Determining factors in the differential activation of microglia

  • Author / Creator
    Lai, Aaron
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Todd, Kathryn (Neuroscience/Psychiatry)
  • Examining committee members and their departments
    • Baker, Glen (Neuroscience/Psychiatry)
    • Power, Christopher (Neuroscience/Medical Microbiology & Immunology)
    • Kar, Satyabrata (Neuroscience/Medicine)
    • Kerr, Bradley (Neuroscience/Anesthesiology & Pain Medicine)
    • Julien, Jean-Pierre (Centre de recherche du CHUL, Quebec)