Microglial dynamics in the healthy adult and ageing brain

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.

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Identifiers

ORCID for Diego Gomez-Nicola: orcid.org/0000-0002-5316-2682

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