Abstract
BackgroundWhile post-traumatic stress disorder (PTSD) is defined by behavioral/cognitive symptoms most directly relevant to brain function, it can be considered a systemic disorder characterized by a distinct inability to reinstate homeostasis after trauma.MethodsIn this study, we conducted a secondary analysis of gene expression profiles in key PTSD-relevant tissues, namely blood, amygdala, and hippocampus, from a rat model of PTSD, to identify sex-specific and shared processes associated with individual differences in response to recent trauma exposure.ResultsOur findings suggest both shared and sex-specific mechanisms underlying individual differences associated with vulnerability and resilience to trauma in hippocampus, amygdala, and blood. By disentangling cell composition from transcriptional changes, we found higher proportions of hippocampal oligodendrocytes in the PTSD-like, extreme behavioral response (EBR) group for both sexes and also identified modules for transcriptional activity associated with group differences (i.e., response to trauma) in the hippocampus that appeared to be sex-specific. By contrast, we found prominent sex differences, but no group differences, in amygdalar cell composition, and both shared and sex-specific modules representing PTSD-relevant transcriptional activity in the amygdala. Across amygdala and hippocampus, both sex-specific and shared processes were relevant to an overarching framework for EBR implicating disrupted TNFα/NFκΒ signaling and excitatory/inhibitory imbalance in dysregulated synaptic/structural plasticity with important implications for fear learning and memory. Our main finding in peripheral blood was consistent with the human literature and identified wound healing processes and hemostasis to be upregulated in the resilient, minimal behavioral response (MBR) group across sexes, but disrupted in a sexually dimorphic manner in the EBR group.ConclusionIn contrast to the varied characterization of the PTSD-like EBR group, characterization of MBR across blood, amygdala, and hippocampus suggests a common theme of upregulated wound healing and extracellular matrix (ECM) remodeling shared between sexes. In all, we identified differential oligodendrocyte proportions in hippocampus between PTSD-like EBR and resilient MBR, and identified processes and pathways that characterize the EBR and MBR-associated transcriptional changes across hippocampus, amygdala, and blood. The sex-specific mechanisms involved in EBR may contribute to the pronounced disparity in risk for PTSD, with women much more likely to develop PTSD.
Highlights
Identification of robust peripheral markers for posttraumatic stress disorder (PTSD) would be invaluable for developing post-traumatic stress disorder (PTSD) management strategies, especially since accessing human brain tissue is often not a viable option
Higher proportions of hippocampal oligodendrocytes observed in EBR compared to MBR and CON groups, in both sexes Non-parametric Mann-Whitney U test revealed higher median proportions of hippocampal oligodendrocytes in the extreme behavioral response (EBR; PTSD-like) group compared to the minimal behavioral response (MBR; resilient) group in both sexes, Z = − 2.78, Holm-adj p = 0.024, r = 0.66 (Fig. 1)
While the module was not significantly enriched for GO terms, in the curated chemical and genetic perturbation gene set collection (C2 CGP) from the MSigDB database, the top hit enriched in this EBR–MBR module was for oligodendrocyte markers
Summary
Identification of robust peripheral markers for posttraumatic stress disorder (PTSD) would be invaluable for developing PTSD management strategies, especially since accessing human brain tissue is often not a viable option. Systemic inflammation may underlie the pathophysiology of PTSD, as well as the consistent link between PTSD and chronic medical conditions associated with aging, such as cardiovascular, metabolic, autoimmune, and neurodegenerative diseases [4,5,6,7,8], and other markers of accelerated aging [6, 7, 9,10,11,12,13,14] This dysregulated inflammatory state is itself partially coordinated by maladaptive alterations of hypothalamic-pituitary adrenal (HPA) axis activity and sympathetic nervous system (SNS) sensitivity/responsivity [15, 16], which affect both peripheral immune cells in blood and neuroimmune dynamics in brain. While post-traumatic stress disorder (PTSD) is defined by behavioral/cognitive symptoms most directly relevant to brain function, it can be considered a systemic disorder characterized by a distinct inability to reinstate homeostasis after trauma
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