Neuroinflammatory Alterations in Post-Traumatic Stress Disorder and Chronic Traumatic Encephalopathy

Abstract: Post-traumatic stress disorder (PTSD) is a psychiatric disorder affecting up to 25% of people who
have been exposed to a traumatic event characterized by maladaptive anxiety with increased risk for suicide
and cognitive impairment. In rodent models of PTSD microglia-mediated synaptic loss has been shown to be a
significant contributing factor to disease. In humans, magnetic resonance imaging illustrates reduced activity in
the frontal cortices among PTSD patients and reports indicate PTSD confers an increased risk for inflammatory
and autoimmune disorders with elevated T-cell activity and cytokine levels in the blood. However, little is known
about the neuroinflammatory changes in human PTSD brains. Moreover, our brain banks have found that
individuals pathologically diagnosed with the degenerative tauopathy, chronic traumatic encephalopathy (CTE),
have an increased incidence of antemortem PTSD. CTE is an Alzheimer’s Disease related dementia (ADRD)
that heavily impacts the frontal cortices and there is a significant gap in knowledge of how comorbid ADRD may
affect PTSD pathology. Based on previous literature we hypothesize that neuroinflammation may result in
synaptic loss in the frontal cortex leading to anxiety and memory impairment in PTSD. We also suspect that
comorbid CTE will further exacerbate these changes. To address our hypotheses, we will use the frontal cortex
of postmortem tissue from clinically confirmed cases of PTSD for histological and genomic analysis, as well as
corresponding clinical data. The role of CTE comorbidity in the development of PTSD pathologies will be
established through the inclusion of controls, PTSD subjects, individuals with comorbid PTSD and CTE
(PTSD+CTE), and those with only CTE. In Aim 1 we will define microglia-mediated synapse loss and its
association with clinical symptoms in PTSD and CTE compared to controls and PTSD+CTE via multiplex
immunofluorescence (IF) and high-resolution confocal microscopy. In Aim 2 we will quantitate CNS T-cell
infiltration and activation in PTSD and CTE compared to controls and PTSD+CTE using multiplex IF and in-situ
hybridization. In Aim 3, we will utilize single nucleus RNA sequencing, a powerful genomic technique, to
characterize inflammatory signatures of immune cells and their clinicopathological significance in PTSD and CTE
compared to controls and PTSD+CTE.

Grant Number: 5F30NS134280-02
NIH Institute/Center: NIH
Principal Investigator: Samantha Calderazzo