- Title
- Involvement of microglia activation in the development of CNS diseases
- Creator
- Pietrogrande, Giovanni
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Microglia are the resident immune cells within the brain, however, in the last 20 years it has become clearer that their function is more complex than ordinary macrophages and goes well beyond guarding CNS from pathogens. In fact microglia are also responsible for maintaining the homeostatic balance within the brain. Factors that can modulate this balance can be of differing natures: for instance they can include subtle and prolonged factors like hormonal changes driven by stress; alternatively they can be dramatic like an ischemic injury; or prolonged and sustained as during the processes of secondary neurodegeneration associated with stroke. During my PhD I focused my attention on all these aspects, which can be considered at the opposite poles in the spectrum of events threatening homeostasis. In this thesis I describe the current knowledge about these CNS pathologies and how they are linked to inflammation in general and microglia activation in particular. Only by analysing microglia in such different conditions it is possible to fully appreciate the different shades that characterize microglia activation, and especially how different tuning of inflammation can have very different consequences for the CNS. There is already quite an extensive literature that describes the role of microglia in chronic stress and in stroke. These studies show the pivotal importance of microglia in these pathologies and especially the importance of microglia activation as modulator of inflammation. Thus, I decided to take an innovative approach and investigate aspects that are crucial to fully understand the role of microglia but that have not been yet characterised. More specifically, in the first study I investigated the status of microglia activation in a murine model of chronic stress. Higher levels of basal inflammation correlate in a unique way with development of depression in humans but the leading mechanism is still largely uncharacterised. Using in vivo and in vitro models, I found that the extracellular matrix (ECM) is dysregulated after chronic stress and influences microglia activation. This finding makes ECM a potential key player in the development of mood disorders. The focus of the second study was the role of microglia activation in the post-acute phase after stroke, which is a leading cause of disability worldwide (1). In this context, the reports about microglia activation are mixed, since they can have both a positive and a negative influence on the outcome. Using a novel intervention, low oxygen post conditioning (LOPC), I analysed the correlation between its neuroprotective effect and microglia activation, and I validated LOPC therapeutic potential in improving motor function. In the third study, I extended my previous findings to the stroke-associated neurodegenerative event called secondary neurodegeneration (SND). SND develops in areas distal but connected to the infarct site and is characterised by progressive neuronal loss concomitant to glial activation. Microglia activation is inextricably linked to SND; however microglial involvement in SND and its contribution are still largely not understood. Using LOPC as intervention and analysing the temporal evolution of microglia activation in the site of SND, I concluded that LOPC can ameliorate neuronal loss and promote the return of microglia to a basal state in later stages. In conclusion, in this thesis I present novel observations into microglia involvement in the development of CNS pathologies and provide useful insights in the mechanism leading to microglia activation, with important implications for future research.
- Subject
- microglia; neuroscience; stroke; chronic stress; low oxygen post conditioning; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1401058
- Identifier
- uon:34863
- Rights
- Copyright 2019 Giovanni Pietrogrande
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 31 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 585 KB | Adobe Acrobat PDF | View Details Download |