Repetitive Mild Traumatic Brain Injury Alters Glymphatic Clearance Rates in Limbic Structures of Adolescent Female Rats

Jennaya Christensen,Richelle Mychasiuk,David K Wright,Sandy R Shultz,Glenn R Yamakawa

doi:10.1038/s41598-020-63022-7

Jennaya Christensen, Richelle Mychasiuk + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-63022-7

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Abstract

The glymphatic system is the macroscopic waste clearance system for the central nervous system. Glymphatic dysfunction has been linked to several neurological conditions, including traumatic brain injury (TBI). Adolescents are at particularly high risk for experiencing a TBI, particularly mild TBI (mTBI) and repetitive mTBI (RmTBI); however, glymphatic clearance, and how it relates to behavioral outcomes, has not been investigated in this context. Therefore, this study examined glymphatic function in the adolescent brain following RmTBI. Female adolescent Sprague Dawley rats were subjected to either three mTBIs or sham injuries spaced three days apart. One-day after their final injury, the animals underwent a beam walking task to assess sensorimotor function, and contrast-enhanced MRI to visualize glymphatic clearance rate. Behavioural measures indicated that the RmTBI group displayed an increase in loss of consciousness as well as motor coordination and balance deficits consistent with our previous studies. The contrast-enhanced MRI results indicated that the female adolescent glymphatic system responds to RmTBI in a region-specific manner, wherein an increased influx but reduced efflux was observed throughout limbic structures (hypothalamus, hippocampus, and amygdala) and the olfactory bulb but neither the influx or efflux were altered in the cortical structures (primary motor cortex, insular cortex, and dorsolateral prefrontal cortex) examined. This may indicate a role for an impaired and/or inefficient glymphatic system in the limbic structures and cortical structures, respectively, in the development of post-concussive symptomology during adolescence.

Highlights

The glymphatic system relies on three specialized pathways; para-arterial cerebrospinal fluid (CSF), paravenous ISF, and the intracellular trans-astrocytic pathway[4]
Given that repetitive mTBI (RmTBI) is associated with neurodegenerative disorders in which tau and amyloid-β protein aggregates are pathological trademarks, it seems possible that RmTBI causes impairment of the glymphatic system, which may play a key role in the development of the behavioural and neurological deficits associated with RmTBI
With regards to time-to-right, animals in the RmTBI group required significantly more time to regain consciousness compared to the sham animals, which is consistent with the literature[26,31,32]

Summary

Introduction

The glymphatic system relies on three specialized pathways; para-arterial cerebrospinal fluid (CSF), paravenous ISF, and the intracellular trans-astrocytic pathway[4]. The aquaporin-4 (AQP4) water channels found on astrocytic end feet are believed to be play an critical role in the exchange of CSF and ISF5. These interstitial proteins and solutes are degraded by the liver, which circumvents the requirement for local protein processing and degradation in the CNS4. An animal model of moderate TBI has been shown to impair glymphatic clearance function and incite accumulation of phosphorylated tau[5], suggesting that glymphatic dysfunction plays a key role in the development of TBI-related neuropathology and neurological deficits. We hypothesized that RmTBI would impair the glymphatic system, producing reductions in the glymphatic clearance rate of RmTBI animals in comparison to controls

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