Adolescent M-CSF Administration Provides Durable Protection Against Trauma-Induced PTSD-Like Phenotypes in Male Mice...

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition for which effective preventive strategies are lacking. Innate immune preconditioning has shown promise for the prevention of PTSD, yet the transient nature of such protection when induced in adulthood poses a substantial limitation. Using male C57BL/6J mice, we tested whether administration of macrophage colony-stimulating factor (M-CSF, 100 µg/kg, intraperitoneally) during adolescence, a developmental period characterized by heightened microglial plasticity, could establish enduring resilience against trauma-induced PTSD-like behaviors. Mice received a single M-CSF injection at postnatal day 28 (PND28) and were subsequently subjected to single prolonged stress (SPS/FS) at 4, 16, or 32 weeks thereafter, with behavioral and molecular assessments conducted at PND70, PND154, and PND266, respectively. Our results showed that adolescent M-CSF exposure substantially prevented SPS/FS-induced anxiety-like behaviors assessed by the elevated plus maze and open field test, and SPS/FS-induced fear-like behaviors evaluated by contextual and cued fear conditioning tests, at all three post-administration intervals. Concurrently, M-CSF pretreatment prevented SPS/FS-induced interleukin-1β (Il-1β), Il-6, and tumor necrosis factor-α (Tnf-α) mRNA expression within the hippocampus and medial prefrontal cortex across all time points examined. These protective phenotypes were eliminated when microglial function was pharmacologically inhibited or when microglia were depleted before M-CSF administration, establishing that microglial integrity at the time of adolescent immune challenge is required for the establishment of long-term resilience. Taken together, these findings demonstrate that a single developmental immune intervention confers lifelong protection against SPS/FS-induced PTSD-like behaviors through microglia-dependent mechanisms, introducing a vaccine-like paradigm for the prevention of PTSD.