Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments

Sub-concussive brain injuries may result in neurophysiological changes, cumulative effects, and neurodegeneration. The current study investigated the effects of a mild lateral fluid percussion injury (0.50-0.99 atm) on rat behavior and neuropathology to address the need to better understand sub-concussive brain injury. Male Long-Evans rats received either a single mild lateral fluid percussion injury or a sham-injury, followed by either a short (24 h) or long (4 weeks) recovery period. After recovery, rats underwent extensive behavioral testing consisting of tasks for rodent cognition, anxiety- and depression-like behaviors, social behavior, and sensorimotor function. At the completion of behavioral testing rats were sacrificed and brains were examined immunohistochemically with markers for neuroinflammation and axonal injury. No significant group differences were found on behavioral and axonal injury measures. However, rats given one mild fluid percussion injury displayed an acute neuroinflammatory response, consisting of increased microglia/macrophages and reactive astrogliosis, at 4 days post-injury. Neuroinflammation is a mechanism with the potential to contribute to the cumulative and neurodegenerative effects of repeated sub-concussive injuries. The current findings are consistent with findings in humans experiencing a sub-concussive blow, and provide support for the use of mild lateral fluid percussion injury in the rat as a model of sub-concussive brain injury.

[1]  F. Gomez-Pinilla,et al.  Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition , 2006, Experimental Neurology.

[2]  T. Kuroiwa,et al.  Transient cognitive deficits are associated with the reversible accumulation of amyloid precursor protein after mild traumatic brain injury , 2006, Neuroscience Letters.

[3]  B. Trapp,et al.  Amyloid Load and Neural Elements in Alzheimer's Disease and Nondemented Individuals with High Amyloid Plaque Density , 1996, Experimental Neurology.

[4]  J. Bailes,et al.  Chronic traumatic encephalopathy in a professional American wrestler , 2010, Journal of forensic nursing.

[5]  A. Walf,et al.  The use of the elevated plus maze as an assay of anxiety-related behavior in rodents , 2007, Nature Protocols.

[6]  D. Hovda,et al.  Repeat Traumatic Brain Injury in the Juvenile Rat Is Associated with Increased Axonal Injury and Cognitive Impairments , 2010, Developmental Neuroscience.

[7]  K. Waterloo,et al.  Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. , 1999, Neurosurgery.

[8]  R. Cantu,et al.  Consensus Statement on Concussion in Sport – The Third International Conference on Concussion in Sport Held in Zurich, November 2008 , 2009, The Physician and sportsmedicine.

[9]  M. Morganti-Kossmann,et al.  Inflammatory response in acute traumatic brain injury: a double-edged sword , 2002, Current opinion in critical care.

[10]  Tim J. Anderson,et al.  Concussion and mild head injury , 2006, Practical Neurology.

[11]  G. Kreutzberg,et al.  Microglia: Intrinsic immuneffector cell of the brain , 1995, Brain Research Reviews.

[12]  V. Haughton,et al.  Diffusion tensor MR imaging in diffuse axonal injury. , 2002, AJNR. American journal of neuroradiology.

[13]  P. Stahel,et al.  Closed head injury—an inflammatory disease? , 2005, Brain Research Reviews.

[14]  R. Bullock,et al.  Repeated mild brain injuries result in cognitive impairment in B6C3F1 mice. , 2002, Journal of neurotrauma.

[15]  D. Cain,et al.  A single mild fluid percussion injury induces short-term behavioral and neuropathological changes in the Long–Evans rat: Support for an animal model of concussion , 2011, Behavioural Brain Research.

[16]  F. Gomez-Pinilla,et al.  Vitamin E Protects Against Oxidative Damage and Learning Disability After Mild Traumatic Brain Injury in Rats , 2010, Neurorehabilitation and neural repair.

[17]  D. Graham,et al.  Lateral fluid percussion brain injury: a 15-year review and evaluation. , 2005, Journal of neurotrauma.

[18]  G. Sébire,et al.  Cytokines and Brain Injury: Invited Review , 2008, Journal of intensive care medicine.

[19]  G. Allen,et al.  Conditioning effects of repetitive mild neurotrauma on motor function in an animal model of focal brain injury , 2000, Neuroscience.

[20]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[21]  Brandon E Gavett,et al.  Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. , 2011, Clinics in sports medicine.

[22]  E. Yan,et al.  Animal models of traumatic brain injury: is there an optimal model to reproduce human brain injury in the laboratory? , 2010, Injury.

[23]  R. Morris Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D- aspartate receptor antagonist AP5 , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  Valeria Conte,et al.  Temporal Window of Vulnerability to Repetitive Experimental Concussive Brain Injury , 2005, Neurosurgery.

[25]  D. Hovda,et al.  Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function , 2004, Neuroscience.

[26]  R. Raghupathi,et al.  Traumatic brain injury elevates glycogen and induces tolerance to ischemia in rat brain. , 2004, Journal of neurotrauma.

[27]  L. Pitts,et al.  Altered immunoexpression of microglia and macrophages after mild head injury. , 1995, Journal of neurotrauma.

[28]  Craig A Branch,et al.  Diffusion-tensor imaging implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury. , 2009, Radiology.

[29]  T. Talavage,et al.  Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. , 2014, Journal of neurotrauma.

[30]  M. O’Banion,et al.  Neuroinflammation and Memory: The Role of Prostaglandins , 2009, Molecular Neurobiology.

[31]  A. Mayer,et al.  A prospective diffusion tensor imaging study in mild traumatic brain injury , 2010, Neurology.

[32]  A. McKee,et al.  Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy After Repetitive Head Injury , 2009, Journal of neuropathology and experimental neurology.

[33]  D. Cain,et al.  Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: Further development of a rodent model of autism , 2009, Behavioural Brain Research.

[34]  S. DeKosky,et al.  Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions , 2010, Journal of forensic nursing.

[35]  T. O'Brien,et al.  Experimental traumatic brain injury induces a pervasive hyperanxious phenotype in rats. , 2008, Journal of neurotrauma.

[36]  D. Hovda,et al.  Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. , 1990, Journal of neurosurgery.

[37]  D. Hovda,et al.  Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation , 2009, Brain Research.

[38]  D. Brody,et al.  Repetitive Closed-Skull Traumatic Brain Injury in Mice Causes Persistent Multifocal Axonal Injury and Microglial Reactivity , 2011, Journal of neuropathology and experimental neurology.

[39]  K.,et al.  Mild head injury increasing the brain's vulnerability to a second concussive impact. , 2001, Journal of neurosurgery.

[40]  L. Weaver,et al.  Early anti‐inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats , 2004, Journal of neurochemistry.

[41]  G. Lynch,et al.  Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5 , 1986, Nature.

[42]  Melissa D. Laird,et al.  Opposing Roles for Reactive Astrocytes following Traumatic Brain Injury , 2008, Neurosignals.

[43]  R. Porsolt,et al.  Depression: a new animal model sensitive to antidepressant treatments , 1977, Nature.

[44]  R. Schwarting,et al.  Behavioral and neurochemical asymmetries following unilateral trephination of the rat skull: Is this control operation always appropriate? , 1994, Physiology & Behavior.

[45]  D. Jacobowitz,et al.  Craniotomy: true sham for traumatic brain injury, or a sham of a sham? , 2011, Journal of neurotrauma.

[46]  D. Hovda,et al.  Lateral fluid percussion injury in the developing rat causes an acute, mild behavioral dysfunction in the absence of significant cell death , 2006, Brain Research.

[47]  R. Cantu Consensus statement on concussion in sport--the 3rd International Conference on Concussion, Zurich, November 2008. , 2009, Neurosurgery.

[48]  D. Hovda,et al.  Developing experimental models to address traumatic brain injury in children. , 2003, Journal of neurotrauma.

[49]  Joseph T. Gwin,et al.  HEAD IMPACT SEVERITY MEASURES FOR EVALUATING MILD TRAUMATIC BRAIN INJURY RISK EXPOSURE , 2008, Neurosurgery.

[50]  S. Hogg A review of the validity and variability of the Elevated Plus-Maze as an animal model of anxiety , 1996, Pharmacology Biochemistry and Behavior.

[51]  D. Saucier,et al.  Sex differences in object location memory and spatial navigation in Long-Evans rats , 2007, Animal Cognition.

[52]  Adam J. Bartsch,et al.  Subconcussive impact in sports: a new era of awareness. , 2011, World neurosurgery.

[53]  A. Alavi,et al.  Dynamic imaging in mild traumatic brain injury: support for the theory of medial temporal vulnerability. , 2002, Archives of physical medicine and rehabilitation.

[54]  W. Brück,et al.  Evidence for frequent focal and diffuse acute axonal injury in human bacterial meningitis. , 2009, Clinical neuropathology.

[55]  D. Sharp,et al.  Inflammation after trauma: Microglial activation and traumatic brain injury , 2011, Annals of neurology.

[56]  D. Cain,et al.  Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism , 2008, Neuropharmacology.

[57]  J. Borg,et al.  Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. , 2004, Journal of rehabilitation medicine.

[58]  D. Cain,et al.  Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. , 2012, Journal of neurotrauma.

[59]  D. Hovda,et al.  The molecular pathophysiology of concussive brain injury. , 2011, Clinics in sports medicine.