Microglial functional alteration and increased diversity in the challenged brain: Insights into novel targets for intervention

Microglia are the resident immune cells of the central nervous system (CNS) parenchyma, which perform beneficial physiological roles across life. These immune cells actively maintain CNS health by clearing toxic debris and removing dysfunctional or degenerating cells. They also modify the wiring of neuronal circuits, by acting on the formation, modification, and elimination of synapses—the connections between neurons. Microglia furthermore recently emerged as highly diverse cells comprising several structural and functional states, indicating a far more critical involvement in orchestrating brain development, plasticity, behaviour, and cognition. Various environmental factors, together with the individual genetic predispositions, confer an increased risk for neurodevelopmental and neuropsychiatric disorders, as well as neurodegenerative diseases that include autism spectrum disorders, schizophrenia, major depressive disorder, and Alzheimer's disease, across life. Microglia are highly sensitive to chronic psychological stress, inadequate diet, viral/bacterial infection, pollution, and insufficient or altered sleep, especially during critical developmental periods, but also throughout life. These environmental challenges can compromise microglial physiological functions, resulting notably in defective neuronal circuit wiring, altered brain functional connectivity, and the onset of behavioral deficits into adolescence, adulthood, and aging. This short review provides a historical and technical perspective, notably focused on my contribution to the field, on how environmental challenges affect microglia, particularly their physiological functions, and increase their diversity, which provides novel targets for intervention.