(A) Schematic of rIFN-β administration into WT mice via bilateral intracerebroventricular (i.c.v.) stereotaxic injection. (B) Transcriptional analysis of ISGs, microglial markers, and cytokines in cortical tissue of mice 36 hours after vehicle (n = 6 mice) or rIFN-β (n = 5 mice) injection. (C) Representative confocal images of CD68 and 3D skeletonization of Iba1⁺ microglia from hippocampi (CA1) of vehicle- and rIFN-β–injected mice. Scale bar: 10 μm. Total dendrite length of microglia (n = 135–192 cells from 5–6 mice/treatment) and CD68⁺ occupancy (percentage of Iba1⁺ cell volume; n = 5–6 mice/treatment) is quantified. Additional analysis is shown in Supplemental Figure 15. (D) Left: Representative confocal images of Stat1, Iba1, and PU.1 on brain tissues from vehicle- and rIFN-β–injected mice. Insets show Stat1 single-channel images of areas within dashed squares, with PU.1⁺ nuclear areas outlined. Stat1 occupancy within PU.1⁺ nuclei is quantified (n = 3 mice/treatment). Right: Representative images of Iba1 and Clec7a in treated mice (n = 5–6 mice/treatment). Scale bars: 10 μm. (E) Representative high-magnification confocal images of CA1 dendritic spines and quantification of spine density in Thy1-eGFP mice that received bilateral i.c.v. administration of vehicle (n = 44 dendrites from 2 mice) or rIFN-β (n = 73 dendrites from 3 mice) for 36 hours. Scale bar: 1 μm. (F) Representative high-magnification confocal images of pre- and postsynaptic terminals labeled by synaptophysin (Syp) and PSD95, respectively, in hippocampi (CA1) of vehicle- and rIFN-β–injected mice. Scale bar: 2 μm. Quantification of puncta density for both synaptic compartments, and of degree of colocalization between the 2 markers; n = 5–6 mice/treatment. For all panels, data are presented as mean ± SEM, or median and quartiles (dendrite length). *P < 0.05, **P < 0.01, ***P < 0.001 by 2-sided t tests.