ORIGINAL RESEARCH article

Front. Neuroanat.

Volume 19 - 2025 | doi: 10.3389/fnana.2025.1607396

This article is part of the Research TopicNew Insights in Marine Mammal NeurosciencesView all articles

Potential for flexible lactate shuttling between astrocytes and neurons to mitigate against diving-induced hypoxia

Provisionally accepted
Chiara  CicconeChiara Ciccone1*Sari  Elena DöttererSari Elena Dötterer1Sigrid  Vold JensenSigrid Vold Jensen1Cornelia  GeßnerCornelia Geßner2Alexander  C WestAlexander C West1Shona  Hiedi WoodShona Hiedi Wood1David  G HazleriggDavid G Hazlerigg1Lars  P FolkowLars P Folkow1*
  • 1UiT The Arctic University of Norway, Tromsø, Norway
  • 2Thünen Institute of Forest Genetics, Großhansdorf, Germany

The final, formatted version of the article will be published soon.

For most non-diving mammals, lack of O2 (hypoxia) has detrimental effects on brain function. Seals, however, display a series of systemic, cellular, and molecular adaptations that enable them to tolerate repeated episodes of severe hypoxia. One as yet unresolved question is whether seal neurons in part employ anaerobic metabolism during diving: the "reverse astrocyte-neuron lactate shuttle" (rANLS) hypothesis (Mitz et al, 2009) postulates that seal neurons, by shuttling lactate to the astrocytes, may be relieved 1) from the lactate burden and 2) from subsequent ROS-production as lactate is oxidised by astrocytes upon re-oxygenation after the dive. Here, we have investigated this possibility, through histological and functional comparisons of the metabolic characteristics of neocortical neurons and astrocytes from the deep-diving hooded seal (Cystophora cristata), using mice (Mus musculus) as a non-diving control. We found that seal astrocytes have higher mitochondrial density and larger mitochondria than seal neurons, and that seal neurons have an atypical and significantly higher representation of the monocarboxylate lactate exporter MCT4 compared to mouse neurons. Also, measurements of mitochondrial O2 consumption suggest that the aerobic capacity of primary seal astrocytes is at least equal to that of primary seal neurons. Transcriptomics data from seals vs mice suggest that specific adaptations to the electron transport system in seals may contribute to enhance hypoxia tolerance. These observations are consistent with the rANLS hypothesis.

Keywords: Diving mammals, hooded seal, mitochondrial respiration, hypoxia, Neuron, astrocyte, lactate shuttling

Received: 07 Apr 2025; Accepted: 13 May 2025.

Copyright: © 2025 Ciccone, Dötterer, Vold Jensen, Geßner, West, Wood, Hazlerigg and Folkow. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Chiara Ciccone, UiT The Arctic University of Norway, Tromsø, Norway
Lars P Folkow, UiT The Arctic University of Norway, Tromsø, Norway

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