title: Glymphatic clearance controls state-dependent changes in brain lactate concentration.
abstract: Brain lactate concentration is higher during wakefulness than in sleep. However, it is unknown why arousal is linked to an increase in brain lactate and why lactate declines within minutes of sleep. Here, we show that the glymphatic system is responsible for state-dependent changes in brain lactate concentration. Suppression of glymphatic function via acetazolamide treatment, cisterna magna puncture, aquaporin 4 deletion, or changes in body position reduced the decline in brain lactate normally observed when awake mice transition into sleep or anesthesia. Concurrently, the same manipulations diminished accumulation of lactate in cervical, but not in inguinal lymph nodes when mice were anesthetized. Thus, our study suggests that brain lactate is an excellent biomarker of the sleep-wake cycle and increases further during sleep deprivation, because brain lactate is inversely correlated with glymphatic-lymphatic clearance. This analysis provides fundamental new insight into brain energy metabolism by demonstrating that glucose that is not fully oxidized can be exported as lactate via glymphatic-lymphatic fluid transport.
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Iben
authors.initials: I
authors.lastname: Lundgaard
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.|2 Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, UK.
authors.forename: Minh Lon
authors.initials: ML
authors.lastname: Lu
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Ezra
authors.initials: E
authors.lastname: Yang
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Peng
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Humberto
authors.initials: H
authors.lastname: Mestre
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Hitomi
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.affiliation: 1 Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, NY, USA.|3 Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004569:Electroencephalography; D005260:Female; D019344:Lactic Acid / Q000378:metabolism*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D012890:Sleep / Q000502:physiology*; D014851:Wakefulness / Q000502:physiology*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D019344:Lactic Acid
keywords: Metabolism; astrocytes; cerebrospinal fluid; glymphatic system; lactate; stroke