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Early life injury alters spinal astrocyte development

ABSTRACT: Neonatal injury alters synaptic transmission and plasticity 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 have been shown to play a critical role in the emergence and maintenance of persistent pain. However, very 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 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 demonstrated that injury-evoked changes to astrocyte gene expression occur acutely. We found 76 differentially expressed genes (DEGs) at P4, many of which are related to cell motility and cytoskeletal organization (Thbs1, Efemp1, Acta1, Acta2, Tpm2, Fgf14) but very few DEGs at P10 and P24. Lastly, we identified that microglial engulfment of astrocytes occurs in the developing dorsal horn, and that this process is altered by neonatal injury in a sex-dependent manner. These data illustrate, for the first time, that neonatal injury alters the postnatal development of spinal astrocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE289540 | GEO | 2025/09/02

REPOSITORIES: GEO

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Project description:Purpose: Mounting evidence suggests that the spinal dorsal horn (SDH) contains multiple subpopulations of inhibitory interneurons that play distinct roles in somatosensory processing, as exemplified by the importance of spinal dynorphin-expressing neurons for the suppression of mechanical pain and chemical itch. While it is clear that GABAergic transmission in the SDH undergoes significant alterations during early postnatal development, little is known about the maturation of discrete inhibitory “microcircuits” within the region. As a result, the goal of the present study was to elucidate the gene expression profile of spinal dynorphin (pDyn)-lineage neurons throughout life. Methods: We isolated nuclear RNA specifically from pDyn-lineage SDH interneurons at postnatal days 7, 21, and 80 using the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) technique in conjunction with Fluorescence-activated Nuclei Sorting (FANS), followed by RNAseq analysis. Results: Over 650 genes were ≥2-fold enriched in adult pDyn nuclei compared to non-pDyn spinal cord nuclei, including targets with known relevance to pain such as galanin (Gal), prepronociceptin (Pnoc), and nitric oxide synthase 1 (Nos1). In addition, the gene encoding a membrane-bound guanylate cyclase, Gucy2d, was identified as a novel and highly selective marker of the pDyn population within the SDH. Differential gene expression analysis comparing pDyn nuclei across the three ages revealed sets of genes that were significantly upregulated (such as Cartpt encoding cocaine- and amphetamine-regulated transcript peptide) or downregulated (including Npbwr1 encoding the receptor for neuropeptides B/W) during postnatal development. Conclusions: Our study represents the first detailed analysis of retinal transcriptomes, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within a cell or tissue. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic functions.

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Early life injury alters spinal astrocyte development

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