Juvenile Traumatic Brain Injury Results in Cognitive Deficits Associated with Impaired Endoplasmic Reticulum Stress and Early Tauopathy

Abstract

The leading cause of death in the juvenile population is trauma, and in particular neurotrauma. The juvenile brain response to neurotrauma is not completely understood. Endoplasmic reticulum (ER) stress has been shown to contribute to injury expansion and behavioral deficits in adult rodents and furthermore has been seen in adult postmortem human brains diagnosed with chronic traumatic encephalopathy. Whether endoplasmic reticulum stress is increased in juveniles with traumatic brain injury (TBI) is poorly delineated. We investigated this important topic using a juvenile rat controlled cortical impact (CCI) model. We proposed that ER stress would be significantly increased in juvenile rats following TBI and that this would correlate with behavioral deficits using a juvenile rat model. A juvenile rat (postnatal day 28) CCI model was used. Binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP) were measured at 4 h in the ipsilateral pericontusion cortex. Hypoxia-inducible factor (HIF)-1α was measured at 48 h and tau kinase measured at 1 week and 30 days. At 4 h following injury, BiP and CHOP (markers of ER stress) were significantly elevated in rats exposed to TBI. We also found that HIF-1α was significantly upregulated 48 h following TBI showing delayed hypoxia. The early ER stress activation was additionally asso­ciated with the activation of a known tau kinase, glycogen synthase kinase-3β (GSK-3β), by 1 week. Tau oligomers measured by R23 were significantly increased by 30 days following TBI. The biochemical changes following TBI were associated with increased impulsive-like or anti-anxiety behavior measured with the elevated plus maze, deficits in short-term memory measured with novel object recognition, and deficits in spatial memory measured with the Morris water maze in juvenile rats exposed to TBI. These results show that ER stress was increased early in juvenile rats exposed to TBI, that these rats developed tau oligomers over the course of 30 days, and that they had significant short-term and spatial memory deficits following injury.

Rebuilding Microbiome for Mitigating Traumatic Brain Injury: Importance of Restructuring the Gut-Microbiome-Brain Axis

“…Reiner and colleagues 2014 reported that Novel CB2 Inverse Agonist SMM-189 reduce motor, visual, and emotional deficits after closed-head mild traumatic brain injury mouse model via mitigation of microglial inflammatory action [ 28 ]. ER stress was found to be increased early in juvenile rats exposed to TBI and that these rats developed tau oligomers over the course of 30 days and had significant short-term and spatial memory deficits following injury [ 29 ]. Treangen and colleagues suggested that acute bacterial dysbiosis within the gut microbiome was observed after TBI post-injury in mice [ 30 ].…”

Neuroprotective Effects of the Inert Gas Argon on Experimental Traumatic Brain Injury In Vivo with the Controlled Cortical Impact Model in Mice

“…In-vivo CCI in juvenile rats leads to upregulation of binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP) as early as 4 h. After 72 h, there was increased expression of hypoxia-inducible factor (HIF)-1α. In the first case, this indicates an increased load on the endoplasmic reticulum, in the second case, a delayed onset of tissue hypoxia [ 33 ]. After an in-vivo blast-type TBI in rats, there is diffuse microvasculature damage and axonal injury with reactive gliosis, in the absence of macroscopic lesions such as brain edema.…”

Posterior Fossa Tumor Rehabilitation: An Up-to-Date Overview

“…Tau oligomers measured by R23 were significantly increased by 30 days following TBI. The biochemical changes following TBI were associated with increased impulsive-like or anti-anxiety behavior measured with the elevated plus maze, deficits in short-term memory measured with novel object recognition and deficits in spatial memory measured with the Morris water maze in juvenile rats exposed to TBI [ 20 ].…”