Neurogliovascular dysfunction in a model of repeated traumatic brain injury

Abstract

Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period.Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence.Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival.Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.

DNA repair deficiency and senescence in concussed professional athletes involved in contact sports

“…In the context of TBI, markers of senescence have been shown to elevate in microglia and astrocytes following a controlled cortical impact protocol [153]. Contrary to studies showing vascular dysfunction in mTBI [2, 157], we did not see evidence of cellular senescence in endothelial cells. Furthermore, we did not specifically evaluate senescent microglia in this cohort.…”

Implantation of regenerative complexes in traumatic brain injury canine models enhances the reconstruction of neural networks and motor function recovery

“…The co-expression of CD-90 and CD-105 confirmed the long-term survival of hUCMSCs. Moreover, as representative markers of newborn neurons (DCX) and mature neurons (NeuN), the immunohistochemical results confirmed that hUCMSCs implantation enhanced regeneration of neuronal tissue under the shelter of scaffolds in CB group 40 . Indicating that collagen/silk fibroin scaffolds may create a favorable microenvironment for the survival and oriented differentiation of seed cells.…”

Optogenetic Modulation for the Treatment of Traumatic Brain Injury

“…After inducing repeated mild TBI in mice expressing ChR2, Adams et al measured neuronal function through bilateral intracranial electrophysiological recordings in response to optogenetic photostimulation. They found that this photostimulation resulted in reduced evoked neuronal response and neuronal functional deficits, in both pericontusional tissue and in tissue in the contralateral hemisphere [102]. This study thus represents the first in-situ application of optogenetic photostimulation as a tool for TBI treatment and analysis.…”