Sex-specific and shared expression profiles of vulnerability and resilience to trauma in brain and blood

Abstract

Background: 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. Methods: In 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. Results: Our 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. Conclusion: In 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 MBRassociated 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.

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans

“…Our work expands upon such results by detailing additional gray matter regions in which oligodendrocytes may influence behavior; specifically, we implicate oligodendrocytes and increased myelin protein histology in the hippocampus and amygdala in anxiety-like phenotypes following stress exposure. In addition, our data support and expand upon a recent study that utilized microarray gene expression data from animals exposed to acute stress, which demonstrated that hippocampal oligodendrocyte proportions are elevated in animals displaying PTSD-like behavioral responses [ 78 ]. Here, we find similar increases in oligodendrocyte density in the hippocampus of animals with high composite anxiety-like behavior scores.…”

Region-specific, maladaptive, gray matter myelination is associated with differential susceptibility to stress-induced behavior in rats and humans

“…Our work expands upon such results by detailing additional gray matter regions in which oligodendrocytes may influence behavior; specifically, we implicate oligodendrocytes and increased myelin in the hippocampus and amygdala in anxiety-like phenotypes following stress exposure. In addition, our data support and expand upon a recent study that utilized microarray gene expression data from animals exposed to acute stress, which demonstrated that hippocampal oligodendrocyte proportions are elevated in animals displaying PTSD-like behavioral responses (79). Here, we find similar increases in oligodendrocyte density in the hippocampus of animals with high composite anxiety-like behavior scores.…”

“…Habituation is, therefore, Sensitization*(-1). From the threshold phase, we averaged startle scores from the 5 presentations of each of the decibel levels (70,80,90,100, and 110 dB) to generate a startle threshold curve for each animal, and we quantified the area under the curve (AUC).…”

Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders

“…However, the study also revealed gender-dependent alterations in several signaling modules (IL-12, MAPK, wound healing, and lipid metabolism), which were associated with specific modes of trauma (Breen et al, 2018). Correspondingly, in a recent PTSD rodent model, researchers detected sex-specific transcriptional responses to trauma involving NF-kB activation (TNF-a upregulation) and dysregulated synaptic plasticity in female HPC (Kim and Uddin, 2020).…”