转录组分析鉴定出 C58/J 杏仁核中的少突胶质细胞和小胶质细胞存在 ASD 样表型，该表型依赖于性别和社交能力。
Transcriptome analysis identifies an ASD-Like phenotype in oligodendrocytes and microglia from C58/J amygdala that is dependent on sex and sociability.
机构信息
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27701, USA.
Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27516, USA.
出版信息
Behav Brain Funct. 2024 Jun 19;20(1):14. doi: 10.1186/s12993-024-00240-3.
BACKGROUND
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model.
METHODS
Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala.
RESULTS
C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression.
LIMITATIONS
Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic.
CONCLUSIONS
Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.
背景
自闭症谱系障碍（ASD）是一组神经发育障碍，男性发病率较高，其特征是言语/非言语交流异常、兴趣受限，可能伴有重复行为，以及社会行为障碍。本研究调查了 ASD 动物模型中导致社交能力缺陷和性别差异的大脑机制。
方法
使用 3 室社交选择测试测量 C58/J 和 C57BL/6J 小鼠的社交能力。全转录组 RNA-Seq 和 snRNA-Seq 鉴定了 C58/J 和 C57BL/6J 杏仁核中的转录变化，其中 DMRseq 用于测量杏仁核中的差异甲基化区域。
结果
C58/J 小鼠在 3 室测试中表现出不同的社交层次。转录和途径特征表明，C58/J 和 C57BL/6J 杏仁核中的免疫相关生物学过程不同。在 C58/J 与 C57BL/6J 杏仁核中鉴定到超甲基化和低甲基化基因。C58/J 杏仁核中的 snRNA-Seq 数据鉴定了少突胶质细胞和小胶质细胞内的差异转录特征，其特征是 ASD 风险基因表达增加和预测的髓鞘形成受损，且这种受损依赖于性别和社交能力。RNA 速度、基因调控网络和细胞通讯分析显示少突胶质细胞/小胶质细胞分化减少。使用全转录组 RNA-Seq 进行了验证，并证明了催产素对髓鞘基因表达的有益影响。
局限性
我们的发现意义重大。然而，需要注意一些局限性。需要进一步研究将少突胶质细胞分化减少和髓鞘形成减少与 C58/J 小鼠 ASD 表型联系起来的细胞机制。更多的 snRNA-Seq 和空间研究将确定少突胶质细胞/小胶质细胞的影响是否仅局限于杏仁核，或者是否发生在其他脑区。还需要进一步研究催产素的作用，以了解其作为 ASD 治疗药物的潜力。
结论
我们的工作表明，C58/J 小鼠模型可用于评估性别和社交能力对 ASD 相关伴生脑区转录组的影响。我们的单细胞转录组分析阐明了少突胶质细胞和小胶质细胞在 ASD 中的潜在病理作用。该研究提供了有关这些细胞类型中受干扰的调节特征的详细信息，包括转录基因失调、异常细胞分化、改变的基因调控网络以及促进小胶质细胞/少突胶质细胞分化的关键途径的变化。我们的研究提供了对与不同依附行为和缺乏积极社交能力相关的遗传风险和表观遗传过程之间相互作用的深入了解。
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