时机很重要：重复爆炸轻度创伤性脑损伤后炎症和行为结果的性别差异。
Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury.
机构信息
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, USA; Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
出版信息
Brain Behav Immun. 2023 May;110:222-236. doi: 10.1016/j.bbi.2023.03.003. Epub 2023 Mar 10.
BACKGROUND
Repetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction at multiple timepoints.
METHODS
In this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. At the one-month timepoint, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms.
RESULTS
Repetitive blast exposure resulted in both similar (e.g., increased IL-6), and disparate (e.g., IL-10 increase only in females) patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited adverse behavioral outcomes that lasted at least one-month.
DISCUSSION
Representing a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.
背景
随着 2016 年以来女性在具有爆炸物暴露风险的军事岗位上服役的增加，由接触高能炸药引起的重复性爆炸相关轻度创伤性脑损伤（mTBI）在作战人员和普通民众中越来越常见。尽管女性在具有爆炸物暴露风险的军事岗位上服役的情况有所增加，但在爆炸性 mTBI 模型中，将性别作为生物学变量进行研究的文献报道很少，这极大地限制了诊断和治疗能力。因此，在这里我们研究了重复性爆炸创伤对雌性和雄性小鼠的影响，并在多个时间点检查了潜在的行为、炎症、微生物组和血管功能障碍。
方法
在这项研究中，我们利用一种成熟的爆炸超压模型，对雌性和雄性小鼠进行了重复性（3 次）爆炸 mTBI。在重复暴露后，我们测量了血清和大脑细胞因子水平、血脑屏障（BBB）破坏、粪便微生物丰度以及在开阔场试验中的运动和焦虑样行为。在一个月的时间点，我们在雌性和雄性小鼠中评估了具有爆炸性 mTBI 病史的退伍军人常报告的 mTBI 和 PTSD 相关症状的行为相关性，使用高架零迷宫、听觉惊跳和条件性厌恶回避范式。
结果
重复性爆炸暴露导致雌性和雄性小鼠的急性血清和大脑细胞因子以及肠道微生物组发生相似（例如，IL-6 增加）和不同（例如，仅在雌性中 IL-10 增加）的变化。重复爆炸暴露后，急性 BBB 破坏在两性中均可见。虽然雌性和雄性爆炸小鼠在开阔场试验中均表现出急性运动和焦虑样缺陷，但只有雄性小鼠表现出至少持续一个月的不良行为结果。
讨论
这代表了对重复性爆炸创伤后潜在性别差异的新调查，我们的结果表明，雌性和雄性小鼠的爆炸诱导功能障碍具有独特的相似但又不同的模式，并突出了未来诊断和治疗开发的新靶点。
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