Article

Cortical spreading depression causes and coincides with tissue hypoxia

  • Nature Neuroscience volume 10, pages 754762 (2007)
  • doi:10.1038/nn1902
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Abstract

Cortical spreading depression (CSD) is a self-propagating wave of cellular depolarization that has been implicated in migraine and in progressive neuronal injury after stroke and head trauma. Using two-photon microscopic NADH imaging and oxygen sensor microelectrodes in live mouse cortex, we find that CSD is linked to severe hypoxia and marked neuronal swelling that can last up to several minutes. Changes in dendritic structures and loss of spines during CSD are comparable to those during anoxic depolarization. Increasing O2 availability shortens the duration of CSD and improves local redox state. Our results indicate that tissue hypoxia associated with CSD is caused by a transient increase in O2 demand exceeding vascular O2 supply.

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Acknowledgements

This work was supported in part by grants NS30007 and NS38073 from the US National Institutes of Health and the National Institute of Neurological Disorders and Stroke (to M.N.), the New York State Spinal Cord Injury Program, The Dana Foundation and the Philip-Morris Organization.

Author information

Affiliations

  1. Center for Aging and Developmental Biology, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, New York 14642, USA.

    • Takahiro Takano
    • , Guo-Feng Tian
    • , Weiguo Peng
    • , Nanhong Lou
    • , Ditte Lovatt
    • , Karl A Kasischke
    •  & Maiken Nedergaard
  2. Discovery, Novo Nordisk A/S, DK-2760, Maaloev, Denmark.

    • Anker J Hansen

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Takahiro Takano.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Local cerebral blood flow change during CSD in mice anesthetized with urethane + α-chloralose, 2% isoflurane, or 50 mg kg−1 sodium pentobarbital.

Videos

  1. 1.

    Supplementary Video 1

    Imaging of NADH fluorescence change during CSD in mouse cortex at a depth of 50 μm (same experiments as shown in Fig. 1a in pseudocolor). Time-course images were captured with 3-s interval and displayed as 3.5 frames per second.

  2. 2.

    Supplementary Video 2

    A small penetrating artery imaged 45 μm below the cortical surface (same as shown in Fig. 3a). The artery first dilated during the passage of a CSD wave followed by a prolonged constriction. The artery was visualized by systemic administration of FITC-dextran. Images were captured at 2-s interval and displayed as 12 frame per second.

  3. 3.

    Supplementary Video 3

    Simultaneous imaging of NADH fluorescence and blood vessels. NADH signal is in grayscale and blood vessels are shown in green. Both arteries and veins are visible in the field. Images were taken at 50 μm from the surface, and captured at 3-s interval and displayed as 9 frame per second.

  4. 4.

    Supplementary Video 4

    Imaging of a YFP-expressing neuron cell body at 125 μm deep during a wave of CSD (same as shown in Fig. 5d). The cell body swelled during CSD. Images were captured at 3-s interval and displayed as 12 frame per second.

  5. 5.

    Supplementary Video 5

    Imaging of NADH fluorescence change during CSD in mouse anesthetized with 50 mg kg−1 pentobarbital. Different anesthesia did not alter the appearance of NADH pattern. Time-course images were captured with 5-s interval and displayed as 3.5 frames per second.