Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Center to Advance Chronic Pain Research, University of Maryland, Baltimore, MD 21201, USA.
Brain Behav Immun. 2022 Mar;101:1-22. doi: 10.1016/j.bbi.2021.12.017. Epub 2021 Dec 23.
Whereas human spinal cord injury (SCI) is more common in men, the prevalence is growing in women. However, little is known about the effect of biological sex on brain dysfunction and injury mechanisms. To model the highest per capita rate of injury (ages between 16 and 30 years old) in humans, in the present study, young adult or a young/middle-aged male and female C57BL/6 mice were subjected to moderate contusion SCI. When mice were injured at 10-12-week-old, transcriptomic analysis of inflammation-related genes and flow cytometry revealed a more aggressive neuroinflammatory profile in male than females following 3 d SCI, ostensibly driven by sex-specific changes myeloid cell function rather than cell number. Female mice were generally more active at baseline, as evidenced by greater distance traveled in the open field. After SCI, female mice had more favorable locomotor function than male animals. At 13 weeks post-injury, male mice showed poor performance in cognitive and depressive-like behavioral tests, while injured female mice showed fewer deficits in these tasks. However, when injured at 6 months old followed by 8 months post-injury, male mice had considerably less inflammatory activation compared with female animals despite having similar or worse outcomes in affective, cognitive, and motor tasks. Collectively, these findings indicate that sex differences in functional outcome after SCI are associated with the age at onset of injury, as well as disrupted neuroinflammation not only at the site of injury but also in remote brain regions. Thus, biological sex should be considered when designing new therapeutic agents.
虽然人类脊髓损伤（SCI）在男性中更为常见，但女性的发病率正在上升。然而，人们对生物性别对大脑功能障碍和损伤机制的影响知之甚少。为了模拟人类最高的人均损伤率（16 至 30 岁之间），在本研究中，年轻成年或年轻/中年雄性和雌性 C57BL/6 小鼠接受中度挫伤性 SCI。当小鼠在 10-12 周龄时受伤时，炎症相关基因的转录组分析和流式细胞术显示，雄性小鼠在 3 天后的 SCI 后表现出比雌性小鼠更具攻击性的神经炎症特征，这显然是由特定于性别的髓样细胞功能变化驱动的，而不是细胞数量的变化。雌性小鼠通常在基线时更活跃，这表现在旷场中的行进距离更大。SCI 后，雌性小鼠的运动功能比雄性动物更有利。在损伤后 13 周，雄性小鼠在认知和抑郁样行为测试中表现出较差的表现，而受伤的雌性小鼠在这些任务中表现出较少的缺陷。然而，当在 6 个月大时受伤，然后在 8 个月大时受伤时，尽管在情感、认知和运动任务中出现相似或更差的结果，但雄性小鼠的炎症激活程度明显低于雌性动物。总的来说，这些发现表明，SCI 后功能结果的性别差异与损伤起始年龄以及不仅在损伤部位而且在远程脑区的神经炎症失调有关。因此，在设计新的治疗剂时应考虑生物学性别。
