Three weeks of sleep fragmentation activates microglia specifically in hippocampus but not striatum or prefrontal cortex. Sleep fragmentation increases CRH, CRHR1, and CRHR2 levels in hippocampus. CRH upregulates pro-inflammatory cytokines il1β, il6, tnfα, and ccl2 in primary microglia and BV2 cells. CRH increases galectin-3 protein levels and puncta formation indicating lysosomal damage in microglia. CRH boosts LC3BII, beclin1, and SQSTM1 levels causing autophagy dysregulation in microglia. CRH triggers cathepsin B leakage from lysosomes into cytoplasm in microglia. CRHR2 antagonist As-2B blocks CRH effects on galectin-3, CD11b, and cathepsin B in microglia. Sleep fragmentation elevates galectin-3, LC3BII, and cathepsin B in hippocampal tissue. Hippocampal microglia show co-localization of galectin-3 and Iba1 after sleep fragmentation. Sleep fragmentation raises peripheral inflammation in liver and spleen but minimally in gut. Microglia activation precedes astrocyte changes in hippocampus during sleep fragmentation. CRH system upregulation correlates directly with hippocampal microglial activation. Targeting hippocampal CRH system blocks sleep fragmentation-induced neuroinflammation. Sleep fragmentation increases CD11b but not GFAP in hippocampus. Purified hippocampal microglia from sleep-fragmented mice show 2-3 fold rises in cytokines.