title: Neurogenesis upregulation on the healthy hemisphere after stroke enhances compensation for age-dependent decrease of basal neurogenesis.
abstract: Stroke is a leading cause of death and disability worldwide with no treatment for the chronic phase available. Interestingly, an endogenous repair program comprising inflammation and neurogenesis is known to modulate stroke outcome. Several studies have shown that neurogenesis decreases with age but the therapeutic importance of endogenous neurogenesis for recovery from cerebral diseases has been indicated as its ablation leads to stroke aggravation and worsened outcome. A detailed characterization of the neurogenic response after stroke related to ageing would help to develop novel and targeted therapies. In an innovative approach, we used the DCX-Luc mouse, a transgenic model expressing luciferase in doublecortin-positive neuroblasts, to monitor the neurogenic response following middle cerebral artery occlusion over three weeks in three age groups (2, 6, 12months) by optical imaging while the stroke lesion was monitored by quantitative MRI. The individual longitudinal and noninvasive time profiles provided exclusive insight into age-dependent decrease in basal neurogenesis and neurogenic upregulation in response to stroke which are not accessible by conventional BrdU-based measures of cell proliferation. For cortico-striatal strokes the maximal upregulation occurred at 4days post stroke followed by a continuous decrease to basal levels by three weeks post stroke. Older animals effectively compensated for reduced basal neurogenesis by an enhanced sensitivity to the cerebral lesion, resulting in upregulated neurogenesis levels approaching those measured in young mice. In middle aged and older mice, but not in the youngest ones, additional upregulation of neurogenesis was observed in the contralateral healthy hemisphere. This further substantiates the increased propensity of older brains to respond to lesion situation. Our results clearly support the therapeutic relevance of endogenous neurogenesis for stroke recovery and particularly in older brains.
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany; Percuros B.V., Drienerlolaan 5-Zuidhorst, 7522 NB Enschede, The Netherlands.
authors.forename: Joanna
authors.initials: J
authors.lastname: Adamczak
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Aswendt
authors.affiliation: Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Kreutzer
authors.affiliation: Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Rotheneichner
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Adrien
authors.initials: A
authors.lastname: Riou
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Selt
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyrau
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Ulla
authors.initials: U
authors.lastname: Uhlenküken
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Diedenhofen
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Nelles
authors.affiliation: Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Austria.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
authors.affiliation: Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Austria.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, 50931 Cologne, Germany; Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; Percuros B.V., Drienerlolaan 5-Zuidhorst, 7522 NB Enschede, The Netherlands. Electronic address: mathias@sf.mpg.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hoehn
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D000089662:Doublecortin Protein; D007839:Functional Laterality; D007150:Immunohistochemistry; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D061848:Optical Imaging; D020521:Stroke / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*
keywords: Age dependence of neurogenesis after stroke; Bioluminescence imaging; Doublecortin; Magnetic resonance imaging; Neurogenesis; Stroke