Transl. Stroke Res. DOI 10.1007/s12975-014-0327-0

REVIEW ARTICLE

Traumatic Brain Injury Using Mouse Models Yi Ping Zhang & Jun Cai & Lisa B. E. Shields & Naikui Liu & Xiao-Ming Xu & Christopher B. Shields

Received: 3 August 2013 / Revised: 9 December 2013 / Accepted: 5 January 2014 # Springer Science+Business Media New York 2014

Abstract The use of mouse models in traumatic brain injury (TBI) has several advantages compared to other animal models including low cost of breeding, easy maintenance, and innovative technology to create genetically modified strains. Studies using knockout and transgenic mice demonstrating functional gain or loss of molecules provide insight into basic mechanisms of TBI. Mouse models provide powerful tools to screen for putative therapeutic targets in TBI. This article reviews currently available mouse models that replicate several clinical features of TBI such as closed head injuries (CHI), penetrating head injuries, and a combination of both. CHI may be caused by direct trauma creating cerebral concussion or contusion. Sudden acceleration–deceleration injuries of the head without direct trauma may also cause

intracranial injury by the transmission of shock waves to the brain. Recapitulation of temporary cavities that are induced by high-velocity penetrating objects in the mouse brain are difficult to produce, but slow brain penetration injuries in mice are reviewed. Synergistic damaging effects on the brain following systemic complications are also described. Advantages and disadvantages of CHI mouse models induced by weight drop, fluid percussion, and controlled cortical impact injuries are compared. Differences in the anatomy, biomechanics, and behavioral evaluations between mice and humans are discussed. Although the use of mouse models for TBI research is promising, further development of these techniques is warranted. Keywords Traumatic brain injury . Mouse . Animal models

Y. P. Zhang : L. B. E. Shields : C. B. Shields (*) Norton Neuroscience Institute, Norton Healthcare, 210 East Gray Street, Suite 1102, Louisville, KY 40202, USA e-mail: [email protected] Y. P. Zhang e-mail: [email protected] L. B. E. Shields e-mail: [email protected] J. Cai Department of Pediatrics, School of Medicine, University of Louisville, Donald Baxter Building, Suite 321B, 570 South Preston Street, Louisville, KY 40292, USA e-mail: [email protected] N. Liu : X.90 days [225]. Football and other sports injuries are common in humans, therefore, models of these injuries would be beneficial to study the effects of concussion/contusion related to sports injuries. A rat model using a 7.4- to 11.2-m/s velocity at impact using a 50-g impactor on a helmet-protected head replicating cerebral concussion arising from football injuries

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has been described [75]. Gross pathological changes were observed in 11, 28, and 33 % of animals subjected to 7.4-, 9.3-, and 11.2-m/s single impacts, respectively. When a 100-g impactor was used, greater energy transfer further increased the frequency and severity of injury [75]. A blast injury model using mice has been developed to recapitulate the pathological changes of tau-body encephalopathy observed in football players [71]. Using the wild-type C57BL/6 mouse exposed to a single blast, phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration were observed in the absence of macroscopic tissue damage or hemorrhage. Memory deficits persisting for >1 month correlated directly with impaired axonal conduction along with defective long-term potentiation of synaptic transmission. Such models replicate injuries that occur in athletes and correlate the magnitude of head trauma to persistent impairments in neurophysiological function, learning, and memory. Head immobilization during blast exposure prevented blast-induced learning and memory deficits [71]. Rodent models of head injury require induction of anesthesthetic agents that limit immediate postinjury behavior assessment such as orientation, memory, and level of consciousness. Head injuries have uncommonly been created in rats without anesthetic agents [161]; however, animal rights laws have largely prevented such injuries without sedation or anesthesia. Cumulative Effects of Multiple Head Injuries A single impact to the head may cause minimal or no clinical symptoms in humans. Cumulative mild head injuries may become symptomatic following boxing and football injuries as well as battlefield trauma [92, 199]. Repetitive head injuries or blast injuries may increase the risk of developing major delayed neurological diseases such as Alzheimers disease, motor neuron disease, and Lewy body disease [143, 147]. The so-called second-impact syndrome may cause rapid neurological deterioration following a second cerebral concussion after the effects of the initial one have fully resolved, resulting in long-term cognitive or behavioral abnormalities [71] or even an abrupt increase in intracranial pressure which may lead to brain herniation and death [26, 142]. It is unknown why repetitive concussions causing chronic traumatic encephalopathy lead to cognitive deficits (memory loss and conceptual computation problems) and post-traumatic stress disorders (PTSD) [75, 213]. Using a rat model, repetitive blast injuries under general anesthesia induced a variety of PTSDrelated behavioral traits, such as increased anxiety, enhanced contextual fear conditioning, and altered response to predator scent assay, that lasted for several months after the blast exposure [56]. As these injuries were performed in anesthetized rats, we are unable to evaluate psychological factors in

producing PTSD-like injuries. A repetitive concussion model in rats was developed to study the effects of multiple brain injuries [34, 49, 151]. DeRoss et al. reported that multiple concussions in rats caused immediate transient impairment in spatial recognition as well as extended effects on baseline performance [49]. These injuries cause impairment in motor function, memory, and learning abilities [87]. Chen et al. developed a projectile concussive impact (PCI) model in rats that replicated cerebral concussion in humans causing significant sensorimotor abnormalities 1 to 24 h after PCI injury [31]. Repeated blast injuries exacerbate histopathological and functional outcomes in rat and mouse models [94, 114, 206, 212]. Repetitive TBI can be created experimentally [188]. Usually, the CHI method [95] is utilized, but combining CCI and CHI methods may be performed sequentially to produce such injuries [44]. The effects of multiple cerebral concussions/contusions are cumulative in the mouse, with cognitive impairment observed only after repetitive concussions [42, 46, 220]. Brain damage may be significant when mild repeatitive TBI occur within a brief time window or during a period of vulnerability [145, 167, 168]. Single cerebral concussions do not cause cognitive impairment in mice [220]. Using a rat model of two consecutive head injuries using the mild cortical impact model, brain injuries 1 or 3 days apart revealed significantly greater lesion volumes observed on MRI compared with a single mild TBI and shams [85]. This finding was further supported by increased cortical tissue damage, extravascular iron, and glial activation in the multiple head injured rats with an interval of 1 and 3 days between impact. Behavioral changes at 1 month postinjury included reduced exploratory behavior and spatial learning impairment [85]. A model of repetitive closed TBI in mice has been developed with 24 h between controlled rubber impact injuries [186]. The injuries produced deficits in the Morris water maze performance which lasted as long as 7 weeks postinjury, with extensive abnormalities observed in the corpus callosum, bilateral external capsule, and ipsilateral cerebral cortex and thalamus noted on silver stain. A mouse model of repetitive mild TBI has been developed using the modified Marmarou WD method under mild anesthesia [95]. These animals were not restrained which allowed rapid acceleration of the head and torso. A scalp incision was not required. The procedure can be completed in 1–2 min. Minor deficits in motor coordination and locomotion hyperactivity recovered over time. This method is simple, cost effective, and is ideal for high throughput screening of potential new therapies [95]. Additional evidence of increased cognitive effects following multiple concussive brain injuries in mice has been reported with improvement of cognition following vitamin E administration [39, 42, 71]. Head immobilization during blast exposure prevented blast-induced learning and memory deficits in mice [71].

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Brain Injury Without Direct Head Impact Forces arising from the shock wave of an explosion or from a sudden acceleration–deceleration motion of the head may cause a TBI constituting a double hit [135].

brain produced a cumulative effect on the pathological appearance of the brain and behavioral recovery [29, 105, 213]. Use of single and repeated blast exposures to the entire mouse has caused changes in several plasma enzymes suggesting that these enzymes may be used as a marker of trauma severity [9].

Blast-Induced Traumatic Brain Injury

Acceleration–Deceleration Induced Brain Injuries

Explosive forces may cause brain injury without direct impact to the head. Mechanisms of such an injury may be due to: (1) shock waves to the brain emanating from the explosion, (2) projectiles jettisoned from the explosive device causing brain trauma, (3) uncontrolled movement of the head in any direction (acceleration–deceleration), and (4) secondary damage to the brain arising from hemorrhagic shock, burns, and respiratory damage [30, 135, 153]. The first mechanism of blastinduced traumatic brain injury (bTBI) is unique and frequently occurs on the battlefield. Veterans may present with PTSD and other behavioral brain disturbances. These injuries occur most frequently following exposure to multiple explosions [7, 33, 48, 65, 71, 115, 122, 196, 214]. The mechanisms of brain damage caused by shock waves are unclear, however, it has been suggested that (1) shock waves cause an acoustic impedance mismatch that induces a shock-bubble effect in brain tissue and (2) the blast may cause increased pressure in body cavities that induce a blood surge to the brain that produces brain dysfunction [41], and (3) mitochondrial dysfunction [8]. Experimental bTBI has been studied in animals by subjecting them to a Friedlander blast wave that instigates a positive pressure wave followed immediately by a negative suction force. Rat models may consist of a “shock tube” that is closed at one end and open at the other with a shock wave generated by detonation of an explosive device or release of compressed air [29, 171, 194]. The shock wave is created by rupturing a membrane separating two compartments with different air pressures. An animal is placed in the chamber with the lower pressure and is subjected to a brief, sudden high-pressure shock wave when the membrane is punctured [171]. Rodents sustain a bTBI after the shock wave is transmitted to it. Shock waves may be produced by the release of compressed air generated by an oxygen–hydrogen combustion system or by an explosive detonation as demonstrated in several animal models: rats [108, 122, 170, 171, 173] and swine [14]. The peak and duration of the pressure wave may be measured which creates a scalable injury in these bTBI models. Severe high-pressure shock waves may kill the animal as a result of lung damage. However, this effect may be mitigated by a protective vest applied to animals [122]. Mild nonrepetitive blast injuries have replicated the behavior, cognitive, and MRI changes compatible with diffuse mild head injuries observed clinically [175]. These deficits may persist during the subacute and chronic phases following injury. Mouse bTBI models demonstrate that multiple exposures of shock waves to the

Violent repetitive shaking of the head may induce brain injury due to unsynchronized motion of the brain within the skull without skull impact or any external evidence of head trauma (Fig. 2) [160, 183]. Shaken baby syndrome (SBS) refers to abusive shaking of a child’s trunk that is often overlooked because of the lack of scalp trauma [183]. Neck muscles of infants and children are weak and unable to limit acceleration– deceleration or rotational movement of the head [160]. Although SBS is usually observed in children less than 2 years of age, it has been reported in older and heavier children up to 7 years old [178]. This injury is caused by the brain striking the internal bony surfaces of the skull. SBS usually causes the pathological picture of subdural, subarachnoid and retinal hemorrhages, and encephalopathy that may result in impairment of vision as well as motor and cognitive function [191]. A similar injury is frequently observed in adults caused by unanticipated flexion–extension movement of the unrestrained head when protective effects of neck muscles are overcome by major forces occurring in motor vehicle accidents (whiplash injury) [68]. Short-term effects of brain injury consist of behavioral regression, whereas long-term effects include mental health disorders and chronic neuropsychiatric complaints throughout life [24]. Models of TBI caused by acceleration–deceleration injuries have been developed to investigate mechanisms of brain damage and measures of biomarkers [174]. Models of TBI caused by acceleration–deceleration injuries have been developed to investigate mechanisms of brain damage producing effects that can be seen immediately or long term. Sudden deceleration of the head in monkeys creates a whiplash-like injury that produces brain damage similar to that seen in humans [106, 132, 157]. Rats subjected to rotational acceleration–deceleration head motion in a sagittal rotational direction (≤30° in 0.4 ms) caused significant brain injury [45, 211], transient impairment in walking and memory, and elevation of several serum biomarkers (neurofilament heavy chain, Tau, S100B, and myelin basic protein) at 1, 3, and 13 days postinjury [174]. Inertial forces required to create brain damage by acceleration–deceleration and rotational forces are dependent on a combination of brain mass and acceleration vectors. The brain of the adult mouse is approximately 1/3,000 the weight and 1/30 the radius of the human brain and, therefore, the production of a brain injury in the mouse is more difficult to create than in larger animals. The severity of the brain injury caused

Transl. Stroke Res. Fig. 2 Coup and contrecoup injuries in humans are caused by either a lateral (top left) or frontal (top right) head impact. The brain beneath the initial impact site is contused (large arrow) along with contusion of the contralateral side (small arrow). Inertial forces develop during head acceleration–deceleration injuries that cause remote (contralateral) damage in humans. The greater the volume of the brain, the greater the inertial forces will be. In mice (lower two figures), tiny volumes of brain in a flat-shaped skull are surrounded by thick muscles (arrows) that buffer lateral injury forces. The skull vertex, the site most frequently used for mouse TBI, is not covered by a thick muscle

by head acceleration–deceleration depends on the direction, amplitude, and velocity of the applied forces [82]. Mouse models of SBS have been developed in which anesthetized pups were shaken for 15 s on a horizontally rotating shaker at a frequency of 900 cycles/min [18, 19]. Hemorrhagic lesions of the brain were observed at postnatal day 13 (PN-13), with cysts developing gradually between PN-15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter by PN-31 [18]. This model mimicked several aspects of human SBS and provided evidence that the release of glutamate played a role in its pathophysiology [18]. Repeat head shaking or flexion–extension rotational acceleration also increased levels of oxidative stress markers in the brain [156]. Acute subdural hematomas (aSDH) are common causes of death in humans following head injury, reaching 16–40 % in different series [79, 112, 176, 198]. Alesandri et al. developed a rat model of an a SDH that consisted of 300 microL blood injected into the subdural space [5]. Their study demonstrated a peak of TUNEL-positive cells indicating the presence of apoptosis processes and that caspase-dependent mechanisms play a major role in lesion development [5]. A mouse model of SDH has also been developed by the injection of nonheparinized blood into the subdural space with the magnitude of injury modulated by injecting different volumes of blood [179]. Sasaki and Dunn reported that this mouse model provided a method of investigating the effects of genotype on the brain’s response to acute SDH [179]. Epidural hematomas (EDH) may complicate acute head injury in humans. EDH is often associated with skull fractures and bleeding from meningeal arteries or venous sinuses into the epidural space. Survival depends on expeditious clot

evacuation, and mortality increases with associated intracranial pathology such as aSDH, cerebral contusion, or DAI [113]. To date, no mouse model of EDH has been developed.

Penetrating Traumatic Brain Injuries These injuries are customarily caused by high-velocity projectiles (shrapnel) or low-velocity objects (bone fragments) that impale the brain. Tissue damage and clinical manifestations depend on the anatomical path and degree of energy transfer [217]. High-speed objects such as bullets create greater tissue damage due to shock waves that destroy adjacent tissue than those caused by the direct laceration [151, 216, 217]. Open head injury models have been developed in rats to replicate tissue destruction caused by high energy penetrating objects in the brain [215, 218]. The progression of a nonfatal injury with a unilateral frontal penetrating traumatic brain injuries (pTBI), including the frontal cortex and striatum, showed that the volume of brain damage in the mouse increased over a course of 7 days [216]. It was converted from a state of intracerebral hemorrhage (0–6 h), to a core area of necrosis, infiltration of neutrophils, and macrophages, to degeneration of neurons and fiber tracts (thalamus, internal and external capsule, and cerebral peduncle) remote from the core lesion (3–7 days) [216]. Replicating heat-based TBI caused by high kinetic energy such as that produced by high-velocity penetrating objects is not feasible in mice because of the small volume of the brain. The use of slow penetrating objects caused by blast or projectiles in this review was not associated with heat-based damage of the brain. Penetrating injuries have also been reproduced in mice by inserting a sharp object into the

Mouse Rat

Rat

Rat

WDI

Temporal FPI (4.9±0.3 atm)

Parasagittal FPI (1.8–2.1 atm)

Moderate parasagittal FPI (1.14–2,18 atm) FPI (1.8–2.17 atm)

Hypotension and pyrexia

Gp I: 5 min forebrain ischemia. Gp II: 60 min forebrain ischemia. Gp III: TBI. Gp IV: TBI followed by 15 min ischemia. Alcohol consumption

Swine

Rat

Mouse Mouse Rat

Rat

Rat Rat

Mouse

FPI (3 atm)

Mild lateral CCI (3 m/s, 2.5 mm deformation)

CCI

CCI

Major TBI using the modified Richmond impact acceleration model Impact acceleration/TBI

TBI

Mild mechanical injury

TBI

Hemorrhagic hypotension (2 ml/100 g caused mBP=35–40 for 90 min. Resuscitated by (1) LR, (2) Hestend, and (3) PNPH

Forebrain ischemia

Effect of CCI model and hemorrhagic shock (90 min) CCI and hemorrhagic shock (HS)

Hemorrhagic hypotension (30 mg Hg) rescucitated to baseline for >60 mins. 2 gps studied: 1) tap water through G-tube, 2) ethanol (4 g/kg) through G-tube Bilateral CAO produced 1 h after CCI

Swine

Rat

Hemorrhagic hypotension (60 mmHg for 30 min) induced 5 min after FPI Rats subjected to FPI when anesthetized followed by 30 min normoxic or hypoxic states Rats subjected to FPI when anesthetized followed by 30 min normoxic or hypoxic states Cocaine administration IV 10 min (4 mg/kg) and 1 min (2 mg/kg) prior to injury

Hypoxia 30 min

Hypoxia (PaO2 =40 Hg for 30 min)

Effect of TBI and hypoxia (9 % oxygen)

Complication studied

Parasagittal FPI (1.94–2.18 atm) FPI (3 atm)

Rat

Animal

Type of brain injury

Table 5 Models used to study different types of brain injuries

TBI and ischemia separately produced identical ion dysfunction (increased [K+]e and decreased [Na+]e. Secondary ischemia (Gp IV) sustained ion dysfunction and increased ICP Alcohol produced a decrease in [Na+]serum 24 h postinjury producing edema Extensive EEG spike activity and delayed return of EEG+EP. Extensive bilateral CA1 and subarticular cell loss in hippocampus in combined TBI and ischemic group (but not either alone) PNPH and Hextend required less volume to resuscitate than RL. PNPH improved mBP and Hextend and LR did not. Fewer dying neurons in CA1 in mice treated with PNPH vs. LR and Hextend.

Bilateral CAO alone produced no cortical or hippocampal damage. 1–3 m/s CCI caused no detectible cortical contusion and minimal HC neuronal loss. 5 m/s caused small cortical contusion. 1, 3, and 5 m/s CCI followed by bilat CAO produced increased contusion volume an increased neuronal loss in HC Hemorrhagic shock exacerbated PI ischemia in mediating secondary injury in CCI Increased functional deficits and neuropath changes when CCI/HS combined compared to the effect on either alone No evidence of worsening of brain damage when studied pathologically at 4.5 h postinjury

Neuronal apoptosis inhibitor protein increased the vulnerability of brain cells to hypoxia Increased morbidity; weakness 71 % greater with hypoxia+TBI vs. 29 % with impact alone vs. 0 % weakness with hypoxia alone (24 h postinjury) Post-traumatic hypoxia increases contusion volume compared to normoxic rats. Post-traumatic hypothermia followed by slow rewarming (120 m) significantly decreases contusion volume Hypotension increased area and total volume of contusion compared with normotensive FPI rats Rats under hypoxic state had increased SM deficits and cognitive impairments 3 days FPI rats killed. Hypoxic rats had increased cortical contusion volumes and increased damage to HC (CA1 and CA2). No significant difference in CPP & CBF in cocaine treated vs. control groups. Nonsignificant trend to decrease ICP in group administered cocaine (1) Hemorrhage volume greater; (2) resuscitation requirements higher; (3) metabolic parameters worse; (4) survival time decreased in ethanol compared with tap water-infused group

Results

[58]

[91]

[96]

[192]

[109]

[81]

[62]

[36]

[224]

[141]

[22]

[22]

[137]

[137]

[89]

[146]

Reference

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FPI fluid percussion injury, SDH subdural hematoma, CCI controlled cortical injury, HC hippocampus, PI postinjury, RL Ringer’s lactate, PNPH Polynitroxylated pegylated hemoglobin, SM sensorimotor, TBI traumatic brain injury

[180] Gp I: ASDH. Gp II: ASDH and DBI (?). Gp III: ASDH and DBI and hypoxia Rat Acute SDH and impact acceleration model

[88] Mouse TBI and intracerebral hemorrhage (ICH)

TBI

Mouse

[118]

[73]

Hypoxia after TBI produces increased inflammatory response and severity of secondary brain injury Treatment with propranolol increased CPP and decreased cerebral hypoxia Statins increase functional outcome, decrease neuronal degeneration, increase preserved neuronal density, and downregulate inflammatory gene expression Early evacuation of ASDH caused no change in edema at 5 h PI. Gp II: early evacuation caused decreased ICP and brain water content. Gp III: Progressive increased ICP, decreased CBF, and severe brain swelling. Early evacuation of ASDH increased brain edema. Hypoxic environment vs. normal O2 for 5 h after TBI Treatment with propranolol (beta blocking agent) vs. placebo after TBI TI and ICH treated with statins Mouse Blast TBI

Reference Results Complication studied Animal Type of brain injury

Table 5 (continued)

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brain [76, 165]. In the latter series, the authors developed a nonfatal model of pTBI based on a modified air rifle that accelerated a pellet which impacted a small probe causing a penetrating injury of the rodent brain. They characterized brain tissue destruction and subsequent behavior models to examine the neurological function and impairment of memory function [165]. Stab wounds produced by driving a sharp instrument through a 4×2 mm midline craniotomy are unable to replicate the ballistic effects that transpire during a bTBI in rats [6, 57]. Mouse models of high-velocity missile PBI have not been developed, however, several examples of stab wounds into the cerebral cortex in mice have been reported during studies of glial scar formation [84]. Studies on the blood–brain barrier disruption and angiogenesis in urokinase-type plasminogen activators have also been conducted [97].

Combined Traumatic Brain Injuries TBI models that combine multiple types of head injuries and associated comorbidities (hemorrhage, hypoxia, multiple organ trauma) replicate the complex clinical picture of several pathological events such as DAI, cerebral contusion, and intracerebral hemorrhage observed in humans. Use of such a variety of models will increase our understanding of numerous deleterious factors that contribute to the clinical course following TBI. Most combination TBI models were developed in rats and swine (Table 5) [22, 36, 70, 89, 91, 96, 109, 137, 141, 180, 184, 192, 224]. Many behavioral, neuropathological, and immunological studies have been performed using CCI, WDI, and FPI models combined with known damaging effects following trauma (Table 5).

Limitations of Mouse Models in Replicating Clinical TBI Human TBI has been replicated in several mouse models using multiple forces including shock waves, FP, or cortical contusion. Even under forces of similar parameters, the type of brain injuries in humans and mice differ in several respects. Differences in Size and Shape of the Brain Between Humans and Mice Although mice and humans share many similarities in brain structure and function, differences in size and shape of the skull result in significant obstacles in creating mice models that mimic human TBI [208]. The mouse brain lies within an oblong skull and has inherent anatomical differences from the human that causes brain injuries in different locations. TBI in humans is usually caused by forces striking the frontal, occipital, or temporal areas of the skull. Contrarily, forces producing experimental TBI in mice are usually applied to the skull

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vertex. Coup and contrecoup injuries occur frequently in humans following head injuries in which a cerebral contusion occurs directly beneath the impact site as well as contralaterally (Fig. 2). Most mice models of TBI do not reproduce this type of injury. Kilbourne et al. created an injury model in rats by creating a frontal impact injury with lateral rotation that did not produce skull fractures, prolonged apnea, or death [100]. However, petechial hemorrhage and DAI affected the orbitofrontal cortex (coup), corpus callosum, caudate, putamen, thalamus, cerebellum, and brainstem. Neurobehavioral dysfunction lasted for more than 1 week. They concluded that this frontal sagittal rotation acceleration injury produces diffuse injuries that may be relevant to human brain injury [100]. Difficulty in Comparing the Behavior Status in Mice and Humans Quantitative evaluation of neurological and behavioral deficits following clinical TBI is crucial in assessing the severity of brain injury, clinical recovery, and the effect of putative therapies. Functional deficits following human TBI are assessed by the evaluation of cognition and speech, alteration in social skills, depression, anxiety, personality changes, and motor/sensory abnormalities. Humans who sustain TBI may demonstrate measurable long-term neurological disabilities that impair daily activities [28]. These disabilities may include deficits in visual selective attention and decreased attention

function that may recover beyond 1 year postinjury [13]. Deficits in attention, nonverbal fluency, and verbal memory as well as slower visual and tactile reaction times may occur [136]. Evaluation of these psychological and neurological parameters depends on the patient’s verbal communication skills, which are unable to be performed in mice. Studies in rats have also demonstrated that multiple subacute mild head injuries using a FP device cause immediate transient impairment of spatial recognition. As the number of concussions increases from 1 to 3, a greater number of trials are required to return to baseline function using the Morris water maze [49]. By contrast, impairment is less obvious, and neurological recovery is more rapid and complete in mice. The open-field locomotor test using the Basso Mouse Scale measures hindlimb function following SCI but is not a sensitive motor behavioral assay following TBI in mice [12]. Evaluation of gait in mice following CCI-TBI has been performed using a computer-assisted automated gait analysis system. Neumann reported that the area of paw contact was decreased and that relative paw placement between fore- and hindpaw was altered, suggesting that TBI affected sensorimotor function and reduced interlimb coordination [154]. Sensitive evaluation tools or challenge tests are used to assess neurological dysfunction in rodents. The Rotarod or beam-walking tests detect motor dysfunction, and the whisker nuisance task detects somatosensory impairment [110, 144]. Cognitive skills in mice may be assessed using attention deficit testing, reduction in novelty exploration, and observation of hyperactivity/

Table 6 Rodent assessment tools used to mimic human cognitive, sensorimotor, and psychiatric function

Cognitive and sensorimotor function

Humans

Mice

Shortened attention span Memory difficulties Problem solving difficulties Learning difficulties Poor judgment Language deficits Inability to understand abstract concepts Loss of reading and writing skills Motor/Sensory dysfunction

Morris water maze; swimming T-maze/passive avoidance test; multivariate concentric square field test; forced swimming test [23, 38, 55, 64, 77, 123, 130, 148, 202, 205, 225]

Post-traumatic epilepsy

Psychiatric deficits

Changes in sexual function Sleep problems Inability to empathize with others Tendency to be more self-centered Inability to control emotions; increased irritability, frustration, aggressive behavior, depression, and mood swings

N/A N/A N/A Rotarod test, adhesive removal test, motor recovery score, wire grip score (grip strength), footprint, cylinder test, beam-walking task [20, 38, 63, 127, 140, 159, 163, 219, 228], whisker nuisance task [110, 144, 154] Electrically induced convulsions, seizure activity assessed by EEG [37, 80, 99, 104] N/A N/A N/A N/A Forced swimming [182, 226], tail suspension test, elevated plus-maze test [43, 164, 182], and ultrasonic vocalization [128]

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hypoactivity (Table 6). A unique composite behavioral score index from individual complimentary behavioral tests in mice provided excellent discrimination across mild, moderate, and severe injuries compared to individual tests [223]. Nevertheless, without effective verbal communication, it is difficult to measure high-level cerebral function in mice [164]. Behavior and affective functioning may be assessed using ultrasonic vocalization in rats. Vocalization in ultrasonic frequencies expresses emotional states with high frequency calls (50 kHz) associated with a positive effect and low frequency calls (22 kHz) representing a negative emotional state [128]. The functional status of mice after TBI may be evaluated using the Neurological Severity Score which includes ten tasks that predict motor dysfunction, cognitive damage, and neurobehavioral function [205]. However, mice that were exposed to a very low intensity blast-induced brain injury demonstrate cognitive, behavioral, and MRI changes compatible with diffuse mild brain injury [175].

Conclusions Current mouse models replicate several biomechanical forces seen in human TBI and produce several pathological changes such as hemorrhage, necrosis, axon damage, scar formation, and alterations in behavior. There is a need to develop more models of mouse TBI that more effectively mimic human TBI. The use of mouse models is highly desirable because of the availability of genetically modified strains. Loss-offunction or gain-of-function mutations will provide the ability to create inexpensive models to purchase and maintain and, most importantly, will provide insight into mechanisms of TBI. Gene modifications may affect injury outcomes including fatality rates. The selection of injury models/injury parameters using transgenic mice must be carefully chosen to meet desired behavioral or pathological outcomes. However, animal models, including those in mice, will not completely replicate TBI in humans because trauma is produced by many biomechanical forces that are not easily replicated in animals. Animals are able to receive biomechanically controlled TBI in the laboratory whereas humans are not [158]. Furthermore, effective treatments for TBI in one animal model does not guarantee efficacy in another model due to variable responses in different species, sexes, ages, and weights [133, 139].

Conflict of Interest Yi Ping Zhang declares that he has no conflict of interest. Jun Cai declares that he has no conflict of interest. Lisa B.E. Shields declares that she has no conflict of interest. Naikui Liu declares that he has no conflict of interest. Xiao-Ming Xu declares that he has no conflict of interest. Christopher B. Shields declares that he has ownership in the Louisville Impactor System, Inc.

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