Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.
Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.
复制标题
新生儿低剂量丙泊酚暴露后 PGC-1α 激活 OXPHOS 介导的海马神经发生增强
DOI：
10.3389/fnagi.2022.925728
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
发育中的大脑是高度可塑的，很容易受到影响。越来越多的儿科在无痛手术中使用麻醉剂，引起了人们对低剂量麻醉剂对神经发育影响的担忧。目前迫切需要确定小剂量异丙酚（一种广泛应用于儿科的麻醉剂）对发育中大脑的神经元作用。通过对新生小鼠暴露于低剂量和高剂量异丙酚后的行为学测试，阐明异丙酚对小鼠认知功能的影响。进一步鉴定海马内处于增殖分化阶段的新生细胞和培养的神经干细胞。此外，进行单核RNA测序（snRNA-seq）、NSC批量RNA-seq和代谢试验以进行通路研究。此外，小干扰RNA和立体定向腺病毒注射，分别在神经干细胞和海马，以确定潜在的机制。小鼠的行为测试显示，暴露于低剂量丙泊酚后，空间认知能力增强。在海马和培养的NSCs中均观察到激活的神经发生。此外，snRNA-seq、bulk RNA-seq和代谢试验的转录组分析揭示了NSC中显著增强的氧化磷酸化（OXPHOS）水平。此外，体内和体外研究发现，丙泊酚暴露后，线粒体代谢的主要调节因子PGC-1α均上调。重要的是，PGC-1α的下调显著阻止了低剂量丙泊酚激活OXPHOS和神经发生的作用。总之，本研究表明，低剂量丙泊酚暴露后海马神经发生中线粒体功能发生了新的改变，表明低剂量丙泊酚在儿科使用中的安全性，甚至潜在的有益作用。
Developing brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains. The behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism. Behavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis. Taken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.
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