February 27, 2021

Midbrain microglia exhibit early proliferative and inflammatory responses during aging that are modulated by CX3CR1 and microglial ablation and repopulation

Microglia maintain tissue health and can critically influence synaptic connectivity and function. During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to insults. In addition, risk genes for neurodegenerative disease are highly expressed by microglia. These findings argue that microglial function is likely to critically shape vulnerability or resilience of neurons during aging. We recently discovered that microglia in the ventral tegmental area (VTA) of young adult mice differ markedly from their counterparts in other brain regions. Whether this regional variation in microglia persists, diminishes, or increases during aging has not been determined. Here, we analyze microglia in several nuclei of the basal ganglia throughout the lifespan in mice and find that VTA microglia exhibit increased proliferation and production of inflammatory factors months prior to microglia in other basal ganglia nuclei. Comparable early proliferative responses were observed in the substantia nigra pars compacta where disease-vulnerable dopamine neurons reside. These proliferative and inflammatory responses of VTA microglia began as early at 13 months of age in mice and were not accompanied by substantial neuronal loss or changes in local astrocyte number. Finally, these region-specific responses of microglia to aging were enhanced by knockout of the fractalkine receptor (CX3CR1) and reduced by microglial ablation and repopulation, identifying two signaling axes by which region-specific responses of microglia to aging can be modulated. Collectively, these findings indicate that VTA and SNc microglia continue to differ from their counterparts in other basal ganglia nuclei during aging. Moreover, the early phenotypic changes in these cells result in local inflammation near dopamine neurons beginning in middle age, which may be linked to enhanced vulnerability of these neurons to functional decline and degenerative disease.

 bioRxiv Subject Collection: Neuroscience

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