title: Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration.
abstract: Zebrafish maintain a greater capacity than mammals for central nervous system repair after injury. Understanding differences in regenerative responses between different vertebrate species may shed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has been used to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected into the adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblast migration to injury. However, most new neurons fail to survive and lesion repair is minimal. We used quinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also used conditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integration of neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extent vehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhanced neurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injection than after vehicle injection. Fate mapping of her4-expressing radial glia showed injury-induced expansion of radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks and formed long-distance projections that crossed the anterior commissure and synapsed in the contralateral hemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adult neural stem cells to produce robust regeneration with long-distance integration of new neurons. This model should prove useful for elucidating reparative mechanisms that can be applied to restorative therapies for mammalian brain injury.
authors.affiliation: Departments of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Kaia
authors.initials: K
authors.lastname: Skaggs
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
authors.forename: Jack M
authors.initials: JM
authors.lastname: Parent
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002552:Cerebral Ventricles / Q000473:pathology; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism; D000067778:ELAV-Like Protein 3; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011801:Quinic Acid / Q000633:toxicity; D013997:Time Factors; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; D000067778:ELAV-Like Protein 3; D005904:Glial Fibrillary Acidic Protein; D014404:Tubulin; D029961:Zebrafish Proteins; C088635:elavl3 protein, zebrafish; D011801:Quinic Acid; D000185:Actinin
keywords: brain regeneration; neural repair; neural stem cells; radial glia