Striatal Neuroplasticity Mechanisms that Preserve Motor Behavior in a model of Parkinsonâs Disease

摘要 帕金森氏病（PD）是一种进行性神经退行性疾病，其中， 多巴胺（DA）导致认知和运动障碍。运动症状包括 静止性震颤、僵硬、步态改变和运动迟缓。DA前体L-多巴胺（L- 3，4-二羟基苯丙氨酸）是金标准疗法，但它可能失去功效， 产生运动障碍。在这项拨款申请中提出的工作将集中在确定 并表征纹状体中的突触和网络水平的变化， 在PD模型中的作用。我们的初步数据表明， 黑质纹状体DA触发了长期可塑性机制， 运动障碍后，诱导背侧纹状体6-羟基多巴胺模型的PD。 为了获得对这种形式的可塑性的机械见解，在目标1中，我们将执行一些 的实验，解决其诱导和维护，包括确定如何 只要正常化的运动行为持续，无论DA受体激动剂（而不是 内源性DA）能够诱导神经可塑性以使运动行为正常化，并且 可塑性是否发生在其他常见的，在某些情况下，更完整的模型 的PD。由于运动行为受到纹状体活动平衡的强烈影响， 直接和间接通路输出神经元，本拨款申请的其他两个目的 将决定纹状体输出神经元的突触和回路水平的变化。在目标2中， 我们将使用电生理学来测量纹状体输出的兴奋性的变化， 神经元及其与皮质和丘脑纹状体输入的连接， 纹状体活动在目标3中，我们将使用体内钙成像来测量活性 这两个神经元群体的模式，同时监测运动行为后， 在纹状体PD模型中诱导新的可塑性机制。中所述工作 这一提议提供了一个难得而令人兴奋的机会，以深入了解纹状体DA 信号和可塑性影响运动正常和PD，并设置阶段，以确定 改善治疗方法。此外，这项工作将奠定基础， 研究可能存在的类似多巴胺介导的神经可塑性机制 在大脑的其他区域，并影响疾病的认知和情感方面。

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which loss of dopamine (DA) leads to cognitive and motor impairments. Motor symptoms include resting tremor, rigidity, altered gait, and bradykinesia. The DA precursor L-dopamine (L- 3, 4-dihydroxyphenyalanine) is the gold standard therapy, but it can lose efficacy and produce dyskinesias. The work proposed in this grant application will focus on identifying and characterizing synaptic and network level changes in the striatum that preserve motor function in models of PD. Our preliminary data indicate that a transient elevation of nigrostriatal DA triggers mechanisms of long-term plasticity that prevent the development of motor impairments after induction of a dorsal striatal 6-hydroxydopamine model of PD. To gain mechanistic insight into this form of plasticity, in Aim 1 we will perform a number of experiments that address its induction and maintenance, including determining how long the normalized motor behavior persists, whether DA receptor agonists (rather than endogenous DA) are able to induce the neuroplasticity to normalize motor behavior, and whether the plasticity occurs in other common and, in some cases, more complete models of PD. Since motor behavior is strongly influenced by the balance of activity in striatal direct and indirect pathway output neurons, the other two Aims of this grant application will determine synaptic and circuit level changes in the striatal output neurons. In Aim2, we will use electrophysiology to measure changes in the excitability of the striatal output neurons and their connections to cortico- and thalamostriatal inputs, the major drivers of striatal activity. In Aim 3, we will use in vivo calcium imaging to measure the activity patterns of these two neuronal populations while monitoring motor behavior after induction of the novel plasticity mechanism in the striatal PD model. Work described in this proposal provides a rare and exciting opportunity to gain insight into how striatal DA signaling and plasticity affect movement normally and in PD, and set the stage to identify improved therapeutic approaches. Additionally, the work will lay the foundation for investigation into similar dopamine-mediated neuroplasticity mechanisms that may exist in other regions of the brain and affect the cognitive and emotional aspects of the disease.