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

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.

Glymphatic System Dysfunction in Central Nervous System Diseases and Mood Disorders

“…Experiments have suggested that TBI can lead to the clearance of radioactive tracers from the mouse brain: the function of the glymphatic system is reduced by approximately 60% and lasts for at least 28 days ( Iliff et al, 2014 ). This dysfunction of the glymphatic system is related to the depolarization of AQP4 ( Ren et al, 2013 ; Mestre et al, 2018 ) and has a certain regional specificity ( Christensen et al, 2020 ). As the severity of TBI increases, the recovery time of the AQP4 polarization distribution is correspondingly prolonged (no recovery is observed after 28 days) ( Ren et al, 2013 ).…”

Imaging for central nervous system (CNS) interstitial fluidopathy: disorders with impaired interstitial fluid dynamics

“…This craniectomy-related dysfunction of ISF dynamics was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits [ 62 ]. A Another animal experiment by using contrast-enhanced MRI indicated that repetitive mild TBI caused an increased fluid influx to the brain tissue but reduced efflux throughout the limbic structures and olfactory bulb, but neither the influx nor efflux was altered in the cortical structures [ 63 ]. The observation of MRI in human cases of mild TBI revealed that an increased number of enlarged high-convexity perivascular space was detected on T2-weighted images compared to the controls (Fig.…”

Normalized Brain Tissue–Level Evaluation of Volumetric Changes of Youth Athletes Participating in Collision Sports

“…GM changes could be perfusion induced, 64–66 with apoptosis of cortical cells peaking only after 1 week post-injury. 67 , 68 dCSF increase could be attributed to improper waste metabolism within the glymphatic system, 69 , 70 leading to a progressive enlargement of the ventricles. The cumulative effect of these asymptomatic volumetric changes could lead to the manifestation of a more gross and recognizable symptomatic pathology.…”