The synaptic basis of motor impairment following early developmental manganese exposure

 描述(由申请人提供)：虽然锰(Mn)是一种基本元素，但高水平的暴露会导致儿童出现包括认知和精细运动障碍在内的症状。研究表明，锰过量暴露会导致皮质下运动神经回路的改变，特别是基底节和多巴胺神经元的损伤。初级运动皮质(M1)接受皮质下运动神经回路的输入，已知受到锰过量暴露的影响，在精细运动技能学习过程中，M1兴奋性突触动力学发生变化。这增加了M1可能受到发育中锰暴露的影响的可能性，但人们对锰暴露对皮层突触的影响知之甚少。最近的研究表明，由发育性锰暴露引起的啮齿动物精细运动障碍可通过哌醋甲酯(MPH)治疗得到缓解。然而，目前尚不清楚MPH是否影响M1的突触可塑性。我们将通过使用精细运动技能学习范式，结合体内M1突触的双光子和固定组织成像以及中皮质多巴胺神经元的药物遗传激活来解决这一知识缺口，以研究发育期锰暴露和暴露后MPh治疗对小鼠突触、电路和行为的影响。我们推测，发育期锰暴露引起的皮质下改变导致M1突触紊乱和精细运动学习与操作功能障碍，MPH可恢复M1突触动力学和精细运动功能。为了解决这一假说，我们将使用出生后早期锰暴露的小鼠模型来确定：1)确定精细运动技能学习和操作障碍是否与小鼠出生后发育性锰暴露后M1脊椎动力学的变化有关，并确定哌甲酯治疗方案对运动学习和表现以及M1脊椎动力学的影响；2)确定发育性锰暴露后丘脑皮质对M1的输入是否受到干扰，丘脑皮质传入M1是传递基底神经节回路的输出；以及3)确定M1是否改变了多巴胺能神经传递的标志物，或者在发育期锰暴露后中皮质多巴胺神经元活性增加是否改善了精细运动功能或影响了M1突触。总之，这些实验将促进我们对发育中的锰如何影响与微小运动缺陷相关的突触和M1电路的理解。此外，对MPH治疗的拟议研究不仅将进一步确定潜在的药物治疗是否恢复了精细运动功能之外的皮质突触动力学，而且还将提供更多关于儿茶酚胺能神经传递在发育期锰暴露后精细运动功能障碍的神经病理学中的贡献的见解。

 DESCRIPTION (provided by applicant): Although manganese (Mn) is an essential element, high levels of exposure can cause symptoms including cognitive and fine motor deficits in children. Studies have demonstrated that manganese overexposure leads to alterations in subcortical motor circuits, particularly basal ganglia and dopamine neuron impairments. Primary motor cortex (M1) receives input from subcortical motor circuits known to be affected by Mn overexposure, and changes in M1 excitatory synapse dynamics occur during fine motor skill learning. This raises the possibility that M1 could be affected by developmental Mn exposure, yet little is known about the effects of Mn exposure on synapses in the cortex. Recent studies have shown that fine motor deficits induced by developmental Mn exposure in rodents are alleviated with methylphenidate (MPH) treatment. However, it is not known whether MPH affects synapse plasticity in M1. We will address this gap in knowledge by using a fine motor skill learning paradigm coupled with in vivo two-photon and fixed-tissue imaging of synapses in M1 and pharmacogenetic activation of mesocortical dopamine neurons to investigate the synaptic, circuit, and behavioral effects of developmental Mn exposure and post-exposure MPH treatment in mice. We hypothesize that subcortical alterations caused by developmental Mn exposure give rise to M1 synapse disruptions and fine motor learning and performance dysfunction, and that MPH restores M1 synapse dynamics together with fine motor function. To address this hypothesis, we will use a mouse model of early postnatal Mn exposure to: 1) determine whether fine motor skill learning and performance impairments are associated with alterations in M1 spine dynamics following developmental postnatal Mn exposure in mice, and determine the effects of a methylphenidate regimen on motor learning and performance and M1 spine dynamics; 2) determine whether thalamocortical inputs to M1, which relay output of basal ganglia circuits, are disrupted following developmental Mn exposure; and 3) determine whether markers of dopaminergic neurotransmission are altered in M1, or whether increasing activity of mesocortical dopamine neurons improves fine motor function or impacts M1 synapses following developmental Mn exposure. Together, these experiments will advance our understanding of how developmental Mn affects the synapses and circuits of M1 associated with fine motor deficits. In addition, the proposed investigation of MPH treatment will not only further determine whether a potential pharmacological treatment restores cortical synapse dynamics in addition to fine motor function, but also will provide greater insight into the contribution of catecholaminergic neurotransmission to the neuropathology underlying fine motor dysfunction following developmental Mn exposure.