School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
Purdue Institute for Integrative Neurosciences, Purdue University, West Lafayette, IN 47907, USA.
Biomolecules. 2021 Sep 6;11(9):1315. doi: 10.3390/biom11091315.
Disrupted systemic copper (Cu) homeostasis underlies neurodegenerative diseases with early symptoms including olfactory dysfunction. This study investigated the impact of Cu dyshomeostasis on olfactory function, adult neurogenesis, and neurochemical balance. Models of Cu deficiency (CuD) and Cu overload (CuO) were established by feeding adult rats with Cu-restricted diets plus ip. injection of a Cu chelator (ammonium tetrathiomolybdate) and excess Cu, respectively. CuD reduced Cu levels in the olfactory bulb (OB), subventricular zone (SVZ), rostral migratory stream (RMS), and striatum, while CuO increased Cu levels in these areas. The buried pellet test revealed both CuD and CuO prolonged the latency to uncover food. CuD increased neural proliferation and stem cells in the SVZ and newly differentiated neurons in the OB, whereas CuO caused opposite alterations, suggesting a "switch"-type function of Cu in regulating adult neurogenesis. CuO increased GABA in the OB, while both CuD and CuO reduced DOPAC, HVA, 5-HT and the DA turnover rate in olfactory-associated brain regions. Altered mRNA expression of Cu transport and storage proteins in tested brain areas were observed under both conditions. Together, results support an association between systemic Cu dyshomeostasis and olfactory dysfunction. Specifically, altered adult neurogenesis along the SVZ-RMS-OB pathway and neurochemical imbalance could be the factors that may contribute to olfactory dysfunction.
系统性铜（Cu）稳态紊乱是神经退行性疾病的基础，其早期症状包括嗅觉功能障碍。本研究探讨了 Cu 稳态紊乱对嗅觉功能、成年神经发生和神经化学平衡的影响。通过给成年大鼠喂食 Cu 限制饮食并腹腔注射 Cu 螯合剂（四硫钼酸铵）和过量 Cu 来分别建立 Cu 缺乏（CuD）和 Cu 过载（CuO）模型。CuD 降低了嗅球（OB）、侧脑室下区（SVZ）、额顶迁移流（RMS）和纹状体中的 Cu 水平，而 CuO 则增加了这些区域的 Cu 水平。埋藏丸测试表明，CuD 和 CuO 均延长了揭开食物的潜伏期。CuD 增加了 SVZ 中的神经增殖和干细胞以及 OB 中的新分化神经元，而 CuO 则导致相反的变化，表明 Cu 在调节成年神经发生中具有“开关”型功能。CuO 增加了 OB 中的 GABA，而 CuD 和 CuO 均降低了嗅觉相关脑区中的 DOPAC、HVA、5-HT 和 DA 周转率。在两种情况下，还观察到受测脑区中 Cu 转运和储存蛋白的 mRNA 表达发生改变。总之，结果支持系统性 Cu 稳态紊乱与嗅觉功能障碍之间存在关联。具体来说，SVZ-RMS-OB 通路中成年神经发生的改变和神经化学失衡可能是导致嗅觉功能障碍的因素。
