Role and mechanisms of excretion in manganese neurotoxicity

摘要 这项工作的多样性补充将（1）测试的影响，早期生活抑制锰排泄， 利用微透析技术研究大脑中的多巴胺代谢;（2）为以下人员提供职业发展机会： 斯蒂芬妮·格兰特我们的具体理由如下。 在母基金中，我们曾提议询问锰在肝脏或肠道中的神经毒性作用- 特异性Slc 30 a10敲除或敲入菌株，使用4种方法：（1）神经行为测定以评估Mn- 诱导熟练运动功能和运动/探索活动的变化;（2）诱导耦合血浆 质谱（ICP-MS）金属分析，以定量脑Mn水平;（3）显微镜检查，以评估神经元 变性、神经炎症和细胞凋亡;和（4）组织神经化学，以评估纹状体的 儿茶酚胺为了增加研究的影响力和重要性，我们现建议增加一项 通过这种多样性补充，在选定的动物组中量化Mn神经毒性的方法-体内 微透析以量化诱发的多巴胺释放。通过这种多样性纳入微透析研究 补充将（1）大大增加母提案调查结果的重要性;以及（2）提供 Stephanie拥有一个高影响力的独立项目，促进她的科学和职业发展。

ABSTRACT Work on this diversity supplement will (1) test the impact of early-life inhibition of manganese excretion on dopamine metabolism in the brain using microdialysis; and (2) provide career development opportunities for Stephanie Grant. Our specific rationale is below. In the parent grant, we had proposed to interrogate the neurotoxic effects of Mn in the liver or intestine- specific Slc30a10 knockout or knockin strains using 4 approaches: (1) neurobehavioral assays to assess Mn- induced changes in skilled motor function and locomotor/exploratory activity; (2) inductively-coupled plasma mass spectrometry (ICP-MS) metal analyses to quantify brain Mn levels; (3) microscopy to assess neuronal degeneration, neuroinflammation, and apoptosis; and (4) tissue neurochemistry to assess striatal levels of catecholamines. To increase the impact and significance of our studies, we now propose to add one more approach to quantify Mn neurotoxicity in a selected group of animals through this diversity supplement – in vivo microdialysis to quantify evoked dopamine release. Inclusion of the microdialysis study through this diversity supplement will (1) substantially increase the significance of the findings of the parent proposal; and (2) provide Stephanie with a high-impact, independent project that fosters her scientific and career development.