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

Abstract

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to insults, positioning these cells to have profound impact on the functional integrity of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions and CNS insults 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. We demonstrate that microglia in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) exhibit unique and premature responses to aging, compared to microglia elsewhere. This is associated with pockets of VTA/SNc neuroinflammation that are likely to compromise local synaptic function as early as middle age. Surprisingly, these early aging responses of VTA and SNc microglia do not appear to be driven by systemic inflammation, local neuron death, or early responses of astrocytes to aging. Finally, CX3CR1 receptor knockout can exacerbate and microglial ablation/repopulation can suppress early VTA microglial aging; these manipulations have been shown to affect brain-wide microglial aging, and our data demonstrate that their impact is not uniform throughout the CNS. Our findings reveal a previously unappreciated regional variation in the onset and magnitude of microglial aging responses and suggest that there may be important links between local microglial aging and vulnerability of nearby neurons to functional decline and disease.