Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury

Abstract

There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: -30%) and external capsule (EC: -21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (-17%) and EC (-13%), corresponding to histopathological evidence of white matter loss (cl-CC: -68%; cl-EC: -30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration.

Frontal brain injury chronically impairs timing behavior in rats

“…Multiple regions have been implicated, however timing at intervals on the order of multiple seconds, is strongly linked to the frontal cortex and its motor output via the basal ganglia [37, 38]. Given the ongoing and progressive nature of brain damage, these circuits and their white matter connections may continue to degrade over time [39]. While this was not addressed in the current study, investigation of these pathological changes and associated behavioral aberrations at later time points would be of great benefit.…”

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

“…In a mouse hippocampal lesion model, depletion of microglia by 30-day treatment with a CSF1R inhibitor, PLX3397, improved functional recovery and reduced pro-inflammatory gene expression in hippocampus (Rice et al, 2015). Despite evidence that chronic evolving microglial activation is detrimental following moderate-severe TBI (Byrnes et al, 2012;Loane et al, 2014;Pischiutta et al, 2018), prolonged inhibition of microglia is unlikely to be therapeutic because microglia perform critical functions such as synaptic pruning and restoration of tissue homeostasis after pathological insult (Salter and Stevens, 2017).…”

Role of misfolded tau in the onset and progression of brain toxicity after trauma

“…Male B6.129S4(Cg)-Mapt tm1(EGFP)Klt /J, referred to as tau knock-out (KO) mice, were from Jackson Laboratory (#029219, USA) 36 Mouse model of TBI. The controlled cortical impact brain injury mouse model used in this study replicates both the mechanical forces and the main secondary injury processes observed in severe TBI patients with brain contusion and gives clinically-relevant behavioral and histopathological outcomes 14,37 . WT and tau KO mice were anesthetized by isoflurane inhalation (induction 3%; maintenance 1.5%) in an N2O/O2 (70%/30%) mixture and placed in a stereotaxic frame.…”