BACKGROUND Older-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI. METHODS Our approach examined astrocytes in young adult, 4-month-old, versus aged, 18-month-old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: (1) tissue histology and morphological phenotyping, and (2) transcriptomics on enriched astrocytes from the injured brain. RESULTS Aging was found to have a profound effect on the TBI-induced loss of astrocyte function needed for maintaining water transport and edema-namely, aquaporin-4. The aged brain also demonstrated a progressive exacerbation of astrogliosis as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. Transcriptomic data demonstrated disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with the previously defined "A1/A2" dichotomy of reactive astrogliosis. CONCLUSIONS Overall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.

中文翻译：

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高龄对小鼠急性创伤性脑损伤星形胶质细胞特异性反应的影响。

背景技术 老年人因创伤性脑损伤 (TBI) 导致残疾的风险最高。星形胶质细胞是大脑中数量最多的胶质细胞，是大脑功能所必需的，但对于 TBI 后老年大脑中星形胶质细胞的独特反应知之甚少。方法 我们的方法在 TBI 后 1、3 和 7 天检查了 4 个月大的年轻成年小鼠与 18 个月大的老年小鼠的星形胶质细胞。我们选择这些时间点来跨越从急性损伤到可能不可逆的组织损伤和残疾过渡的关键时期。有两种方法用于通过年龄相互作用来定义星形胶质细胞对 TBI 的贡献：(1) 组织组织学和形态表型分析，以及 (2) 来自受伤大脑的富集星形胶质细胞的转录组学。结果发现老化对TBI诱导的维持水运输和水肿所需的星形胶质细胞功能丧失（即水通道蛋白4）具有深远的影响。老化的大脑还表现出星形胶质细胞增生的进行性恶化，这是受伤后时间的函数。此外，人们发现在老年大脑中，一种未被充分认识的星形胶质细胞增生症（clasmatodendrosis）显着增加，而在年轻大脑中则没有。作为 TBI 的函数，我们观察到这些星形胶质细胞数量的短暂折射，在老年大脑中受伤 7 天后反弹。转录组学数据表明，与年轻小鼠相比，TBI 后老年小鼠的反应性星形胶质细胞、炎症反应、补体途径和突触支持的基因发生了不成比例的变化。此外，我们的数据强调，TBI 并未引起与先前定义的反应性星形胶质细胞增生的“A1/A2”二分法的明确对齐。结论 总体而言，我们的研究结果表明 TBI 后老年星形胶质细胞出现渐进性表型，我们假设这种表型是适应不良的，这为可能导致老年大脑对创伤的脆弱性增加的潜在可改变的星形胶质细胞特异性机制提供了新的见解。