Glymphatic clearance controls state-dependent changes in brain lactate concentration, 2017, Lundgaard et al.

[SNT Gatchaman]

Glymphatic clearance controls state-dependent changes in brain lactate concentration

Spoiler: Authors

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

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.

Web | DOI | PDF | Journal of Cerebral Blood Flow & Metabolism | Open Access

 

[SNT Gatchaman]

The energy metabolism of the central nervous system (CNS) relies almost exclusively on glucose. Classical studies have shown that the brain’s O2:glucose extraction ratio at rest is 5.5:1 and thus ~9% of glucose is unaccounted for in terms of oxidative metabolism. The fate of glucose that is not fully oxidized remains unclear.

CSF exits the CNS by multiple routes, including the cribriform plate positioned under the olfactory bulb, arachnoid granules, peri-venous spaces, and along cranial and spinal nerves. The outflowing CSF collects in the connective tissues surrounding the brain and is ultimately collected by meningeal and cervical lymph vessels and returned to the general circulation at the level of vena cava. Thus, the possibility exists that lactate generated within the CNS is transported out via the glymphatic-lymphatic clearance system.

the glymphatic system is controlled by the sleep–wake cycle and is primarily active during sleep and anesthesia, while suppressed during wakefulness. Several groups have shown that brain lactate is highest during wakefulness and declines during the transition into either natural sleep or anesthesia.

 

[SNT Gatchaman]

The analysis showed that four mechanistically different approaches to suppress glymphatic activity (pharmacology, genetic, mechanical or body position) all eliminated the rapid decline in brain lactate concentration when awake untreated mice fell asleep or were anesthetized. Conversely, lactate concentration in cervical lymph nodes exhibited the inverse pattern

Acetazolamide inhibits carbonic anhydrase and thereby CSF production in the choroid plexus, CM puncture eliminates the small pressure gradients that provide the hydraulic force that drives the convective exchange of CSF with ISF, whereas deletion of AQP4 water channels reduces intraparenchymal convective fluid fluxes.

(CA10 was pinged by DecodeME and has been previously identified in chronic pain, so speculatively there may be a link to circadian control of CSF production and glymphatic transit. I don't know if this isoform is known to be relevant in the choroid plexus though. Edit: just re looking at our notes and it's acatalytic so won't be relevant to CSF production.)

Overall, the analysis provides direct support for the notion that excess carbon in the form of lactate can exit CNS via the glymphatic-lymphatic transport system.

 

[SNT Gatchaman]

Lactate is transported across the plasma membrane by the monocarboxylate transporters (MCTs) by a driving force of protons and lactate concentration, and transport of lactate across cell membranes is fast; however, differences in intra- and extra-cellular concentrations have been reported.

Past studies have documented that brain lactate concentration follows neural activity and that lactate increases in response to somatosensory stimulation. A substantial body of literature further shows that cerebral lactate concentration is increased during wakefulness, perhaps partially mediated by break down of astrocytic glycogen as a result of noradrenergic stimulation, and declines when an awake mouse or a rat transition into natural sleep or anesthesia. The state-dependent changes in lactate closely follow EEG activity and lactate is considered the best metabolic biomarker of the sleep–wake cycle, together with norepinephrine and glycogen. However, no studies have, to our knowledge, addressed why lactate is so robustly regulated by the sleep–wake cycle. The data presented here suggest that the glymphatic system, which is activated by natural sleep or anesthesia, literally flushes excess lactate out of the brain resulting in transient increases in lactate in nearby cervical, but not distal inguinal, lymph nodes.

The relation between metabolism and sleep is complex, and may also involve the recently appreciated role of lactate as a signaling molecule. Recent work shows that lactate released from astrocytes increases locus coeruleus (LC) activity and thereby increases noradrenergic drive.

we used three mechanistically different manipulations to reduce glymphatic activity during the transition from awake to sleep and four manipulations during the transition from wakefulness to anesthesia. All sets of data presented in this report supported the notion that glymphatic clearance plays a key role in state-dependent changes in brain lactate concentration.

 

[SNT Gatchaman]

During physiological conditions, O2 and glucose are normally consumed in a ratio of 5.5:1, suggesting that 9% of glucose is consumed anaerobically in CNS. During a period of activation, the O2:glucose ratio declines even further leading to the concept that increased neural activity is, at least in part, supported by less efficient ATP production by glycolysis and that brain activity therefore is linked to generation of surplus lactate. However, it is unclear how the excess lactate leaves the brain.

The expression of MCTs in brain endothelial cells is high and lactate is able to permeate the blood–brain barrier, most likely by passing through MCTs on endothelial cells. Nonetheless, Madsen et al. found that in humans, the arterio-venous difference in lactate during activation is minimal and therefore it is unlikely that lactate is exported via the general circulation. A later study monitored arteriovenous lactate differences, as well as brain glucose, lactate, and glycogen after sensory stimulation. The authors concluded that excess glucose consumption during sensory stimulation is not accounted for by lactate efflux to blood or from accumulation within brain tissue. A follow-up analysis based on systemic administration of radiolabeled glucose showed that roughly half of lactate produced during cortical spreading depression is exported to the blood.

More recently, it was documented that lactate diffuses brain wide and it was hypothesized, based on the distribution of a tracer […] that the perivascular space may constitute an efflux pathway for lactate. Our observation provides direct support for this hypothesis.

Of note, although the primary source of lactate in the brain is glucose or glycogen, lactate can also be generated from other sources. For example, astrocytes engage in glutamate metabolism via the Krebs cycle that can result in lactate production. In addition, it is possible that some of the lactate is derived from intermediate metabolites of the Krebs cycle via pyruvate recycling and the alpha a-ketoglutarate glutamate-glutamine pathway in astrocytes, as shown in cultured cells. Independently of the source of lactate, our data point to glymphatic transport as an important path for lactate clearance.

 

[Turtle]

I only partially went through the paper.
Question : Could lactate also be used up as fuel in the brain when there is not enough glucose/pyruvate available, in ME/CFS?

 

[SNT Gatchaman]

They discussed potential implications —

An interesting consequence of state-dependent changes in brain lactate is that it will alter the lactate/pyruvate ratio, and thereby the NADH/NAD redox potential. The glymphatic-lymphatic washout of lactate during sleep, and the lack of lactate clearance during wakefulness is therefore expected to result in an increase of redox state during wakefulness relative to sleep.

A recent study reported that simply increasing extracellular lactate or NADH induced a pattern of immediate early gene expression that was reminiscent of those induced by long-term potentiation (LTP), although physiological levels of brain lactate might not reach 10–20 mM lactate as used in this study. Other studies have in the past noted similar changes in gene expression mediated by LTP versus wakefulness. Thus, it is possible that the suppression of glymphatic lactate clearance during wakefulness contributes to the characteristic expression of immediate early genes and thereby to memory consolidation.