Motor cortical circuitry adaptations in experimental Parkinson's disease

项目总结 帕金森病(PD)是第二常见的神经退行性疾病，因此它 与快速增长的社会经济负担相关联。帕金森病的一个特征是多巴胺能(DA)的丧失 黑质中的神经元，它与衰弱的运动症状有关，这种症状的特征是 这种病。然而，运动功能并不局限于黑质--其他大脑结构，如 控制特定运动技能的初级运动皮质(M1)在帕金森病中受到影响。直到最近， 在帕金森病患者中观察到的M1神经元的异常活动被认为是基础水平升高的直接结果 黑质DA神经元丢失所致的神经节抑制。现在有强有力的证据表明，M1电路 对DA神经元的丢失作出适应性改变。我们的初步数据显示了许多内在的 以及M1回路中的突触适应。然而，我们缺乏对M1回路功能障碍的基本了解 在PD的背景下，其神经元的异质性和突触的复杂性。此外，令人信服的证据 显示M1功能障碍发生在PD的早期，但尚不清楚它是适应性的还是适应不良的 疾病就会发展。 在拟议的研究中，我们将系统地研究黑质DA神经元的丢失是如何导致 M1层第5层锥体神经元亚型固有特性的适应性变化。我们还将 确定与这些变化相关的分子和离子机制(目标1)。EX的组合 将使用药理学和生物物理方法的活体膜片钳记录来解决这些问题 两个问题。此外，通过将体外膜片钳记录与光遗传学、化学遗传学和 连接学：黑质DA神经元的丧失如何改变丘脑皮质的连接强度和可塑性 将确定突触(目标2)。最后，作为神经变性的M1回路功能障碍的时间进程 将使用小鼠模型进行研究，该模型显示黑质DA神经元和左旋多巴的进行性丧失。 反应性运动缺陷。在这些研究中，M1回路功能障碍将与运动发育有关 以确定其在运动功能障碍的发生和发展中的作用(目标3)。 从拟议的研究中产生的信息将填补关于M1电路的知识空白 与黑质DA神经元丢失相关的功能障碍。这一知识将有助于对小说的鉴定 帕金森病进展的生理生物标志物和针对M1的非侵入性治疗方法的设计 帕金森病患者运动功能障碍的治疗。

PROJECT SUMMARY Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging and as such it associates with a rapidly growing socioeconomic burden. A hallmark of PD is the loss of dopaminergic (DA) neurons in the substantia nigra, which is causally linked to the debilitating motor symptoms that characterize this disease. However, motor function is not confined to the substantia nigra –other brain structures, like the primary motor cortex (M1) that controls specific sets of motor skills, are affected in PD. Until recently, the abnormal activity of M1 neurons observed in PD was thought to be a direct consequence of an increased basal ganglia inhibition due to the loss of nigral DA neurons. There is now strong evidence indicating that M1 circuitry exhibits adaptive changes in response to loss of DA neurons. Our preliminary data show numerous intrinsic and synaptic adaptations in M1 circuitry. Yet, we lack fundamental understanding of M1 circuitry dysfunction in PD in the context of its neuronal heterogeneity and synaptic complexity. Moreover, compelling evidence shows M1 dysfunction occurs early in PD, but it remains unclear whether it is adaptative or maladaptive as the disease progresses. In the proposed research, we will systematically study how the loss of nigral DA neurons induces adaptative changes in the intrinsic properties of pyramidal neuron subtypes in the layer 5 of M1. We will also determine molecular and ionic mechanisms that associate with these changes (Aim 1). A combination of ex vivo patch-clamp recording with pharmacological and biophysical approaches will be used to address these two questions. Moreover, by combining ex vivo patch-clamp recording with optogenetics, chemogenetics, and connectomics, how the loss of nigral DA neurons alters the connection strength and plasticity of thalamocortical synapses will be determined (Aim 2). Last, the time course of M1 circuitry dysfunction as neurodegeneration occurs will be studied using a mouse model that shows progressive loss of nigral DA neurons and levodopa- responsive motor deficits. In these studies, M1 circuitry dysfunction will be related to the development of motor deficits to determine its role in the onset and progression of motor dysfunction (Aim 3). The information arising from the proposed research will fill the gap in knowledge regarding M1 circuitry dysfunction associated with the loss of nigral DA neurons. This knowledge will aid the identification of novel physiological biomarkers for PD progression and the design of noninvasive approaches targeting M1 for treatment of motor dysfunction in PD.