MICROGLIAL TNF SIGNALING IS REQUIRED FOR BEHAVIORAL AND COGNITIVE DEFICITS IN A RODENT MODEL OF POST-TRAUMATIC STRESS DISORDER

Post-traumatic stress disorder (PTSD) is a debilitating mental illness that follows trauma and leads to persistent alterations in cognition and emotional regulation. Current treatments, including SSRIs, are slow and ineffective for many patients, highlighting the need for novel therapeutic strategies. Neuroinflammation has emerged as a promising avenue for PTSD treatment.Elevated levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) have been reported in PTSD patients and rodent stress models. Our laboratory previously showed that acute stress induces a sustained increase in TNF in the ventral hippocampus, enhancing AMPA receptor–mediated glutamatergic transmission and driving anxiety-like behavior. The role of TNF in chronic stress, however, remains unclear.
Using the single prolonged stress (SPS) paradigm, a rodent PTSD model, we found persistent anxiety-like behavior and cognitive impairments lasting at least five weeks, accompanied by elevated TNF in hippocampus and frontal cortex. SPS failed to induce deficits in TNF knockout (TNFKO) , TNF receptor 1 knockout (TNFR1KO), or microglial TNF-deficient mice. Moreover, MDMA, a compound under clinical investigation for PTSD with reported anti-inflammatory effects, rescued anxiety-like behavior when administered after SPS, suggesting that modulating inflammatory signalling contributes to its efficacy. These findings identify microglial TNF as a promising therapeutic target for PTSD.