The University of Southampton
University of Southampton Institutional Repository

Microglial dynamics in the healthy adult and ageing brain

Microglial dynamics in the healthy adult and ageing brain
Microglial dynamics in the healthy adult and ageing brain
Microglia, the resident macrophages of the brain, have many crucial functions in central nervous system (CNS) development, homeostasis and function, ranging from control of inflammation in disease to monitoring synaptic activity. Despite this, there are many aspects of basic microglial physiology that remain poorly defined in the healthy CNS, including the mechanisms regulating microglial turnover in the steady state. It is now widely accepted that the adult microglial population is produced from yolk sac-derived erythromyeloid progenitor cells (EMPs) that seed the developing brain and persist into adulthood. It has been suggested that the adult microglial population is long-lived and maintained by self-renewal; however the precise mechanisms regulating this are unknown. Furthermore, it remains unclear whether infiltrating monocytes contribute to the microglial population in the healthy developing, adult and ageing brain.

Complementary techniques were used to determine the relative contributions of microglial self-renewal and monocyte infiltration to the resident population in the mouse. Intra-liver labelling of embryonic haematopoiesis allowed analysis of the contribution of infiltrating monocytes to the brain during the perinatal period, whilst Ccr2-/- mice, with deficient populations of circulating monocytes, were used to investigate monocyte infiltration in the adult brain. Pulse-chase experiments with 5-bromo-2’-deoxyuridine (BrdU) and use of apoptosis-deficient mouse models enabled the study of microglial self-renewal, including establishing the time course of microglial proliferation under steady state conditions. Finally, analysis of the microglial population in the Vav-Bcl-2 mouse, a specific model of apoptotic blockade, allowed investigation the impact of disrupted microglial turnover on their phenotype and function.

We demonstrate that circulating monocytes transiently infiltrate the brain during perinatal stages, however these do not contribute to the adult microglial population. Microglial density remains stable from early postnatal stages through to ageing, with a limited contribution from circulating monocytes. The microglial population self-renews, maintained by a balance of proliferation and apoptosis. Furthermore, we show that adult microglia have a faster proliferation rate than previously described, allowing the whole population to be renewed several times during a lifetime. Finally, we show that disruption of microglial apoptosis results in significantly increased microglial density throughout the brain, peaking during the early postnatal stages and persisting throughout adulthood. Elevated microglial density is associated with a reduction in the territory size of individual cells and reduction in their proliferation rate. Whilst blockade of apoptosis alters the microglial transcriptomic profile, it does not impact their ability to respond to a systemic inflammatory challenge, althoughsome aspects of this inflammatory response are altered. The work in this thesis contributes to our understanding of microglial dynamics under steady state conditions, revealing a more dynamic scenario that opens new avenues into understanding their roles in the maintenance of brain homeostasis.
University of Southampton
Askew, Katharine Elizabeth
ffc96fb4-f94c-4cb7-8479-e9f0b2dae0c7
Askew, Katharine Elizabeth
ffc96fb4-f94c-4cb7-8479-e9f0b2dae0c7
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5

Askew, Katharine Elizabeth (2018) Microglial dynamics in the healthy adult and ageing brain. University of Southampton, Doctoral Thesis, 365pp.

Record type: Thesis (Doctoral)

Abstract

Microglia, the resident macrophages of the brain, have many crucial functions in central nervous system (CNS) development, homeostasis and function, ranging from control of inflammation in disease to monitoring synaptic activity. Despite this, there are many aspects of basic microglial physiology that remain poorly defined in the healthy CNS, including the mechanisms regulating microglial turnover in the steady state. It is now widely accepted that the adult microglial population is produced from yolk sac-derived erythromyeloid progenitor cells (EMPs) that seed the developing brain and persist into adulthood. It has been suggested that the adult microglial population is long-lived and maintained by self-renewal; however the precise mechanisms regulating this are unknown. Furthermore, it remains unclear whether infiltrating monocytes contribute to the microglial population in the healthy developing, adult and ageing brain.

Complementary techniques were used to determine the relative contributions of microglial self-renewal and monocyte infiltration to the resident population in the mouse. Intra-liver labelling of embryonic haematopoiesis allowed analysis of the contribution of infiltrating monocytes to the brain during the perinatal period, whilst Ccr2-/- mice, with deficient populations of circulating monocytes, were used to investigate monocyte infiltration in the adult brain. Pulse-chase experiments with 5-bromo-2’-deoxyuridine (BrdU) and use of apoptosis-deficient mouse models enabled the study of microglial self-renewal, including establishing the time course of microglial proliferation under steady state conditions. Finally, analysis of the microglial population in the Vav-Bcl-2 mouse, a specific model of apoptotic blockade, allowed investigation the impact of disrupted microglial turnover on their phenotype and function.

We demonstrate that circulating monocytes transiently infiltrate the brain during perinatal stages, however these do not contribute to the adult microglial population. Microglial density remains stable from early postnatal stages through to ageing, with a limited contribution from circulating monocytes. The microglial population self-renews, maintained by a balance of proliferation and apoptosis. Furthermore, we show that adult microglia have a faster proliferation rate than previously described, allowing the whole population to be renewed several times during a lifetime. Finally, we show that disruption of microglial apoptosis results in significantly increased microglial density throughout the brain, peaking during the early postnatal stages and persisting throughout adulthood. Elevated microglial density is associated with a reduction in the territory size of individual cells and reduction in their proliferation rate. Whilst blockade of apoptosis alters the microglial transcriptomic profile, it does not impact their ability to respond to a systemic inflammatory challenge, althoughsome aspects of this inflammatory response are altered. The work in this thesis contributes to our understanding of microglial dynamics under steady state conditions, revealing a more dynamic scenario that opens new avenues into understanding their roles in the maintenance of brain homeostasis.

Text
Katie Askew Thesis Final - Version of Record
Available under License University of Southampton Thesis Licence.
Download (135MB)

More information

Published date: 31 October 2018

Identifiers

Local EPrints ID: 428657
URI: http://eprints.soton.ac.uk/id/eprint/428657
PURE UUID: bd302321-af78-449f-a52e-ba30f7594dc9
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

Catalogue record

Date deposited: 05 Mar 2019 17:30
Last modified: 28 Jan 2020 05:01

Export record

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×