The synaptic basis of motor impairment following early developmental manganese exposure

 描述（由申请人提供）：虽然锰（Mn）是一种必需元素，但高水平暴露可导致儿童出现认知和精细运动缺陷等症状。研究表明，锰过量导致皮质下运动回路的改变，特别是基底神经节和多巴胺神经元损伤。初级运动皮层（M1）接收输入皮质下运动电路已知受锰过度，和M1兴奋性突触动力学的变化发生在精细运动技能学习。这提出了M1可能受到发育锰暴露影响的可能性，但关于锰暴露对皮层突触的影响知之甚少。最近的研究表明，精细运动缺陷引起的发育锰暴露在啮齿类动物的缓解与哌醋甲酯（MPH）治疗。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例，结合M1突触的体内双光子和固定组织成像以及中皮层多巴胺神经元的药物遗传学激活，研究小鼠发育Mn暴露和暴露后MPH治疗的突触，电路和行为效应，来解决这一知识差距。我们假设，皮层下的变化引起的发展锰暴露引起M1突触中断和精细运动学习和性能障碍，MPH恢复M1突触动力学与精细运动功能。为了解决这一假设，我们将使用出生后早期Mn暴露的小鼠模型：1）确定精细运动技能学习和表现障碍是否与小鼠出生后发育性Mn暴露后M1脊柱动力学的改变相关，并确定哌甲酯方案对运动学习和表现以及M1脊柱动力学的影响; 2）确定在发育性Mn暴露后，丘脑皮层对M1的输入是否被破坏，M1是基底神经节回路的中继输出;和3）确定M1中多巴胺能神经传递的标志物是否改变，或增加中皮层多巴胺神经元的活性是否改善精细运动功能或影响发育Mn暴露后的M1突触。总之，这些实验将推进我们的理解如何发展锰影响突触和电路的M1与精细运动缺陷。此外，拟定的MPH治疗研究不仅将进一步确定潜在的药物治疗是否能恢复皮质突触动力学以及精细运动功能，还将更深入地了解儿茶酚胺能神经传递对发育性锰暴露后精细运动功能障碍的神经病理学基础的贡献。

 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.