An investigation into regional dependant microglial gene expression and function in the control of hippocampal neural stem and progenitor cell regulation

Adair, Emily 2022. An investigation into regional dependant microglial gene expression and function in the control of hippocampal neural stem and progenitor cell regulation. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Hippocampal neurogenesis is defined as the addition of new neurons to hippocampal circuitry and occurs continuously throughout adult life. What regulates this neurogenic phenomenon within the dentate gyrus (DG) of the hippocampus remains unclear. Previously, our group has suggested a role for microglia, showing the addition of hippocampal microglia to neural progenitor cells (NPC) has a positive neurogenic effect. Furthermore, recent studies have highlighted distinct regional transcriptional phenotypes of microglia, suggesting selective local functionality. I hypothesised that microglia possess differential neurogenic properties between distinct brain regions, which is underpinned by differential gene expression. Firstly, I investigated functional, regional-dependant, differential neurogenic properties of microglia in vitro via the addition of microglia or their conditioned media (CM) from separate brain regions, including the DG, rest of the hippocampus (RH) and cortex, to rat postnatal hippocampal NPC’s cultures. This was assessed using immunocytochemistry and fluorescent microscopy, inspecting markers of the cell cycle, neuronal stem cells and immature neurons. Culture experiments revealed, the addition of microglia or their CM selectively increased NPC, but did not increase neuronal populations. This was consistent across all groups and as a result specialist phenotype of microglia are suspected to be lost during in vitro culture. Secondly, differential gene expression from acutely isolated microglia from mouse DG, RH and cortex was investigated using bulk RNA-sequencing. Significant differential gene expression was observed between microglia isolated from the DG and RH. Furthermore, GO enrichment analysis identified terms of interest including neurogenesis and neuron differentiation. In conclusion, DG microglia show significant differential gene expression compared to RH microglia which may contribute to a functional, regional specific, neurogenic microglial phenotype within the DG. Genes identified here may represent good biological targets to undergo further investigation to prevent and/or slow down hippocampal neurogenesis dysregulation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	3 January 2023
Last Modified:	23 Dec 2023 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/155270

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