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Permanent link (DOI): https://doi.org/10.7939/R3MG89

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Determining factors in the differential activation of microglia Open Access

Descriptions

Other title
Subject/Keyword
ATP
hypoxia
neuroinflammation
neuroscience
microglia
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Lai, Aaron
Supervisor and department
Todd, Kathryn (Neuroscience/Psychiatry)
Examining committee member and department
Power, Christopher (Neuroscience/Medical Microbiology & Immunology)
Julien, Jean-Pierre (Centre de recherche du CHUL, Quebec)
Baker, Glen (Neuroscience/Psychiatry)
Kerr, Bradley (Neuroscience/Anesthesiology & Pain Medicine)
Kar, Satyabrata (Neuroscience/Medicine)
Department
Centre for Neuroscience
Specialization

Date accepted
2010-04-07T15:10:43Z
Graduation date
2010-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Microglia, the resident immune cells of the central nervous system (CNS), become activated in response to danger signals given out by other cells when homeostasis has been disturbed. Microglial activation is a multifaceted phenomenon that includes numerous distinct phenotypes. The type of activation often influences the survival of surrounding CNS tissue, and thus gaining a better understanding of how microglial activation is regulated has important therapeutic implications. Currently, it is known that the phenotype of activated microglia depends on both the type of CNS insult and the specific activating agent. The aim of this thesis was to investigate the potential involvement of other determining factors. Extrinsic regulators of microglial activation, including the severity of CNS insult and the stimulation strength of activating agents, were examined. Intrinsic differences among different microglial populations, namely differences in region of origin and age of origin, were also investigated. To study microglial behavior without interference from other cells, rat primary cultures were used as the system of study. With regard to extrinsic factors, it was found that different severities of hypoxic neuronal injury induced distinct microglial phenotypes. Among the activating agents released by injured neurons, adenosine 5’-triphosphate (ATP) was studied in isolation and was found to induce trophic and toxic effectors in microglia depending on the strength of ATP stimulation. In regards to intrinsic factors, it was found that microglia derived from different regions of the brain had distinct responses to activators, with cortical and hippocampal microglia generating more toxic responses than brainstem, striatal, and thalamic microglia. Microglia derived from various ages of origin also responded differentially to activators, with neonatal and aged microglia being more reactive than microglia derived from other age groups. Together, the results here present several novel concepts, that the phenotype of activated microglia are dependent not only on the type of activating stimulus, but the strength of that stimulus, and that in addition to stimuli from other cells, the regional and age differences among microglia themselves are also crucial in determining their activation phenotype.
Language
English
DOI
doi:10.7939/R3MG89
Rights
License granted by Aaron Lai (aylai@ualberta.ca) on 2010-04-01T22:14:35Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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