During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.

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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.