Seeing Inside a Concussion: The Role of Microglia in Maintaining the Blood-Brain Barrier in Repetitive Mild Traumatic Brain Injury

Concussion, or mild traumatic brain injury, is a common type of brain injury that can cause significant debilitating symptoms despite no evidence of brain damage on common diagnostic imaging modalities. Repetitive concussion has recently come into focus in the public eye and among scientists as there is recognition that repeated injury can lead to chronic brain damage and neurologic impairment. There are currently no treatments or therapies available for concussion. The cellular events occurring in the brain parenchyma following concussion, especially repetitive concussion, are not well known. Neuroinflammation is one of the pathophysiologic mechanisms that is felt to play an important role in secondary mechanisms of injury in traumatic brain injury. Microglia are the resident immune cells of the brain; we hypothesize that they play a crucial role in the pathophysiology of concussion. Therefore, we sought to develop a murine model of repetitive concussion in order to study the neuroimmune response. Using intravital microscopy, we observe microglia to become progressively activated with repetitive injury. Activated microglia phagocytose dysfunctional astrocytes following repetitive concussion. Additionally, microglia rapidly seal areas of blood-brain barrier disruption. This process is dependent on purinergic pathways and microglial scavenger receptors. We also performed single-cell analysis to further dissect whether there exist separate populations of microglia that perform distinct roles following repetitive brain injury. Our results demonstrate that microglia play a critical protective role following concussion, but in doing so, alter the brain milieu. This thesis provides new insight into the response of microglia and astrocytes following repetitive mild traumatic brain injury. Understanding the neuroinflammatory mechanisms that occur following concussion will ultimately guide successful translation of therapeutic treatments.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Medical Sciences

Grantor

Cumming School of Medicine

Year dc:date.issued

2022

Author dc:creator

• Nguyen, Rita H

Advisor dc:contributor.advisor

• Kubes, Paul

Committee members dc:contributor.committeemember

• Gallager, Clare
• Thompson, Roger
• Yong, Wee

• traumatic brain injury
• neuroinflammation
• microglia
• astrocytes
• blood-brain barrier

Language dc:language.iso

English

DOI

https://dx.doi.org/10.11575/PRISM/dspace/41348

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/116504