Yoo Judy J, Serafin Elizabeth K, Kofron J Matthew, Baccei Mark L
Medical Scientist Training Program and Neuroscience Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
J Neurosci. 2025 Sep 11. doi: 10.1523/JNEUROSCI.1197-25.2025.
Neonatal injury alters synaptic transmission in the spinal superficial dorsal horn (SDH), resulting in aberrant amplification of ascending nociceptive transmission. Astrocytes orchestrate synapse development and function across the CNS and play a critical role in the emergence and maintenance of persistent pain. However, little is currently known about the postnatal development of spinal astrocytes, nor about how the maturation of SDH astrocytes is impacted by early life injury. Here, we used a hindpaw incision model of postsurgical pain in postnatal day (P)3 mice of both sexes to elucidate the effects of neonatal injury on the maturation of SDH astrocytes. Three-dimensional morphological analysis of individual astrocytes revealed that incision elicits age-dependent changes to astrocyte structure. At P4, spinal astrocytes in incised mice show increased size and complexity compared to naïve controls. This is reversed at P10 and P24, as astrocytes from incised mice are smaller and less ramified compared to their naïve counterparts. Transcriptomic analysis of spinal astrocytes revealed acute changes to gene expression after neonatal injury, as 76 differentially expressed genes (DEGs) were identified at P4 (such as , , , , and ), which included genes related to cell motility and cytoskeletal organization, but very few DEGs were detected at P10 and P24. Lastly, we identified that microglial engulfment of astrocyte material occurs in the developing dorsal horn, and that this process is altered by neonatal incision in a sex-dependent manner. These data illustrate, for the first time, that neonatal injury alters the postnatal development of spinal astrocytes. Neonatal tissue damage persistently remodels synaptic circuits in the spinal superficial dorsal horn (SDH), which has been implicated in the ability of early life injury to "prime" developing nociceptive pathways. While astrocytes clearly regulate synapse formation, pruning and function across the CNS, nothing is known about the degree to which neonatal injury modulates the properties of astrocytes within the developing SDH. The present study demonstrates that neonatal hindpaw incision evokes age-dependent transcriptional and morphological plasticity in spinal astrocytes, highlighted by a prolonged reduction in the size and complexity of astrocytes following early life injury. These findings yield new insight into the cellular mechanisms by which neonatal tissue damage can exert long-term effects on spinal nociceptive processing.
新生儿损伤会改变脊髓浅表背角（SDH）的突触传递，导致上行伤害性感受传递异常增强。星形胶质细胞在整个中枢神经系统中协调突触的发育和功能，在持续性疼痛的产生和维持中起关键作用。然而，目前对于脊髓星形胶质细胞的出生后发育，以及早期生活损伤如何影响SDH星形胶质细胞的成熟知之甚少。在此，我们利用出生后第3天（P3）的雌雄小鼠后爪切口手术疼痛模型，来阐明新生儿损伤对SDH星形胶质细胞成熟的影响。对单个星形胶质细胞的三维形态分析显示，切口引发了星形胶质细胞结构的年龄依赖性变化。在P4时，与未处理的对照组相比，切口小鼠的脊髓星形胶质细胞体积增大且复杂性增加。在P10和P24时这种情况则相反，因为与未处理的对应细胞相比，切口小鼠的星形胶质细胞更小且分支更少。对脊髓星形胶质细胞的转录组分析显示，新生儿损伤后基因表达发生急性变化，在P4时鉴定出76个差异表达基因（DEG）（如 、 、 、 、 和 ），其中包括与细胞运动和细胞骨架组织相关的基因，但在P10和P24时检测到的DEG很少。最后，我们发现在发育中的背角存在小胶质细胞对星形胶质细胞物质的吞噬作用，并且这个过程会因新生儿切口而以性别依赖的方式改变。这些数据首次表明，新生儿损伤会改变脊髓星形胶质细胞的出生后发育。新生儿组织损伤持续重塑脊髓浅表背角（SDH）中的突触回路，这与早期生活损伤 “启动” 发育中的伤害性感受通路的能力有关。虽然星形胶质细胞显然在整个中枢神经系统中调节突触形成、修剪和功能，但对于新生儿损伤在何种程度上调节发育中的SDH内星形胶质细胞的特性却一无所知。本研究表明，新生儿后爪切口会在脊髓星形胶质细胞中引发年龄依赖性的转录和形态可塑性，其特点是早期生活损伤后星形胶质细胞的大小和复杂性长期降低。这些发现为新生儿组织损伤对脊髓伤害性感受处理产生长期影响的细胞机制提供了新的见解。
