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.

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。因为铜螯合剂铜宗 (CPZ) 被证明会减少新神经元的产生，我们旨在通过使用短期（2 周）CPZ 暴露来进一步了解成人海马神经发生障碍对认知功能的影响范例。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 暴露范式会导致脱髓鞘，但我们发现海马中髓鞘的标记不受 2 周 CPZ 暴露的影响。CPZ 喂养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小鼠，而神经干细胞 (NSC) 的密度在组间相当。然后我们检查了短期 CPZ 暴露是否可能诱导信号转导和转录激活因子 3 (STAT3) 的激活，STAT3 在细胞因子受体信号传导中起主要作用。磷酸化 STAT3 阳性 (pSTAT3⁺ ) CPZ 喂养小鼠的 NSCs 高于正常喂养小鼠，而 pSTAT3 ⁺ NPCs/NGCs 在两组中都非常低。有趣的是，注射 BrdU 2 周后，CPZ 喂养小鼠中溴脱氧尿苷阳性 (BrdU ⁺ ) NSCs的密度高于正常喂养小鼠，而CPZ 喂养小鼠中的 BrdU ⁺ NPC/NGCs 密度低于正常喂养小鼠- 喂老鼠。这些发现表明，短期 CPZ 暴露通过激活 STAT3 抑制 NSCs 向 NPCs 的分化，这可能是认知缺陷的部分原因。