Neuroinflammatory alterations in post traumatic stress disorder and chronic traumatic encephalopathy
OA Version
Citation
Abstract
Post-traumatic stress disorder (PTSD) is a psychiatric disorder affecting up to 25% of people exposed to a traumatic event and characterized by maladaptive anxiety with increased risk for suicide and cognitive impairment. In rodent models of PTSD, microglia-mediated synaptic loss is a significant contributing factor to anxiety behaviors. Human studies of individuals with PTSD report reduced activity in the frontal lobes and an increased risk for inflammatory disorders with elevated T-cell activity and cytokine levels in the blood. However, little is known about the neuroinflammatory changes in human PTSD brains. Our studies show that brain donors pathologically diagnosed with chronic traumatic encephalopathy (CTE) have an increased incidence of antemortem PTSD. CTE is a neurodegenerative tauopathy that heavily impacts the frontal lobes, but there is a significant gap in knowledge of how comorbid CTE may affect neuroinflammation in PTSD. We hypothesize that neuroinflammation increases cortical synaptic loss in individuals with PTSD and subsequent anxiety symptoms. We also hypothesize that comorbid CTE exacerbates these changes with distinct immune signaling. To address our hypotheses, we applied histological and genomic analysis on the frontal cortex of postmortem tissue from controls, PTSD subjects, individuals with comorbid PTSD and CTE (PTSD+CTE), and those with CTE only. Here, we 1) define synapse loss and microglia reactivity, 2) quantify central nervous system T-cell infiltration and its role in pathology, and 3) characterize single-cell signatures of immune cells in PTSD and CTE. We found that cortical synaptic loss is a feature of both PTSD and CTE and correlates with clinical symptoms. In all disease groups, infiltration of activated T-cells was elevated in areas of synaptic loss and were spatially in contact with microglia. Among individuals diagnosed with PTSD, we found an overall decrease of microglia, but single-cell analyses revealed upregulated expression of neuron surveying and complement-mediated phagocytosis genes, indicating close monitoring and pruning of synapses. Moreover, interferon cytokine signaling was noted between T-cells and microglia, further suggesting that activated T-cells likely promote pathology via interactions with microglia.Additionally, the presence of p-tau in comorbid PTSD+CTE individuals shifted immune responses to more cytotoxic and inflammatory phenotypes. Notably, we found upregulation of unique cytokine signaling, hypoxic responses, and cellular stress pathways in individuals with PTSD+CTE. Our findings suggest that immune cell dysfunction may drive synaptic loss in PTSD, and accumulation of tau pathology in comorbid conditions triggers complex responses that may require tailored treatment strategies.
Description
2027
License
Attribution-NonCommercial-NoDerivatives 4.0 International