Green Tabitha R F, Murphy Sean M, Ortiz J Bryce, Rowe Rachel K
Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States.
Phoenix Veterans Affairs (VA) Health Care System, Phoenix, AZ, United States.
Front Neurol. 2022 Jan 17;12:804139. doi: 10.3389/fneur.2021.804139. eCollection 2021.
Few translational studies have examined how age-at-injury affects the glial response to traumatic brain injury (TBI). We hypothesized that rats injured at post-natal day (PND) 17 would exhibit a greater glial response, that would persist into early adulthood, compared to rats injured at PND35. PND17 and PND35 rats ( = 75) received a mild to moderate midline fluid percussion injury or sham surgery. In three cortical regions [peri-injury, primary somatosensory barrel field (S1BF), perirhinal], we investigated the glial response relative to age-at-injury (PND17 or PND35), time post-injury (2 hours, 1 day, 7 days, 25 days, or 43 days), and post-natal age, such that rats injured at PND17 or PND35 were compared at the same post-natal-age (e.g., PND17 + 25D post-injury = PND42; PND35 + 7D post-injury = PND42). We measured Iba1 positive microglia cells (area, perimeter) and quantified their activation status using skeletal analysis (branch length/cell, mean processes/cell, cell abundance). GFAP expression was examined using immunohistochemistry and pixel analysis. Data were analyzed using Bayesian multivariate multi-level models. Independent of age-at-injury, TBI activated microglia (shorter branches, fewer processes) in the S1BF and perirhinal cortex with more microglia in all regions compared to uninjured shams. TBI-induced microglial activation (shorter branches) was sustained in the S1BF into early adulthood (PND60). Overall, PND17 injured rats had more microglial activation in the perirhinal cortex than PND35 injured rats. Activation was not confounded by age-dependent cell size changes, and microglial cell body sizes were similar between PND17 and PND35 rats. There were no differences in astrocyte GFAP expression. Increased microglial activation in PND17 brain-injured rats suggests that TBI upregulates the glial response at discrete stages of development. Age-at-injury and aging with an injury are translationally important because experiencing a TBI at an early age may trigger an exaggerated glial response.
很少有转化研究探讨受伤时的年龄如何影响胶质细胞对创伤性脑损伤（TBI）的反应。我们假设，与出生后第35天（PND35）受伤的大鼠相比，出生后第17天（PND17）受伤的大鼠会表现出更强的胶质细胞反应，且这种反应会持续到成年早期。将75只PND17和PND35大鼠分为两组，分别接受轻度至中度的中线流体冲击伤或假手术。在三个皮质区域[损伤周边、初级体感桶状区（S1BF）、梨状周围区]，我们研究了与受伤时年龄（PND17或PND35）、受伤后时间（2小时、1天、7天、25天或43天）以及出生后年龄相关的胶质细胞反应，以便对PND17或PND35受伤的大鼠在相同出生后年龄时进行比较（例如，PND17受伤后25天 = PND42；PND35受伤后7天 = PND42）。我们测量了Iba1阳性小胶质细胞（面积、周长），并使用骨架分析（分支长度/细胞、平均突起数/细胞、细胞丰度）对其激活状态进行量化。使用免疫组织化学和像素分析检测GFAP表达。数据采用贝叶斯多变量多层次模型进行分析。与未受伤的假手术组相比，无论受伤时的年龄如何，TBI均激活了S1BF和梨状周围皮质中的小胶质细胞（分支更短、突起更少），且所有区域的小胶质细胞数量更多。TBI诱导的小胶质细胞激活（分支更短）在S1BF中持续到成年早期（PND60）。总体而言，PND17受伤的大鼠在梨状周围皮质中的小胶质细胞激活程度高于PND35受伤的大鼠。激活不受年龄依赖性细胞大小变化的影响，PND17和PND35大鼠的小胶质细胞胞体大小相似。星形胶质细胞GFAP表达无差异。PND17脑损伤大鼠中小胶质细胞激活增加表明，TBI在发育的离散阶段上调了胶质细胞反应。受伤时的年龄和受伤后的衰老在转化研究中具有重要意义，因为早年经历TBI可能会引发过度的胶质细胞反应。
