Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes

Abstract

We have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

“…In contrast to pathological tau and TDP-43 accumulation after TBI, persistent α-synuclein and β-amyloid proteinopathy represent less consistent histopathological features after TBI [ 7 , 8 , 22 , 38 , 67 ]. Although several prior animal studies reported increased β-amyloid and α-synuclein after TBI, we did not find this present in our rTBI model [ 1 , 13 , 56 , 62 , 75 , 78 ].…”

“…This indicates that model differences could be leveraged to study the association of pathophysiological mechanisms with varying mechanics of injury [ 9 ] as well as the ability to control for possible confounders. For example, similar to other studies reporting p-Tau accumulation after murine closed-head rTBI [ 56 , 62 , 75 , 78 ] we exposed the skull for precise impact delivery to the same coordinates across animals. Yet, this is inconsistent with the clinical situation, and our systematic review showed that this approach is not critical for inducing pertinent CTE-like neuropathological features.…”

Neurite orientation dispersion and density imaging in a rodent model of acute mild traumatic brain injury

“…Since it is advantageous from an imaging perspective to use a larger brain, rats were used for the current study and the injury model was consistent with previous studies that have used closed head controlled impact to induce mTBI in rodents 34–36 . The injury model was an extension of a mouse model recently characterized by our group 37 …”

Test-retest reproducibility of in vivo magnetization transfer ratio and saturation index in mice at 9.4 Tesla

“…The sample size was chosen to reflect similar sample sizes used in other pre-clinical imaging studies. 31–34 Before scanning, anesthesia was induced by placing the animals in an induction chamber with 4 % isoflurane and an oxygen flow rate of 1.5 L/min. Following induction, isoflurane was maintained during the imaging session at 1.8 % with an oxygen flow rate of 1.5 L/min through a custom-built nose cone.…”