arterioles: slow, large-amplitude oscillations in NREM sleep, a vasodilation in REM sleep, and a vasoconstriction upon awakening at the end of a sleep cycle and microarousals in NREM and intermediate sleep. These vascular dynamics are mirrored by changes in the size of the perivascular spaces of the penetrating arterioles: slow fluctuations in NREM sleep, reduction in REM sleep and an enlargement upon awakening after REM sleep and during microarousals in NREM and intermediate sleep. By biomechanical modeling we demonstrate that these sleep cycle-dependent perivascular dynamics likely enhance fluid flow and solute transport in perivascular spaces to levels comparable to cardiac pulsation-driven oscillations.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-023-36643-5

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 NREM, IS and REM sleep states are associated with specific pial artery diameter changes. a Experimental setup. GLT1-eGFP transgenic mice were fitted with a cranial window exposing the somatosensory cortex, ECoG electrodes and EMG electrodes. The vasculature was outlined with Texas Red-labeled dextran. b (Left) Representative image of a pial artery with Texas-Red labeled dextran in the lumen. Imaging was performed by placing cross sectional x-tline scans. Linescan length 60 μm. (Right) Vessel lumen diameter (Ø) was determined along a line across the vessel. Experiment was repeated on 44 pial arteries from 5 mice. c Representative traces of a pial artery line scan and change in vessel lumen diameter (Ø) during a sleep cycle. d Amplitude of very low frequency (VLF 0.1–0.3 Hz), e amplitude of low frequency (LF 0.3–1 Hz) oscillations and f median diameter of pial artery lumen throughout a sleep cycle. Every gray line (dashed or full) represents an individual vessel, dashed lines are used when an observation is missing in a certain state for a given vessel (for example dashed line between WBS and IS means that we do not have an observation for that particular vessel in NREM state), bold lines and shaded area are the estimates and 95% CI from linear mixed effects models (two sided) d: n = 570, in 44 vessels, and 5 mice, e, f: n = 579 episodes, 44 vessels, 5 mice. *P < 0.05, **P < 0.01, ***P < 0.001, Tukey adjustment for multiple comparisons. See supplementary information for exact p-values, and degrees of freedom for the statistical tests. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; ECoG electrocorticography; EMG electromyography. Source data are provided as a Source Data file.
Fig. 1 NREM, IS and REM sleep states are associated with specific pial artery diameter changes. a Experimental setup. GLT1-eGFP transgenic mice were fitted with a cranial window exposing the somatosensory cortex, ECoG electrodes and EMG electrodes. The vasculature was outlined with Texas Red-labeled dextran. b (Left) Representative image of a pial artery with Texas-Red labeled dextran in the lumen. Imaging was performed by placing cross sectional x-tline scans. Linescan length 60 μm. (Right) Vessel lumen diameter (Ø) was determined along a line across the vessel. Experiment was repeated on 44 pial arteries from 5 mice. c Representative traces of a pial artery line scan and change in vessel lumen diameter (Ø) during a sleep cycle. d Amplitude of very low frequency (VLF 0.1–0.3 Hz), e amplitude of low frequency (LF 0.3–1 Hz) oscillations and f median diameter of pial artery lumen throughout a sleep cycle. Every gray line (dashed or full) represents an individual vessel, dashed lines are used when an observation is missing in a certain state for a given vessel (for example dashed line between WBS and IS means that we do not have an observation for that particular vessel in NREM state), bold lines and shaded area are the estimates and 95% CI from linear mixed effects models (two sided) d: n = 570, in 44 vessels, and 5 mice, e, f: n = 579 episodes, 44 vessels, 5 mice. *P < 0.05, **P < 0.01, ***P < 0.001, Tukey adjustment for multiple comparisons. See supplementary information for exact p-values, and degrees of freedom for the statistical tests. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; ECoG electrocorticography; EMG electromyography. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 2 NREM, IS and REM sleep states are associated with specific penetrating arteriole diameter changes that are mirrored in the size of the PVS. a Experimental setup. GLT1-eGFP transgenic mice were fitted with a cranial window exposing the somatosensory cortex, ECoG electrodes and EMG electrodes. The vasculature was outlined with Texas Red-labeled dextran. b (Left) Representative image of a penetrating arteriole with GLT1-eGFP fluorescence in astrocytic endfeet and Texas-Red labeled dextran in the vessel lumen. Imaging was performed by placing cross sectional x-t line scans. (Right) Vessel lumen diameter (Ø) and astrocyte endfoot tube diameter (Ø) was determined along a line across the vessel. Total width of the PVS was assessed as the difference between the vessel lumen diameter and the endfoot tube diameter. c Representative traces of a penetrating arteriole line scan, change in endfoot tube diameter (Ø), vessel lumen diameter (Ø) and perivascular space diameter during a sleep cycle. d Amplitude of very low frequency (VLF 0.1–0.3 Hz) oscillations and e median diameter of lumen and total width of PVS throughout a sleep cycle. Every gray line (dashed or full) represents an individual vessel, dashed lines are used when an observation is missing in a certain state for a given vessel (for example dashed line between WBS and IS means that we do not have an observation for that particular vessel in NREM state), bold lines and shaded area are the estimates and 95% CI from linear mixed effects models (two-sided), n = 310 episodes, 25 penetrating arterioles, 4 mice. *P < 0.05, **P < 0.01, ***P < 0.001, Tukey adjustment for multiple comparisons. See supplementary information for exact p-values, and degrees of freedom for the statistical tests. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; ECoG electrocorticography; EMG electromyography; PVS perivascular space. Source data are provided as a Source Data file.
Fig. 2 NREM, IS and REM sleep states are associated with specific penetrating arteriole diameter changes that are mirrored in the size of the PVS. a Experimental setup. GLT1-eGFP transgenic mice were fitted with a cranial window exposing the somatosensory cortex, ECoG electrodes and EMG electrodes. The vasculature was outlined with Texas Red-labeled dextran. b (Left) Representative image of a penetrating arteriole with GLT1-eGFP fluorescence in astrocytic endfeet and Texas-Red labeled dextran in the vessel lumen. Imaging was performed by placing cross sectional x-t line scans. (Right) Vessel lumen diameter (Ø) and astrocyte endfoot tube diameter (Ø) was determined along a line across the vessel. Total width of the PVS was assessed as the difference between the vessel lumen diameter and the endfoot tube diameter. c Representative traces of a penetrating arteriole line scan, change in endfoot tube diameter (Ø), vessel lumen diameter (Ø) and perivascular space diameter during a sleep cycle. d Amplitude of very low frequency (VLF 0.1–0.3 Hz) oscillations and e median diameter of lumen and total width of PVS throughout a sleep cycle. Every gray line (dashed or full) represents an individual vessel, dashed lines are used when an observation is missing in a certain state for a given vessel (for example dashed line between WBS and IS means that we do not have an observation for that particular vessel in NREM state), bold lines and shaded area are the estimates and 95% CI from linear mixed effects models (two-sided), n = 310 episodes, 25 penetrating arterioles, 4 mice. *P < 0.05, **P < 0.01, ***P < 0.001, Tukey adjustment for multiple comparisons. See supplementary information for exact p-values, and degrees of freedom for the statistical tests. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; ECoG electrocorticography; EMG electromyography; PVS perivascular space. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 3 NREM/IS slow vasomotion increases predicted PVS fluid velocity. a Illustration showing the model of the PVS (top), and representative vasomotion-driven CSF flow simulation (bottom). b–d Peak fluid velocity in penetrating arteriole PVS generated by VLF and LF oscillations during a sleep cycle as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The black circle represents the median, whereas the shading represents the distribution of all modeled vessels (n = 16 vessels, 4 mice). The value of the median is also given in the lower right corner for each box. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.
Fig. 3 NREM/IS slow vasomotion increases predicted PVS fluid velocity. a Illustration showing the model of the PVS (top), and representative vasomotion-driven CSF flow simulation (bottom). b–d Peak fluid velocity in penetrating arteriole PVS generated by VLF and LF oscillations during a sleep cycle as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The black circle represents the median, whereas the shading represents the distribution of all modeled vessels (n = 16 vessels, 4 mice). The value of the median is also given in the lower right corner for each box. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 NREM/IS slow vasomotion enhances predicted dispersion in PVS. a Modeling of the slow vasomotion driven tracer spread in the PVS. b–d Enhancement factor for 2000 kDa tracer spread in penetrating arteriole PVS generated by VLF and LF oscillations during a sleep cycle as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The enhancement factor is the relative increase in solute movement induced by VLF and LF oscillatory flow, compared to pure diffusion. The black circle represents the median, whereas the shading represents the distribution of all modeled vessels (n = 16 vessels, 4 mice). The value of the median is also given in the lower right corner for each box. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.
Fig. 4 NREM/IS slow vasomotion enhances predicted dispersion in PVS. a Modeling of the slow vasomotion driven tracer spread in the PVS. b–d Enhancement factor for 2000 kDa tracer spread in penetrating arteriole PVS generated by VLF and LF oscillations during a sleep cycle as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The enhancement factor is the relative increase in solute movement induced by VLF and LF oscillatory flow, compared to pure diffusion. The black circle represents the median, whereas the shading represents the distribution of all modeled vessels (n = 16 vessels, 4 mice). The value of the median is also given in the lower right corner for each box. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 NREM slow vasomotion enhances predicted solute influx. a–c Influx of 70 and 2000 kDa solutes from the entrance of the penetrating arteriole PVS at the brain surface driven by dispersion during quiet wakefulness, dispersion during NREM sleep or pure diffusion as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The model used the measurements of PVS size for LF and VLF oscillations and assumed a peak CSF velocity of 50 μm/s for the cardiac oscillations. Thin lines represent observations from individual penetrating arterioles (n = 16 vessels, 4 mice). Bolded lines with the shading are median values of the time-smoothed thin lines over several oscillations with 10th and 90th percentiles. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.
Fig. 5 NREM slow vasomotion enhances predicted solute influx. a–c Influx of 70 and 2000 kDa solutes from the entrance of the penetrating arteriole PVS at the brain surface driven by dispersion during quiet wakefulness, dispersion during NREM sleep or pure diffusion as predicted by biomechanical modeling using three scenarios where we added a fixed volume to the PVS obstructing flow corresponding to 0, 25, and 50% of our measured PVS in quiet wakefulness. The model used the measurements of PVS size for LF and VLF oscillations and assumed a peak CSF velocity of 50 μm/s for the cardiac oscillations. Thin lines represent observations from individual penetrating arterioles (n = 16 vessels, 4 mice). Bolded lines with the shading are median values of the time-smoothed thin lines over several oscillations with 10th and 90th percentiles. WBS wake before sleep; NREM non-rapid eye movement sleep; IS intermediate state sleep; REM rapid eye movement sleep; WAS wake after sleep; PVS perivascular space; VLF very low frequency; LF low frequency. Source data are provided as a Source Data file.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 42 references

Research works printed but not linked: 1

  1. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012). · DOI · Paper page

Cited by

Sorted by citations

See all 149

Related

Metadata

Authors
Bojarskaite, L., Vallet, A., Bjørnstad, D. M., Gullestad Binder, K. M., Cunen, C., Heuser, K., Kuchta, M., Mardal, K.-A., & Enger, R.
Affiliations
  • Oslo University Hospital (NO)
  • University of Oslo (NO)
  • Norwegian Computing Center (NO)
  • Simula Research Laboratory (NO)
Corresponding author
  • Bojarskaite, Laura
  • Enger, Rune
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-02-20
Volume
14
Issue
1
Pages
953-953
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36643-5
PMC
PMC9941497
OpenAlex
W4321367779
Cited by
149
References
42
Citations by year
2026: 30 · 2025: 59 · 2024: 36 · 2023: 24
FWCI
18.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
  • Norges Forskningsråd (249988, 271555/F20, 302326, 300305, 301013, 303362)
  • Ministry of Health and Care Services | Helse Sør-Øst RHF (2016070)
  • Olav Thon Foundation, Letten Foundation, University of Oslo, UNINETT Sigma2 AS, grant NN9279K.
Topics
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
sleep cycles, vascular dynamics, perivascular spaces, cerebrospinal fluid flow, solute transport, NREM sleep, REM sleep, microarousals, pial arteries, penetrating arterioles, vasodilation, vasoconstriction, brain waste clearance, biomechanical modeling, two-photon imaging
MeSH terms
Sleep, Slow-Wave, Animals, Arteries, Male, Sleep, Sleep, REM, Vasodilation, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review