Scientific Online Resource System

Biomedical Reviews

Modeling traumatic brain injury: mechanisms of early neuronal and axon degeneration in the infant rodent brain

Krikor Dikranian


Traumatic brain injury (TBI) remains a major health challenge and affects the young disproportionately. Accidental and non-accidental TBI in children is a major contributor to morbidity, disability, and death. TBI in this critical period leads to profound neuronal and axonal degeneration followed by cognitive, psychological and memory impairment, altered processing speed, impaired executive functions, emotional liability as well as word finding difficulties. Cognitive and behavioral changes may remain unrecognized for periods even after sustaining mild injury. Although accidental and non-accidental inflicted injury (blunt force or violent shaking-inflicting brain injury or “Shaken baby” syndrome) posits a major clinical and sociological problem, mechanisms of tissue degeneration might be largely similar. The scope of this review will be the experimental research related to modeling blunt (concussive) head trauma specifically to the infant rodent brain resulting in acute (early) and protracted (late) degenerative changes such as axonal degeneration and apoptotic neuronal cell death. Similarly, discussion will be limited to therapeutic windows and potentials for ameliorating the development of early brain injury.


traumatic brain injury, excitotoxic cell death, apoptotic cell death, axonal injury

Full Text


Adelson PD, Robichaud P, Hamilton RL, Kochanek PM. A model of diffuse traumatic brain injury in the immature rat. J Neurosurg 1996; 85:877-884. DOI: 10.3171/jns.1996.85.5.0877.

Adelson PD, Dixon CE, Robichaud P, Kochanek PM. Motor and cognitive deficits following diffuse traumatic brain injury in the immature rat. J Neurotrauma 1997; 14:99-108. DOI: 10.1089/neu.1997.14.99.

Adelson P, Kochanek P. Head injury in children. J Child Neurol 1998; 13:2-15. DOI: 10.1177/088307389801300102.

Adelson D, Wisniewski S, Beca J, Brown D, Bell M, Muizelaar P, Okada P, Beers S, Balasubramani G, Hirtz D. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet 2013; 12:546-552. DOI: 10.1016/S1474-4422(13)70077-2.

Bailey CD, Johnson GV. Developmental regulation of tissue transglutaminase in the mouse forebrain. J Neurochem 2004; 91(6):1369-79. DOI: 10.1111/j.1471-4159.2004.02825.x

Bayly P, Dikranian K, Black E, Young C, Qin Y, Labruyere J, Olney JW. Spatiotemporal evolution of apoptotic neurodegeneration following traumatic injury to the developing rat brain. Brain Res 2006; 1107(1): 70-81. DOI: 10.1016/j.brainres.2006.05.102

Bayly PV, Black EE, Pedersen RC, Leister EP, Genin GM. In vivo imaging of deformation and strain in an animal model of traumatic brain injury. J Biomechem 2006; 39(6):1086-95. DOI: 10.1016/j.jbiomech.2005.02.014

Benesova, O. Brain maldevelopment and delayed neuro-behavioral deviations, induced by perinatal insults, and possibilities of their prevention. J Hyg Epidemiol Microbiol Immunol. 1983; 27(4):373-380. PMID: 6663069.

Bennett R, Mac Donald Ch., Brody D. Diffusion Tensor Imaging Detects Axonal Injury in a Mouse Model of Repetitive Closed-Skull Traumatic Brain Injury. Neurosci Lett 2012; 513(2): 160–165. DOI: 10.1016/j. neulet.2012.02.024.

Bernal J, Nunez J. Thyroid hormone action, and brain development. Trends Endocrinol Metab 2000; 133:390-398. DOI: 10.1530/eje.0.1330390

Bittigau P, Pohl D, Sifringer M, Shimizu H, Ikeda M, Stadthaus D, et al. Modeling pediatric head trauma: mechanisms of degeneration and potential strategies for neuroprotection. Restor Neurol Neurosci 1998; 13:11-23. PMID: 12671284.

Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, et al. Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 1999; 45:724-735. DOI: 10.1002/1531-8249(199906)45:6<724::aid-ana6>;2-p.

Bittigau P, Sifringer M, Felderhoff-Mueser U, Hansen HH, Ikonomidou C. Neuropathological and biochemical features of traumatic injury in the developing brain. Neurotox Res 2003; 5(7):475-90. DOI: 10.1007/bf03033158.

Bittigau P, Sifringer M, Felderhoff-Mueser U, Ikonomidou Ch. Apoptotic neurodegeneration in the context of traumatic injury to the developing brain. Exp Tox Pathol 2004; 56:83-89. DOI: 10.1016/j.etp.2004.04.006.

Büki A, Okonkwo D, Povlishock J. Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J Neurotrauma 1999; 16 (6):511-21. DOI: 10.1089/neu.1999.16.511.

Calderó J, Prevette D, Mei X, Oakley RA, Li L, Milligan C, et al. Peripheral target regulation of the development and survival of spinal sensory and motor neurons in the chick embryo. J Neurosci. 1998; 18(1):356-70. DOI: 10.1523/JNEUROSCI.18-01-00356.1998.

Cheng Y, Deshmukh M, D’Costa A, Demaro J, Gidday JM, Shah A, et al. Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Invest 1998; 9:1992-1999. DOI: 10.1172/JCI2169.

Conti AC, Raghupathi R, Trojanowski JQ, McIntosh TK. Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 1998; 18:5663-5672. DOI: 10.1523/JNEUROSCI.18-15-05663.1998.

Coulter I. Forsyth R. Pediatric traumatic injury. Curr Opin Pediatr 2019; 31:1040-8703. DOI:10.1097/MOP.0000000000000820.

Dikranian K, Cohen R, Mac Donald Ch, Pan Y, Brakefield D, Bayly P, Parsadanian A. Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons. Exp Neurol 2008; 211(2): 551–560. DOI:10.1016/j.expneurol.2008.03.012

Dixon CE, Clifton GL, Lighthall JW, Yaghmai A, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 1991; 39:253-262. DOI: 10.1016/0165-0270(91)90104-8.

Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child 1973; 48:757–767. DOI: 10.1136/adc.48.10.757. DOI: 10.1136/adc.48.10.757.

Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979; 3:79-83. DOI: 10.1016/0378-3782(79)90022-7.

Dutschke J, Finnie J, Manavis, Anderson R. Semiquantitation of Axonal Injury in Traumatically Damaged Brains Using Color Deconvolution, Appl Immunohistochem Mol Morphol 2017; 25:277–281. DOI: 10.1097/PAI.0000000000000273

Ewing-Cobbs L, Prasad M, Kramer L, Louis PT, Baumgartner J, Fletcher JM, et al. Acute neuroradiologic findings in young children with inflicted or noninflicted traumatic brain injury. Childs Nerv Syst 2000; 16:25–33. DOI: 10.1007/s003810050006

Farkas O, Povlishock J. Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. Prog Brain Res 2007; 161:43–59. DOI: 10.1016/S0079-6123(06)61004-2

Faden A, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989; 44:798-800. DOI: 10.1126/science.2567056

Feng G, Mellor R, Bernstein M, Keller-Peck C, Nguyen Q, Wallace M, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 2000; 28:41–51. DOI: 10.1016/s0896-6273(00)00084-2

Felderhoff-Mueser U, Ikonomidou, Ch. Mechanisms of neurodegeneration after pediatric brain injury. Curr Opin Neurol 2000; 13 (2):141-145. DOI: 10.1097/00019052-200004000-00005.

Feeney D, Boyeson M, Linn R, Murray H, Dail W. Responses to cortical injury. I. Methodology and local effects of contusions in the rat. Brain Res 1981; 211:67-77. DOI: 10.1016/0006-8993(81)90067-6

Geddes J, Hackshow, G. Vowles, Nickols C., Whitwell H. Neuropathology of inflicted injury in children. I. Patterns of brain damage. Brain 2001; 124:1290-1298. DOI: 10.1093/brain/124.7.1290

Geddes J, Hackshow, G. Vowles, C. Nickols, H. Whitwell, Neuropathology of inflicted injury in children. II. Microscopic brain injury in infants. Brain 2001; 124:1299-1306. DOI: 10.1093/brain/124.7.1299

Gentleman S, Nash MJ, Sweeting CJ, Graham DI, Roberts G. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 1993; 160 (2):139-44. DOI: 10.1016/0304-3940(93)90398-5.

Girard T, Thomas J, Garrison M, Ehlers C, Riley E. Nicotine exposure during the neonatal growth spurt produces hyperreactivity in preweanling rats. Neurotoxicol Teratol 2000; 22(5):695-701. DOI: 10.1016/s0892-0362(00)00096-9.

Gleckman AM, Bell MD, Evans RJ, Smith TW. Diffuse axonal injury in infants with nonaccidental craniocerebral trauma: enhanced detection by beta-amyloid precursor protein immunohistochemical staining. Arch Pathol Lab Med 1999; 123:146–151. DOI: 10.1043/0003-9985(1999)123<0146:DAIIIW>2 .0.CO;2.

Gremelt A, Braun U. Analgesia and sedation in patients with head trauma. Anaesthesist, 1995; 44:559-565. PMID: 8592967.

Gunitz G. Early management of head-brain trauma patients. Anaesthesist 1995; 44:369-391. DOI: 10.1007/s001010050166.

Han B, Holtzman DB. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000; 20:5775-5781. DOI: 10.1523/JNEUROSCI.20-15-05775.2000.

Helland I, Smith L, Saarem K, Saugstad OD, Drevon Ch. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 2003; 111(1):39-44. DOI: 10.1542/peds.111.1.e39.

Huh J, Widing A, Raghupathi R. Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration. Experimental Neurology 2008; 213:84–92. DOI: 10.1016/j.expneurol.2008.05.009.

Ikonomidou C, Qin Y, Labruyere J, Kirby C, Olney J. Prevention of trauma-induced neurodegeneration in infant rat brain. Pediatr Res 1996; 39(6):1020-1027. DOI: 10.1203/00006450-199606000-00015.

Ishimaru MJ, Ikonomidou C, Tenkova TI, Der TC, Dikranian K, Sesma MA, Olney JW. Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain. J Comp Neurol 1999; 408:461-476. PMID: 10340498.

Johnson V, Meaney D, Cullen K, Smith D. Animal models of traumatic brain injury. Grafman and Salazar, Editors. Handbook of Clinical Neurology, Vol. 127 (3rd series) Traumatic Brain Injury, Part I, Ch. 8, 2015. DOI:10.1016/B978-0-444-52892-6.00008-8

Kelley B, Farkas O, Lifshitz J, Povlishock J. Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration. Exp Neurol 2006; 198(2):350-360. DOI: 10.1016/j. expneurol.2005.12.017.

Kempe CH, Silverman FN, Steele BF, et al. The battered child syndrome. JAMA1962; 181:17-24. DOI: 10.1001/jama.1962.03050270019004.

Kochanek P, Bell M. Tackling the challenges of clinical trials for severe traumatic brain injury in children: Screening, phenotyping, and adapting. Critical Care Medicine 2015; 45(7):1544-1546. DOI: 10.1097/CCM.0000000000001041.

Kolb B, Whishaw IQ. An introduction to brain and behavior. New York: Worth Publishers, 2001.

Koskiniemi M, Kykka T, Nybo T, Jarho L. Long-term outcome after severe brain injury in pre-schoolers is worse than expected. Arch Pediatr Adolesc Med 1995; 49:249-254. DOI: 10.1001/archpedi.1995.02170150029004.

Kretschmann H, Kammradt G, Krauthausen I, Sauer B, Wingert F. Brain growth in man. Bibl Anat 1986; 28:1-26. PMID: 3707509.

Levchakov A, Linder-Ganz E, Raghupathi R, Margulies S, Gefen A. Computational studies of strain exposures in neonate and mature rat brains during closed head impact. J Neurotrauma. 2006; O23(10):1570-1580. DOI: 10.1089/neu.2006.23.1570.

Mac Donald Ch, Dikranian K, Bayly Ph, Holtzman D, Brody D. Diffusion tensor imaging reliably detects experimental traumatic axonal injury and indicates approximate time of injury. J Neurosci 2007; 27(44):11869–11876. DOI: 10.1523/JNEUROSCI.3647-07.2007

Mac Donald Ch, Dikranian K, Song SK, Bayly PV, Holtzman DM, Brody D. Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury. Exp Neurol 2007; 205(1):116–131. DOI: 10.1016/j.expneurol.2007.01.035

Mahoney W, D’Souza B, Haller A, Rogers M, Epstein M, Freeman J. Long-term outcome of children with severe head trauma and prolonged coma. Pediatrics 1983; 71:756-762. PMID: 6835758.

Markou K, Georgopolous N, Kyriazopoulou V, Vagenakis GA. Iodine induced hypothyroidism. Thyroid 2001; 11:501-507. DOI: 10.1089/105072501300176462.

Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K. A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg 1994; 80:291-300. DOI: 10.3171/jns.1994.80.2.0291.

McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Faden AI. Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 1989; 28:233-244. DOI: 10.1016/0306-4522(89)90247-9.

Maroles M. Vester R. Bilo A, Loeve R, Van Zandwijk J. Modeling of inflicted head injury by shaking trauma in children: what can we learn? Part I: A systematic review of animal models Forensic Science, Medicine and Pathology 2019; 15:408–422. DOI: 10.1007/s12024-019-0082-3.

Natale J, Cheng Y, Martin L. Thalamic neuron apoptosis emerges rapidly after cortical damage in immature mice. Neuroscience 2002; 112:665-676. DOI: 10.1016/s0306-4522(02)00098-2.

Okonkwo D, Povlishock T. An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury. J Cereb Blood Flow Metab 1999; 19:443-451. DOI: 10.1097/00004647-199904000-00010.

Okonkwo D, Buki A, Siman R, Povlishock T. Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 1999; 10:353-358. DOI: 10.1097/00001756-199902050-00026.

Paul A, Adamo M. Non-accidental trauma in pediatric patients: a review of epidemiology, pathophysiology, diagnosis and treatment. Transl Pediatr 2014; 3(3):195-207. DOI: 10.3978/j.issn.2224-4336.2014.06.01.

Price JL. Thalamus. Paxinos, G. Editor. In: The Rat Nervous System. London, Acad Press, 1995.

Prins ML, Lee SM, Cheng CL, Becker DP, Hovda DA. Fluid percussion brain injury in the developing and adult rat: a comparative study of mortality, morphology, intracranial pressure and mean arterial blood pressure. Dev Brain Res 1996; 95:272-282. DOI: 10.1016/0165-3806(96)00098-3.

Pohl D, Bittigau P, Ishimaru M, Stadthaus D, Hubner C, Olney JW, Turski L, Ikonomidou C. N-methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc Natl Acad Sci 1999; 96:2508-2513. DOI: 10.1073/pnas.96.5.2508.

Pullela R, Raber J, Pfankuch T, Ferriero D, Claus C, Koh E, Yamauchi T, Rola R, Fike J, Noble-Haeusslein L. Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Dev Neurosci 2006; 28(4-5):396-409. DOI: 10.1159/000094166.

Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000; 108 (Suppl 3):511-533.. DOI: 10.1289/ehp.00108s3511.

Raghupathi R, Margulies S. Traumatic axonal injury after closed head injury in the neonatal pig. J Neurotrauma.2002; 19(7):843-53. DOI: 10.1089/08977150260190438.

Reeves TM, Phillips LL, Povlishock JT. Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury. Exp Neurol 2005; 196 (1):126–137. DOI: 10.1016/j.expneurol.2005.07.014.

Rivara F, Tennyson, R Mills B, Browd S, Emery C, Gioia G, Giza Ch, Herring S, Janz K, LaBella C, Valovich MT, Meehan Wi, Patricios J. Consensus statement on sports-related concussions in youth sports using a modified Delphi approach. JAMA Pediatrics 2019; E1-E7. DOI: 10.1001/jamapediatrics.2019.4006.

Ruppel R, Kochanek P, Adelson P, Rose E, Wisniewski R, Bel J, Clark S, Marion D, Graham H. Excitatory amino acid concentrations in ventricular cerebrospinal fluid after severe traumatic brain injury in infants and children: the role of child abuse. J Pediatr 2001; 138:18–25. DOI: 10.1067/mpd.2001.110979.

Salmaso N, Jablonska B, Scafidi J, Vaccarino F, Gallo V. Neurobiology of premature brain injury. Nat Neurosci 2014; 17(3):341-346. DOI:10.1038/nn.3604.

Shibata H. Efferent projections from the anterior thalamic nuclei to the cingulate cortex in the rat. J Comp Neurol 1993; 330:533–542. DOI: 10.1002/cne.903300409.

Singleton R, Stone J, Okonkwo D, Pellicane A, Povlishock J. The immunophilin ligand FK506 attenuates axonal injury in an impact-acceleration model of traumatic brain injury. J Neurotrauma 2001; 18(6):607-614. DOI: 10.1089/089771501750291846.

Stein D, Geddes S, Sribnick E. Recent developments in clinical trials for the treatment of traumatic brain injury. Grafman and Salazar, Editors. Handbook of Clinical Neurology, Vol. 127 (3rd series) Traumatic Brain Injury, Part I J. Elsevier B.V. 2015. DOI: 10.1016/B978-0-444-52892-6.00028-3.

Stein SC, Spettell CM. Delayed and progressive brain injury in children and adolescents with head trauma. Pediatr Neurosurg 1995; 23:299-304. DOI: 10.1159/000120975.

Su E, Bell MJ, Wisniewski SR, Adelson PD, Janesko-Feldman KL, Salonia R, et al. α-Synuclein levels are elevated in cerebrospinal fluid following traumatic brain injury in infants and children: the effect of therapeutic hypothermia. Dev Neurosci 2010; 32(5-6):385-95. DOI: 10.1159/000321342

Thabet F, Tabarki B. Therapeutic hypothermia in children: Which indications remain in 2018? Archives de Pediatrie 2019; 26: 308–311. DOI: 10.1016/j.arcped.2019.05.010.

Tolias C, Bullock M. Critical appraisal of neuroprotection trials in head injury: What have we learned? NeuroRx 2004; 1:71–79. DOI: 10.1602/neurorx.1.1.71.

Wang Ch, Zhao C, He Y, Li L, W, Huang Z, Deng Y, Li W. Mild hypothermia reduces endoplasmic reticulum stress induced apoptosis and improves neuronal functions after severe traumatic brain injury. Brain Behav 2019 (in press). DOI: 10.1002/brb3.1248

Wozniak J, Krach L, Warda E, Mueller B, Muetzel R, Schnoebelen S, Kiraguc A, Lim K, Neurocognitive and neuroimaging correlates of pediatric traumatic brain injury: A diffusion tensor imaging (DTI) study. Arch Clin Neuropsychol 2007; 22(5): 555–568. DOI: 10.1016/j. acn.2007.03.004.

Xiang H, Girard T, Ward GR, Nguyen H, Wainwright PE. Exposure to ethanol and nicotine during the brain growth spurt: spatial DMP performance in male rats. Pharmacol Biochem Behav 2001; 68(3):515-23. DOI: 10.1016/s0091-3057(01)00452-x.

Yager J, Thornhill J. The effect of age on susceptibility to hypoxic-ischemic brain damage. Neurosci Biobehav Rev 1997; 21(2):167-74. DOI: 10.1016/s0149-7634(96)00006-1.

Yakovlev A, Knoblach S, Fan L, Fox G, Goodnight R, Faden A. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 1997; 17:7415-7424. DOI: 10.1523/JNEUROSCI.17-19-07415.1997.

Yakovlev A, Faden A. Caspase-dependent apoptotic pathways in CNS injury. Mol Neurobiol 2001; 24(1-3):131-44. DOI: 10.1385/MN:24:1-3:131.

Zhang X., Chen Y, Jenkins L, Kochanek P, Clark R. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care 2005; 9:66–75. DOI:10.1186/cc2950



Article Tools
Email this article (Login required)
About The Author

Krikor Dikranian
Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO
United States

Font Size