Multiple Episodes of Mild Traumatic Brain Injury Result in Impaired Cognitive Performance in Mice

Abstract

Objectives: Results from recent studies on animal models of concussion suggest that multiple, rather than single, episodes of mild traumatic brain injury result in impaired cognitive performance in mice. The objective of the present study was to administer multiple impacts to the heads of mice while directly measuring the force of the impacts to determine how these parameters are related to transient loss of consciousness, cognitive deficits, and potential neuropathologic effects. Methods: Seven-week-old male C57BL/6 mice were randomly assigned to experimental conditions involving three impacts (weight-drop method) to the head to induce mild traumatic brain injury or to sham control procedures. Some impacted (n ¼ 10) and sham control (n ¼ 10) mice were evaluated behaviorally and tested for spatial learning using the Morris water maze (MWM), whereas other impacted (n ¼ 10) and sham control (n ¼ 5) mice were used for histopathologic analysis. Results: The mean (6SD) force of impact was 19 (63.5) N. Impacted mice took longer to regain consciousness compared with sham control mice (p \ 0.0005). Behavioral test results showed that the groups did not differ on activity or sensorimotor tests or during cued trials in the MWM. Impacted mice exhibited impaired spatial learning performance during place trials in the MWM (p \ 0.05). Silver staining revealed a contra-coup type of injury involving ventral brain structures in contact with or in close proximity to the skull. Conclusions: This multiple-impact model, delivered within a specifiable force range, results in transient, reversible loss of consciousness, a contra-coup brain injury, and cognitive impairment. Key words: traumatic brain injury; concussion; memory; cognition; mice. ACADEMIC EMERGENCY MED-ICINE 2004; 11:809-819. It is not clear whether mild traumatic brain injury (TBI) causes demonstrable long-term cognitive impairment in humans. A number of earlier epidemiologic studies suggest that this may be the case, but the use of retrospective designs, lack of appropriate control groups, and an inability to correct for several confounding factors did not allow for a straightforward interpretation of the results. [1][2][3][4] More recently, a number of studies of athletes who have experienced a sports-related concussion suggest that symptomatology and cognitive impairment can last for one week 5 and, in some cases, up to three months. 6 Animal models have been used to study the behavioral and neuropathologic sequelae associated with TBI. [7][8][9][10] In three of these studies, in which slightly different murine models of mild TBI were used, the results suggested that mild single impacts did not produce discernible learning/memory deficits when behavioral testing was conducted more than three days after impact. [8][9][10] In contrast, multiple mild impacts have usually been found to produce significant effects on behavior, but the nature of these changes has been inconsistent across studies. For example, DeFord et al. 10 reported that multiple mild impacts ...

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…23,24,[30][31][32][33][34][35][36][37] In the present study, we chose a mouse model of rmCHI with three impacts at an interval of 24 hours, as reported previously. 5,23,24 As shown in our results, our model displayed mild brain trauma with low NSS scores and the absence of intracranial hemorrhage and convulsions. Overall the model was noninvasive, simple, and reproducible.…”

“…19 Repetitively Mild Closed Head Injury A mouse model of rmCHI was used as described previously with modification. 5,23,24 Repetitive brain injuries were induced using an electromagnetic controlled stereotaxic impact device (Impact One Stereotaxic Impactor, Leica Biosystem, Buffalo Grove, IL, USA). Mice were placed in a stereotaxic frame after intraperitoneal anesthesia with Avertin (200 mg/kg body weight).…”

Current Understanding and Experimental Approaches to the Study of Repetitive Brain Injury

“…These deficits occurred even in the absence of cell death within the cortex and hippocampus. Cognitive deficits after multiple mild TBIs (using MWM analysis) were demonstrated in a similar study using a weight drop model (Creeley et al, 2004). In a recent study, Shitaka et al (2011) used a controlled cortical impact model in mice and found that animals receiving two injuries 24 hr apart displayed MWM deficits for several weeks.…”

“…For example, what are the best inter-injury interval, or intervals, to use? Although 24 hr between injuries is the most common (and perhaps practical) interval in the laboratory (Conte et al, 2004;Creeley et al, 2004;DeFord et al, 2002;Friess et al, 2009;Kanayama et al, 1996;Laurer et al, 2001;Shitaka et al, 2011;Uryu et al, 2002;Weitbrecht & Noetzel, 1976;Yoshiyama et al, 2005), is it the most appropriate in mimicking what occurs in humans? Also, how many injuries should a researcher administer?…”

“…Based on these criteria, there were very few of these types of experiments conducted before the year 2000, with only a handful of repetitive injury studies being published (Kanayama et al, 1996;Olsson et al, 1976;Weitbrecht & Noetzel, 1976). Several additional in vivo studies of repeated injuries in rodents have now been conducted over the past decade (Allen et al, 2000;Conte et al, 2004;Creeley et al, 2004;DeFord et al, 2002;Friess et al, 2009;Huh et al, 2007;Laurer et al, 2001;Longhi et al, 2005;Raghupathi et al, 2004;Shitaka et al, 2011;Uryu et al, 2002;Yoshiyama et al, 2005). All of these repeated mild injury studies were conducted using rodent models of TBI with the exception of the studies by Friess et al (2009) and Raghupathi et al (2004), which used a pediatric model of repeated injury in pigs.…”