The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.

Elucidation of structure–function relationships in the nervous system necessitates biological circuit control with genetic and temporal precision. Here the authors engineer a genetically encoded magnetically sensitive actuator, “Magneto,” and remotely manipulate behavior in live zebrafish and mice. The magnetogenetic control over neural activity promises greater access to previously intractable tissues. Optogenetic and chemogenetic actuators are critical for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or slow on/off kinetics. We have overcome these disadvantages by synthesizing a single-component, magnetically sensitive actuator, “Magneto,” comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin. We validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together our results present Magneto as an actuator capable of remotely controlling circuits associated with complex animal behaviors.

Single-cell analysis of CNS interactions: Despite their importance in the physiology and pathology of the central nervous system (CNS), few methods are available for the unbiased, systematic investigation of cell-to-cell interactions at single-cell resolution. Clark et al. developed RABID-seq, a method that combines barcoded viral tracing with single-cell RNA sequencing (see the Perspective by Silvin and Ginhoux). RABID-seq identified the axon guidance molecules Sema4D-PlexinB2 and EphrinB3-EphB3 as mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis and, potentially, multiple sclerosis. These studies also identified candidate therapeutic molecules for the modulation of microglia-astrocyte interactions in multiple sclerosis. Science , this issue p. eabf1230 ; see also p. 342