Our research focus is primarily on the diverse roles of microglia, the immune resident cells of the central nervous system. Microglia emerged since 2005 and especially 2010 as key players in brain development, maturation, function, plasticity, and integrity, across contexts of health and disease, sexes, and stages of life. In 2016, our ultrastructural analyses defined the dark microglia (DM), a state strikingly different from the other ones described so far. DM are distinguished by their unique combination of cellular stress markers: condensation of cytoplasm and nucleoplasm (giving them a dark appearance), mitochondrial alteration, endoplasmic reticulum and Golgi apparatus dilation, and loss of microglial heterochromatin patterning. Rare in healthy young adult mice, DM become prevalent upon exposure to maternal immune activation (using the viral mimic Poly I:C or a Western diet), chronic stress, loss of fractalkine signaling between neurons and microglia, aging, Huntington’s and Alzheimer’s disease pathology, where they reach 40% of the microglial population. These findings support the view that “multitasking” microglia constitute a diverse population, composed of subtypes each exerting specialized functions.
While the biological relevance of transcriptionally-defined disease-associated microglial subtypes remains largely elusive, we recently identified a set of common features between these cells and DM. Moreover, we made significant advances in our understanding of DM’s metabolic state and functional relationships within the brain. DM’s ensheathment of the vasculature, satellite positions onto neurons and other glial cells, and extensive interactions with synapses–phagocytic and non-phagocytic–lead us to propose that DM play crucial roles in vascular and synaptic remodeling. Furthermore, DM uniquely display a high prevalence of glycogen granules indicating a metabolic difference compared to the other microglia. Our work is currently investigating how DM’s actions could be initially beneficial (e.g., during development), but become detrimental in contexts of stress-induced plasticity, aging and diseases. Innovative therapies targeting DM and their effector functions hold the potential to preserve cognitive functions upon exposure to various challenges throughout life.