Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Medical Scholars Program, University of Illinois College of Medicine at Urbana-Champaign, Urbana, IL, USA.
Biol Sex Differ. 2020 Mar 30;11(1):13. doi: 10.1186/s13293-020-00288-6.
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.
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.
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.
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 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.
虽然创伤后应激障碍（PTSD）的定义是最直接与大脑功能相关的行为/认知症状，但它可以被认为是一种系统性障碍，其特征是创伤后明显无法恢复体内平衡。
在这项研究中，我们对 PTSD 相关组织（即血液、杏仁核和海马体）的大鼠 PTSD 模型中的基因表达谱进行了二次分析，以确定与对近期创伤暴露的反应个体差异相关的性别特异性和共享过程。
我们的研究结果表明，在海马体、杏仁核和血液中，与创伤易感性和弹性相关的个体差异存在共同和性别特异性机制。通过从转录变化中分离细胞组成，我们发现 PTSD 样、极端行为反应（EBR）组中，海马体中的少突胶质细胞比例更高，对于两性均如此，并且还发现了与海马体中与组差异（即对创伤的反应）相关的转录活性模块，这些模块似乎具有性别特异性。相比之下，我们发现杏仁核的细胞组成存在显著的性别差异，但没有组差异，并且在杏仁核中发现了与 PTSD 相关的转录活性的共享和性别特异性模块。在杏仁核和海马体中，性别特异性和共享过程都与 EBR 的总体框架有关，该框架涉及 TNFα/NFκΒ 信号传导的破坏和兴奋性/抑制性失衡，这对失调的突触/结构可塑性中的恐惧学习和记忆具有重要意义。我们在外周血中的主要发现与人类文献一致，并且在两性的抗逆、最小行为反应（MBR）组中发现伤口愈合过程和止血过程上调，但在 EBR 组中以性别二态的方式受到破坏。
与 PTSD 样 EBR 组的多样化特征形成对比的是，MBR 组在血液、杏仁核和海马体中的特征在于两性之间共享的上调的伤口愈合和细胞外基质（ECM）重塑。总的来说，我们在 PTSD 样 EBR 和抗逆 MBR 之间的海马体中发现了不同的少突胶质细胞比例，并确定了特征化 EBR 和 MBR 相关转录变化的过程和途径，这些变化发生在海马体、杏仁核和血液中。EBR 涉及的性别特异性机制可能导致 PTSD 风险的明显差异，女性更有可能患上 PTSD。
