Glymphatic clearance controls state-dependent changes in brain lactate concentration

Iben Lundgaard; Minh Lon Lu; Ezra Yang; Weiguo Peng; Humberto Mestre; Emi Hitomi; Rashid Deane; Maiken Nedergaard

doi:10.1177/0271678x16661202

Glymphatic clearance controls state-dependent changes in brain lactate concentration

Iben Lundgaard, Minh Lon Lu, Ezra Yang, Weiguo Peng, Humberto Mestre, Emi Hitomi, Rashid Deane, Maiken Nedergaard

92 Citations (Scopus)

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.

Original language	English
Journal	Journal of Cerebral Blood Flow and Metabolism
Volume	37
Issue number	6
Pages (from-to)	2112-2124
Number of pages	13
ISSN	0271-678X
DOIs	https://doi.org/10.1177/0271678x16661202
Publication status	Published - 1 Jun 2017

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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.",

author = "Iben Lundgaard and Lu, {Minh Lon} and Ezra Yang and Weiguo Peng and Humberto Mestre and Emi Hitomi and Rashid Deane and Maiken Nedergaard",

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T1 - Glymphatic clearance controls state-dependent changes in brain lactate concentration

AU - Lundgaard, Iben

AU - Lu, Minh Lon

AU - Yang, Ezra

AU - Peng, Weiguo

AU - Mestre, Humberto

AU - Hitomi, Emi

AU - Deane, Rashid

AU - Nedergaard, Maiken

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

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JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

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ER -

Glymphatic clearance controls state-dependent changes in brain lactate concentration

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