Research reportSub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments
Highlights
► Detailed analysis of sub-concussive mild lateral fluid percussion injury in the rat. ► Mild lateral fluid percussion injury induced acute neuroinflammatory response. ► No evidence of behavioral impairments or axonal injury. ► Neuroinflammation may contribute to neurodegenerative effects of repeated mild TBI. ► Supports use of mild fluid percussion injury as a model of sub-concussive injury.
Introduction
Brain concussion, or mild TBI, is a serious public health concern with an annual injury rate of approximately 1 in 150 individuals [1]. Concussion can be defined as a transient neurological dysfunction resulting from a biomechanical force and is often associated with behavioral symptoms, such as short-term cognitive and emotional disturbances [2], [3]. While evidence suggests that structural brain damage is rare following concussion [3], other pathologies such as axonal injury and neuroinflammatory processes may occur [4], [5], [6], [7]. Individuals who engage in daily combative and bodily contact activities, such as athletes and military personnel, are not only at an increased risk of suffering concussion but can also regularly experience sub-concussive blows to the head that are below the threshold of force required to cause concussion [8], [9], [10], [11], [12]. In a recent study by Talavage et al. [12], significant neurophysiological changes were detected in high school football players who had experienced an impact to the head but displayed no clinical symptoms of concussion. In addition, post-mortem studies on brain tissue obtained from individuals who had experienced repeated sub-concussive head traumas have found evidence that such injuries may have cumulative effects and could ultimately manifest as CTE, a neurodegenerative disorder associated with severe neurological impairments [8], [10], [13], [14]. In light of these findings, there is a need to better understand the effects of sub-concussive brain injuries [3], [8], [10], [11], [15]. Given the current lack of understanding and difficulties associated with assessing sub-concussive impacts in clinical populations, the use of an animal model of sub-concussive brain trauma may be beneficial.
LFP is one of the most commonly used and well-characterized rodent models of TBI [16]. Previous studies administering a single mLFP with a force greater than 1 atm have found that a single mLFP can induce behavioral and pathological changes in the rat consistent with those that occur in humans suffering a single concussion [2], [3], [16], [17], [18]. However, to date, no study has performed a detailed behavioral and pathological examination of the effects of a single mLFP below the force of 1 atm to determine whether it might be used to model sub-concussive brain injury. In an attempt to assess the use of a mLFP as an animal model of sub-concussive brain injury, the current study gave young-adult male Long-Evans rats a mLFP with a force of 0.50–0.99 atm. Following the injury, rats underwent testing on behavioral tasks of anxiety-like behavior, spatial cognition, depression-like behavior, social behavior, locomotion, and sensorimotor ability, as well as immunohistochemical evaluation of neuroinflammation and axonal injury. To assess recovery after mLFP, these analyses were conducted at both short- and long-term recovery intervals.
Section snippets
Subjects
Subjects were 64 adult male Long-Evans hooded rats obtained from Charles River Labs (Quebec). Prior to surgery rats weighed between 250–300 g, were housed in pairs in standard acrylic cages (26 cm × 48 cm × 21 cm) at 21 ± 1.0 °C, and were experimentally naïve. Rats were housed individually post-surgery to maintain the integrity of the injury cap. The light/dark cycle was 12:12 (lights on 07:00–19:00 h) and animals had access to food and water ad libitum. Procedures were in accordance with Canadian Council
Injury force and acute post-injury measures
As shown in Table 1, ANOVA revealed a significant main effect of injury/recovery group (F(3, 63) = 33,276.580, p < .001) on the measure of injury force. Post hoc tests revealed that the SUB-SR and SUB-LR groups experienced a significantly greater injury force than the SHAM groups (all ps < .001). There were no group differences in the duration of apnea, the time to regain hind-limb withdrawal, and the return of the self-righting reflex (all ps > .05). There were no cases of mortality resulting from
Discussion
A single mLFP with a force of 0.5–0.99 atm in the male Long-Evans rat produced a short-term increase in microglia/macrophages and reactive astrogliosis, indicating an acute neuroinflammatory response. This neuroinflammatory response occurred in the absence of any significant axonal injury, or cognitive, emotional, or sensorimotor disturbances. There were no long-term group differences found on any of the behavioral or neuropathological measures at 4 weeks post-injury.
Conclusions
A single mLFP at a force of 0.5–0.99 atm induced a transient neuroinflammatory response in the absence of behavioral impairments. These findings appear consistent with what is observed in humans experiencing a single sub-concussive blow and support the use of mLFP to model sub-concussive brain injury. The finding that a single sub-concussive brain injury can result in neuroinflammation may have important implications for understanding the cumulative and neurodegenerative effects of repeated mild
Acknowledgements
This research was supported by a grant from the Natural Science and Engineering Research Council (NSERC) to Dr. Donald P. Cain, a scholarship from NSERC to Dr. Sandy R. Shultz, and contributions from GoodLife Childrens's Foundation and Round for a Reason Charities to Dr. Derrick F. MacFabe. We thank Drs. Richard Sutton and David Hovda from the UCLA Brain Injury Research Center for their help in LFP training. Additional thanks go to Lisa Tichenoff, Francis Boon, and Acia Blank for their
References (59)
- et al.
Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma
Clin Sports Med
(2011) - et al.
Subconcussive impact in sports: a new era of awareness
World Neurosurg
(2011) - 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
Behav Brain Res
(2011) - et al.
Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition
Exp Neurol
(2006) - et al.
Exercised-induced improvement in cognitive performance in rats is dependent on BDNF activation
Brain Res
(2009) - et al.
Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function
Neuroscience
(2004) - et al.
Lateral fluid percussion injury in the developing rat causes an acute, mild behavioral dysfunction in the absence of significant cell death
Brain Res
(2006) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety
Pharmacol Biochem Behav
(1996)- 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
Behav Brain Res
(2009) - 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
Neuropharmacology
(2008)
Dynamic imaging in mild traumatic brain injury: support for the theory of medial temporal vulnerability
Arch Phys Med Rehabil
Transient cognitive deficits are associated with the reversible accumulation of amyloid precursor protein after mild traumatic brain injury
Neurosci Lett
Amyloid load and neural elements in Alzheimer's disease and nondemented individuals with high amyloid plaque density
Exp Neurol
Microglia: intrinsic immuneffector cell of the brain
Brain Res Brain Res Rev
Closed head injury—an inflammatory disease
Brain Res Brain Res Rev
The molecular pathophysiology of concussive brain injury
Clin Sports Med
Conditioning effect of repetitive mild neurotrauma on motor function in an animal model of focal brain injury
Neuroscience
neurochemical asymmetries following unilateral trephination of the rat skull: is this control-operation always appropriate
Physiol Behav
Animal models of traumatic brain injury: is there an optimal model to reproduce human brain injury in the laboratory
Injury
Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury
J Rehabil Med
Concussion and mild head injury
Pract Neurol
Consensus statement on concussion in sport—the Third International Conference on Concussion in Sport held in Zurich, November 2008
Phys Sportsmed
Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome
Neurosurgery
Diffusion-tensor implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury
Radiology
A prospective diffusion tensor imaging study in mild traumatic brain injury
Neurology
Inflammation after trauma: microglial activation and traumatic brain injury
Ann Neurol
Head impact severity measures for evaluating mild traumatic brain injury risk exposure
Neurosurgery
Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury
J Neuropathol Exp Neurol
Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion
J Neurotrauma
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