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Gray, D. T.

Publications and source records attributed to Gray, D. T..

2 recordsLinked to original sources

Dynamic changes in mitochondria support phenotypic flexibility of microglia

Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotype, we generated transgenic crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression levels of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglia phenotype and phenotypic remodeling that takes place over hours to months.

neuroscience↗

Microglia promote extracellular matrix deposition and restrict excitatory synapse numbers in the mesolimbic dopamine system during healthy aging

Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. Using ECM-optimized proteomic workflows and histological analyses, we discovered striking regional differences in ECM composition and aging-induced ECM remodeling across key basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis to identify robust relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these foundational observations implicate changing microglia-ECM-synapse interactions as a key determinant of cognitive functioning during healthy aging.

neuroscience↗