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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.

SUBMITTER: Adams C

PROVIDER: S-EPMC6160760 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Neurogliovascular dysfunction in a model of repeated traumatic brain injury.

Adams Conner C Bazzigaluppi Paolo P Beckett Tina L TL Bishay Jossana J Weisspapir Iliya I Dorr Adrienne A Mester James R JR Steinman Joe J Hirschler Lydiane L Warnking Jan M JM Barbier Emmanuel L EL McLaurin JoAnne J Sled John G JG Stefanovic Bojana B

Theranostics 20180909 17

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 neu ...[more]

PMID: 30279740

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Project description:BackgroundExo70 is a subunit of the greater exocyst complex, a collection of proteins that oversees cellular membrane addition and polarized exocytosis by acting as a tethering intermediate between the plasma membrane and newly synthesized secretory vesicles. Although Exo70 function has been implicated in several developmental events including cytokinesis and the establishment of cell polarity, its role in neuropathologies is poorly understood. On the other hand, traumatic brain injury is the result of mechanical external force including contusion, fast acceleration, and expansive waves that produce temporal or permanent cognitive damage and triggers physical and psychosocial alterations including headache, memory problems, attention deficits, difficulty thinking, mood swings, and frustration. Traumatic brain injury is a critical health problem on a global scale, constituting a major cause of deaths and disability among young adults. Trauma-related cellular damage includes redistribution of N-methyl-D-aspartate receptors outside of the synaptic compartment triggering detrimental effects to neurons. The exocyst has been related to glutamate receptor constitutive trafficking/delivery towards synapse as well. This work examines whether the exocyst complex subunit Exo70 participates in traumatic brain injury and if it is redistributed among subcellular compartments RESULTS: Our analysis shows that Exo70 expression is not altered upon injury induction. By using subcellular fractionation, we determined that Exo70 is redistributed from microsomes fraction into the synaptic compartment after brain trauma. In the synaptic compartment, we also show that the exocyst complex assembly and its interaction with GluN2B are increased. Finally, we show that the Exo70 pool that is redistributed comes from the plasma membrane.ConclusionsThe present findings position Exo70 in the group of proteins that could modulate GluN2B synaptic availability in acute neuropathology like a traumatic brain injury. By acting as a nucleator factor, Exo70 is capable of redirecting the ensembled complex into the synapse. We suggest that this redistribution is part of a compensatory mechanism by which Exo70 is able to maintain GluN2B partially on synapses. Hence, reducing the detrimental effects associated with TBI pathophysiology.

Project description:BackgroundDizziness and imbalance are common following traumatic brain injury (TBI). While these symptoms are often attributed to vestibular dysfunction, the relative contribution of peripheral vs. central mechanisms is unclear. This study investigated the prevalence of semicircular canal and otolith abnormalities in a cohort of patients with chronic TBI and symptoms of dizziness or imbalance. The relationship between vestibular, oculomotor and posturography results was further explored.MethodsClinical records of patients attending the New Zealand Dizziness and Balance Centre from January 2015 to December 2019 were reviewed for consideration in the study. Inclusion required: an age of 18-80 years, a diagnosed TBI, and vestibular assessment using three-dimensional video head impulses (vHIT), cervical and ocular vestibular-evoked myogenic potentials (c and o VEMPs, respectively) and caloric testing. Severe TBI, pre-existing vestibular diagnoses, and incomplete test results were excluded. Rates of abnormalities were determined for each test and compared with results of oculomotor function testing and postural control, measured using the sensory organization test (SOT).ResultsOf 158 reviewed records, 99 patients aged 49 ± 15 years (59 female) fulfilled criteria for inclusion in the study. The median time between the head injury and the clinical assessment was 12 (IQR 6-21) months. Abnormalities involving one or more components of the vestibular labyrinth and/or nerve divisions were identified in 33 of 99 patients (33.3%). The horizontal semicircular canal was most frequently affected (18.2%), followed by the saccule (14.1%), utricle (8.1%), posterior (7.1%) and anterior (2.0%) semicircular canals. Vestibular test abnormalities were associated with skull-base fractures, superior canal dehiscence, and focal ear trauma. Oculomotor dysfunction and postural instability were recorded in 41.1 and 75.5% of patients, respectively. Postural instability correlated with abnormal oculomotor function (p = 0.008) but not peripheral vestibular hypofunction (p = 0.336).ConclusionsDizziness and/or imbalance in chronic TBI was associated with impaired postural stability for tasks requiring high levels of use of vestibular and visual input for balance. Vestibular hypofunction identified through vHIT, VEMP and caloric testing was recorded but was less common, except when the injury involved a fractured skull-base. There was no specific pattern of end-organ or nerve involvement which characterized this group of patients.

Dataset Information

Neurogliovascular dysfunction in a model of repeated traumatic brain injury.

Publications

Neurogliovascular dysfunction in a model of repeated traumatic brain injury.

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