Signal Transducer and Activator of Transcription 3 Activation in Hippocampal Neural Stem Cells and Cognitive Deficits in Mice Following Short-term Cuprizone Exposure
Signal Transducer and Activator of Transcription 3 Activation in Hippocampal Neural Stem Cells and Cognitive Deficits in Mice Following Short-term Cuprizone Exposure
复制标题
海马神经干细胞中信号转导器和转录激活剂 3 的激活以及短期铜宗暴露后小鼠的认知缺陷
DOI：
10.1016/j.neuroscience.2021.07.031
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发表时间：
2021
期刊：
影响因子：
3.3
通讯作者：
Jinno Shozo
中科院分区：
文献类型：
--
作者：
Ohgomori Tomohiro;Jinno Shozo
最近的研究强调，成人海马神经发生障碍可能与认知问题有关。由于铜宗 (CPZ)（一种铜螯合剂）被证明可以减少新神经元的产生，因此我们旨在通过使用短期（2 周）CPZ 暴露范例来进一步了解成人海马神经发生损伤对认知功能的影响。与正常喂养的小鼠相比，CPZ 喂养的小鼠表现出认知缺陷，即感觉运动门控受损和社交新奇偏好降低。尽管发现长期（例如 5 周）CPZ 暴露模式会导致脱髓鞘，但我们发现海马中髓磷脂的标记不受 2 周 CPZ 暴露的影响。 CPZ 喂养的小鼠的神经元祖细胞 (NPC) 和新生颗粒细胞 (NGC) 的密度低于正常喂养的小鼠，而神经干细胞 (NSC) 的密度在各组之间相当。然后，我们检查了短期 CPZ 暴露是否可能诱导信号转导子和转录激活子 3 (STAT3) 的激活，STAT3 在细胞因子受体信号转导中起主要作用。 CPZ 喂养的小鼠中磷酸化 STAT3 阳性 (pSTAT3+) NSC 的密度高于正常喂养的小鼠，而两组中 pSTAT3+NPC/NGC 的密度都非常低。有趣的是，注射 BrdU 后 2 周，CPZ 喂养的小鼠中溴脱氧尿苷阳性 (BrdU+) NSC 的密度高于正常喂养的小鼠，而 CPZ 喂养的小鼠中 BrdU+NPC/NGC 的密度低于正常喂养的小鼠。这些发现表明，短期 CPZ 暴露通过激活 STAT3 抑制 NSC 分化为 NPC，这可能在一定程度上导致认知缺陷。
Recent studies have emphasized that adult hippocampal neurogenesis impairment may be associated with cognitive problems. Because cuprizone (CPZ), a copper-chelating reagent, was shown to decrease the production of new neurons, we aimed to further understand the involvement of adult hippocampal neurogenesis impairment in cognitive function by using a short-term (2-week) CPZ exposure paradigm. The CPZ-fed mice showed cognitive deficits, i.e., impaired sensorimotor gating and reduced social novelty preference, compared to normal-fed mice. Although a long-term (e.g., 5-week) CPZ exposure paradigm was found to cause demyelination, we encountered that the labeling for myelin in the hippocampus was unaffected by 2-week CPZ exposure. The densities of neuronal progenitor cells (NPCs) and newborn granule cells (NGCs) were lower in CPZ-fed mice than in normal-fed mice, while those of neural stem cells (NSCs) were comparable between groups. We then examined whether short-term CPZ exposure might induce activation of signal transducer and activator of transcription 3 (STAT3), which plays a major role in cytokine receptor signaling. The densities of phosphorylated STAT3-positive (pSTAT3+) NSCs were higher in CPZ-fed mice than in normal-fed mice, while those of pSTAT3+NPCs/NGCs were very low in both groups. Interestingly, the densities of bromodeoxyuridine-positive (BrdU+) NSCs were higher in CPZ-fed mice than in normal-fed mice 2 weeks after BrdU injection, while those of BrdU+NPCs/NGCs were lower in CPZ-fed mice than in normal-fed mice. These findings suggest that short-term CPZ exposure inhibits differentiation of NSCs into NPCs via activation of STAT3, which may in part underlie cognitive deficits.