title: Repetitive Mild Traumatic Brain Injury in the Developing Brain: Effects on Long-Term Functional Outcome and Neuropathology.
abstract: Although accumulating evidence suggests that repetitive mild TBI (rmTBI) may cause long-term cognitive dysfunction in adults, whether rmTBI causes similar deficits in the immature brain is unknown. Here we used an experimental model of rmTBI in the immature brain to answer this question. Post-natal day (PND) 18 rats were subjected to either one, two, or three mild TBIs (mTBI) or an equivalent number of sham insults 24 h apart. After one or two mTBIs or sham insults, histology was evaluated at 7 days. After three mTBIs or sham insults, motor (d1-5), cognitive (d11-92), and histological (d21-92) outcome was evaluated. At 7 days, silver degeneration staining revealed axonal argyrophilia in the external capsule and corpus callosum after a single mTBI, with a second impact increasing axonal injury. Iba-1 immunohistochemistry showed amoeboid shaped microglia within the amygdalae bilaterally after mTBI. After three mTBI, there were no differences in beam balance, Morris water maze, and elevated plus maze performance versus sham. The rmTBI rats, however, showed impairment in novel object recognition and fear conditioning. Axonal silver staining was observed only in the external capsule on d21. Iba-1 staining did not reveal activated microglia on d21 or d92. In conclusion, mTBI results in traumatic axonal injury and microglial activation in the immature brain with repeated impact exacerbating axonal injury. The rmTBI in the immature brain leads to long-term associative learning deficit in adulthood. Defining the mechanisms damage from rmTBI in the developing brain could be vital for identification of therapies for children.
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Emin
authors.initials: E
authors.lastname: Fidan
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lewis
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Department of Physical Medicine and Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kline
authors.affiliation: 4 Consultants in Veterinary Pathology, Inc. , Murrysville, Pennsylvania.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Garman
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Henry
authors.initials: H
authors.lastname: Alexander
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Department of Physical Medicine and Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Cheng
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Department of Physical Medicine and Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Corina O
authors.initials: CO
authors.lastname: Bondi
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Children's Hospital of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Children's Hospital of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Cameron
authors.initials: C
authors.lastname: Dezfulian
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Children's Hospital of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: 3 Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: 1 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|3 Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Children's Hospital of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D001924:Brain Concussion / Q000150:complications / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function
keywords: axonal injury; development; head injury; microglia