Repetitive Mild Traumatic Brain Injury in a Mouse Model Produces Learning and Memory Deficits Accompanied by Histological Changes

Abstract

Concussion or mild traumatic brain injury (mTBI) represents the most common type of brain injury. However, in contrast with moderate or severe injury, there are currently few non-invasive experimental studies that investigate the cumulative effects of repetitive mTBI using rodent models. Here we describe and compare the behavioral and pathological consequences in a mouse model of single (s-mTBI) or repetitive injury (r-mTBI, five injuries given at 48 h intervals) administered by an electromagnetic controlled impactor. Our results reveal that a single mTBI is associated with transient motor and cognitive deficits as demonstrated by rotarod and the Barnes Maze respectively, whereas r-mTBI results in more significant deficits in both paradigms. Histology revealed no overt cell loss in the hippocampus, although a reactive gliosis did emerge in hippocampal sector CA1 and in the deeper cortical layers beneath the injury site in repetitively injured animals, where evidence of focal injury also was observed in the brainstem and cerebellum. Axonal injury, manifest as amyloid precursor protein immunoreactive axonal profiles, was present in the corpus callosum of both injury groups, though more evident in the r-mTBI animals. Our data demonstrate that this mouse model of mTBI is reproducible, simple, and noninvasive, with behavioral impairment after a single injury and increasing deficits after multiple injuries accompanied by increased focal and diffuse pathology. As such, this model may serve as a suitable platform with which to explore repetitive mTBI relevant to human brain injury.

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

“…From a neuropathological perspective, the 24‐month post injury data were consistent with our observations at earlier timepoints 13, 19. Mice exposed to repetitive injury displayed evidence of ongoing microgliosis localized to the CC.…”

“…Moreover, our interinjury interval was 48 h, which is similar to our previous work,13, 19 a temporal window during which the mouse brain is known to be vulnerable to subsequent injuries21 in order to mimic human situations (combat or sports) in which additional injuries are sustained prior to full recovery from the previous injury. At the end of the procedure, each animal was removed from the stereotaxic table and allowed to recover on a heating pad and, upon becoming ambulatory, was returned to its home cage.…”

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

“…Several rodent models of rmCHI have been reported from two, three, five TBIs to 16 or 42 impacts at different intervals or frequencies. 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.…”

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

“…[4][5][6][7] After human TBI, neuropathology studies have shown evidence of inflammation and progressive white matter degeneration following just a single moderate or severe TBI, 8 with imaging studies showing evidence of persistent neuroinflammation and reduced radial diffusivity and fractional anisotropy, even after mild injury. [9][10][11] Consistent with these findings, animal studies have shown persistent inflammation and axonal damage in the corpus callosum of mice exposed to repetitive mild TBI (r-mTBI) at chronic timepoints after injury, 12,13 with white matter disruption and an increase in radial diffusivity 60 days after repetitive mild TBI in rats.…”