Role and mechanisms of excretion in manganese neurotoxicity

摘要 这种多样性补充剂的工作将(1)测试生命早期抑制锰排泄对 使用微透析在大脑中进行多巴胺代谢；以及(2)提供职业发展机会 斯蒂芬妮·格兰特。我们的具体理由如下。 在家长的资助中，我们曾建议研究锰对肝脏或肠道的神经毒性作用- 使用4种方法：(1)用神经行为分析方法评估MN基因敲除或敲除基因的特异性 诱导熟练运动功能和运动/探索活动的改变；(2)感应耦合血浆 电感耦合等离子体质谱(ICPMS)金属分析以量化大脑中的锰水平；(3)显微镜以评估神经元 变性、神经炎症和细胞凋亡；以及(4)组织神经化学以评估纹状体水平 儿茶酚胺。为了增加研究的影响和意义，我们现在建议再增加一项 通过体内多样性补充剂量化选定动物组中的锰神经毒性的方法 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 补充材料将(1)大大增加主要提案的结论的重要性；以及(2)提供 斯蒂芬妮参与了一个高影响力的独立项目，该项目促进了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.