Abstract
BackgroundAlteration of immune status in the central nervous system (CNS) has been implicated in the development of post-traumatic stress disorder (PTSD). However, the nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear.MethodsWe constructed a mouse PTSD model by electric foot-shocks followed by contextual reminders and verified the PTSD-related symptoms by behavior test (including contextual freezing test, open-field test, and elevated plus maze test). We examined the immunocyte panorama in the brains of the naïve or PTSD mice by using single-cell mass cytometry. Microglia number and morphological changes in the hippocampus, prefrontal cortex, and amygdala were analyzed by histopathological methods. The gene expression changes of those microglia were detected by quantitative real-time PCR. Genetic/pharmacological depletion of microglia or minocycline treatment before foot-shocks exposure was performed to study the role of microglia in PTSD development and progress.ResultsWe found microglia are the major brain immune cells that respond to PTSD. The number of microglia and ratio of microglia to immunocytes was significantly increased on the fifth day of foot-shock exposure. Furthermore, morphological analysis and gene expression profiling revealed temporal patterns of microglial activation in the hippocampus of the PTSD brains. Importantly, we found that genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure alleviated PTSD-associated anxiety and contextual fear.ConclusionOur results demonstrated a critical role for microglial activation in PTSD development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition.
Highlights
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops after an individual is exposed to traumatic events
Our results demonstrated a critical role for microglial activation in post-traumatic stress disorder (PTSD) development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition
Administration of sertraline, a commonly used antidepressant, significantly alleviated this fear response. Consistent with this result, in the open-field test, we found that foot-shock exposure largely reduced the time and distance of locomotion in the center area, and administration of sertraline rescued this phenomenon (Figure S1E-H). These findings indicated that the electric foot-shock model was sufficient to induce PTSD in mice
Summary
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops after an individual is exposed to traumatic events. A commonly occurring disorder, the mechanisms underlying PTSD development remain unclear. In the peripheral immune system, PTSD patients have shown higher numbers of Th1 cells and impaired function of Treg cells [3, 4]. Some proinflammatory cytokines including tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were significantly increased in the serum of PTSD patients [5, 6]. Alteration of immune status in the central nervous system (CNS) has been implicated in the development of post-traumatic stress disorder (PTSD). The nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear
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