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Region Hovedstaden - en del af Københavns Universitetshospital
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Hippocampal neurons respond to brain activity with functional hypoxia

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  • Umer Javed Butt
  • Agnes A Steixner-Kumar
  • Constanze Depp
  • Ting Sun
  • Imam Hassouna
  • Liane Wüstefeld
  • Sahab Arinrad
  • Matthias R Zillmann
  • Nadine Schopf
  • Laura Fernandez Garcia-Agudo
  • Leonie Mohrmann
  • Ulli Bode
  • Anja Ronnenberg
  • Martin Hindermann
  • Sandra Goebbels
  • Stefan Bonn
  • Dörthe M Katschinski
  • Kamilla W Miskowiak
  • Klaus-Armin Nave
  • Hannelore Ehrenreich
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Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allows us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control. We report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells.

OriginalsprogEngelsk
TidsskriftMolecular Psychiatry
Vol/bind26
Udgave nummer6
Sider (fra-til)1790-1807
Antal sider18
ISSN1359-4184
DOI
StatusUdgivet - jun. 2021

ID: 65850514