Imaging the effect of the circadian light–dark cycle on the glymphatic system in awake rats

Cai, Xiao; Qiao, Junfei; Kulkarni, Praveen; Harding, Ian C.; Ebong, Eno E.; Ferris, Craig F.

doi:10.1073/pnas.1914017117

Cited by 57 publications

(56 citation statements)

References 73 publications

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“…There are multiple circadian rhythms that may interact to promote rhythmic glymphatic function. Recent work hypothesized increased glymphatic clearance during the sleep phase, driving rhythmic fluid flow in the brain 52 . Cortical neuronal activity as measured by EEG has strong circadian components in humans 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on timeof-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.

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Section: Discussionmentioning

confidence: 99%

Circadian control of brain glymphatic and lymphatic fluid flow

et al. 2020

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“…5,6 For dynamic contrast-enhancement (DCE) MRI, a 3D radiofrequency-spoiled gradient echo is commonly used in combination with the administration of T 1 -shortening paramagnetic contrast agent, such as chelated gadolinium. 7,8 To date, DCE-MRI studies of glymphatic solute transport have mainly been performed using the T 1 -weighted fast low-angle shot (FLASH) sequence in anesthetized or awake rats, [9][10][11][12] mice, 13 nonhuman primates, 14 and humans. 15,16 Although FLASH provides a reliable, quantitative map of glymphatic transport in animals and humans, it's been inadequate in the acquisition of a temporal resolution below 2.5 min, while also obtaining an isotropic voxel size below 0.001 mm 3 , [17][18][19][20][21][22][23] which may result in failure to capture salient physiological details.…”

Section: Introductionmentioning

confidence: 99%

Mapping of CSF transport using high spatiotemporal resolution dynamic contrast‐enhanced MRI in mice: Effect of anesthesia

Stanton

Persson

Gomolka

et al. 2021

Magnetic Resonance in Med

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Purpose Dynamic contrast‐enhanced MRI (DCE‐MRI) represents the only available approach for glymphatic cerebrospinal fluid (CSF) flow 3D mapping in the brain of living animals and humans. The purpose of this study was to develop a novel DCE‐MRI protocol for mapping of the glymphatic system transport with improved spatiotemporal resolution, and to validate the new protocol by comparing the transport in mice anesthetized with either isoflurane or ketamine/xylazine. Methods The contrast agent, gadobutrol, was administered into the CSF of the cisterna magna and its transport visualized continuously on a 9.4T preclinical scanner using 3D fast‐imaging with a steady‐state free‐precession sequence (3D‐FISP), which has a spatial resolution of 0.001 mm3 and a temporal resolution of 30 s. The MR signals were measured dynamically for 60 min in multiple volumes of interest covering the entire CSF space and brain parenchyma. Results The results confirm earlier findings that glymphatic CSF influx is higher under ketamine/xylazine than with isoflurane anesthesia. This was extended to account for new details about the distinct CSF efflux pathways under the two anesthetic regimens. Dynamic contrast MR shows that CSF clearance occurs mainly along the vagus nerve near the jugular vein under isoflurane and via the olfactory bulb under ketamine/xylazine. Conclusion The improved spatial and temporal sampling rates afforded by 3D‐FISP shed new light on the pharmacological modulation of CSF efflux paths. The present observations may have the potential to set a new standard for future experimental DCE‐MRI studies of the glymphatic system.

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“…gadopentetic acid MW 547 Da, gadoteric acid (Gd-DOTA), MW 559 Da) or large MW (e.g. GadoSpin P, MW 200 kDa) paramagnetic tracers into CSF via the cisterna magna (CM) 2 , 3 , cerebral lateral ventricles 11 or lumbar intrathecal route 9 . Transport of the paramagnetic contrast molecule (a.k.a.…”

Section: Introductionmentioning

confidence: 99%

In vivo T1 mapping for quantifying glymphatic system transport and cervical lymph node drainage

Xue

Liu

Koundal

et al. 2020

Sci Rep

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Dynamic contrast-enhanced magnetic resonance imaging (MRI) for tracking glymphatic system transport with paramagnetic contrast such as gadoteric acid (Gd-DOTA) administration into cerebrospinal fluid (CSF) requires pre-contrast data for proper quantification. Here we introduce an alternative approach for glymphatic system quantification in the mouse brain via T1 mapping which also captures drainage of Gd-DOTA to the cervical lymph nodes. The Gd-DOTA injection into CSF was performed on the bench after which the mice underwent T1 mapping using a 3D spoiled gradient echo sequence on a 9.4 T MRI. In Ketamine/Xylazine (KX) anesthetized mice, glymphatic transport and drainage of Gd-DOTA to submandibular and deep cervical lymph nodes was demonstrated as 25-50% T1 reductions in comparison to control mice receiving CSF saline. To further validate the T1 mapping approach we also verified increased glymphatic transport of Gd-DOTA transport in mice anesthetized with KX in comparison with ISO. The novel T1 mapping method allows for quantification of glymphatic transport as well as drainage to the deep and superficial cervical lymph nodes. The ability to measure glymphatic transport and cervical lymph node drainage in the same animal longitudinally is advantageous and time efficient and the coupling between the two systems can be studied and translated to human studies. The glymphatic system (GS) in rodents was first described by Iliff and Nedergaard in 2012 as a brain-wide perivascular transit passageway for cerebrospinal fluid (CSF) facilitating waste clearance in an aquaporin 4 (AQP4) water channel dependent manner 1. Visualization and quantification of GS transport in whole mouse brain was performed ex vivo by first allowing tracers administered into CSF to circulate for a prefixed time interval (30 min-2 h) after which the rodents were euthanized and their brains examined for tracer uptake using fluorescence microscopy 1. In 2013, we introduced dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as an in vivo method for tracking GS transport in the whole rodent brain 2 and later refined gadolinium based contrast administration into CSF and GS quantification 3,4. The DCE-MRI approach for brain-wide GS transport assessment has been widely used and adapted to different species including mice 5-7 , non-human primates 8 , and humans 9,10. Recently, the DCE-MRI approach for GS transport assessment was extended to studies in awake rats. The DCE-MRI GS method involves administering small molecular weight (MW) (e.g. gadopentetic acid MW 547 Da, gadoteric acid (Gd-DOTA), MW 559 Da) or large MW (e.g. GadoSpin P, MW 200 kDa) paramagnetic tracers into CSF via the cisterna magna (CM) 2,3 , cerebral lateral ventricles 11 or lumbar intrathecal route 9. Transport of the paramagnetic contrast molecule (a.k.a. 'solute') from CSF into brain parenchyma is tracked dynamically by a series of 3D T1-weighted MRI scans 1. The time series of 3D T1-weighted spoiled gradient echo (SPGR) brain images acquired before, during and after solute...

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Imaging the effect of the circadian light–dark cycle on the glymphatic system in awake rats

Cited by 57 publications

References 73 publications

Circadian control of brain glymphatic and lymphatic fluid flow

Circadian control of brain glymphatic and lymphatic fluid flow

Mapping of CSF transport using high spatiotemporal resolution dynamic contrast‐enhanced MRI in mice: Effect of anesthesia

In vivo T1 mapping for quantifying glymphatic system transport and cervical lymph node drainage

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