Role of Glutamatergic Neurons in External Globus Pallidus in the Behavioral Deficits in Animal Models of Progressive Dopamine Depletion

摘要 基底节是一组皮质下核团，负责调节运动和认知功能。近期 基底节神经元异质性的鉴定表明，功能上不同的神经回路 由它们的分子同一性和传出投射所定义的，即使在相同的核内也存在。这一区别 可能与帕金森氏症等基底节疾病相关的多种症状有关 (Pd)。然而，我们对基底节功能组织的不完全理解阻碍了进一步的研究 对可能导致不同疾病状态下不同行为症状的个别回路的研究。 苍白球外核群(GPE)是一个中央基底节核团，可影响许多下游核团。 地区。虽然流行的电路模型假设GPE是一个同质的神经元群体 在基底节的间接通路中传递信号，越来越多的证据表明神经元 在GPE中的异质性比之前所认识到的更多。尽管已知GPE是一个具有 ，我们已经鉴定出表达谷氨酸能神经元标记物VGLUT2的新细胞类型，在 GPE的外层。在我们仔细的解剖学和分子检测中发现VGLUT2GPe神经元 主要投射到GPE的内部，与其他神经元群体进行突触接触。最近的证据 表明GPE中不同类型的细胞可能在调节基底节回路和 关联的行为。因此，阐明VGLUT2GPe神经元的解剖和功能组织将 为了解基底节功能提供新的细胞和回路信息。 与帕金森病相关的行为缺陷的进行性本质在人类患者中得到了很好的证明。 然而，在帕金森病的不同阶段，神经适应与行为缺陷的关系并不完全。 明白了。在本应用程序中，我们试图通过两个不同的动物模型来解决这个问题。首先，在我们的预赛中 结果和最近的报道，我们会使用不同剂量的神经毒素来诱导不同的 不同程度的DA神经元丢失，导致不同的行为障碍。第二，我们会确认神经毒素- 诱导MitoPark小鼠帕金森病相关行为，表现为DA神经元进行性丢失。检查 在两种动物模型上的回路适应将提供关于神经机制的重要信息 这是帕金森氏症进步本质的基础。因此，使用尖端技术包括光遗传、遗传 以及病毒介导的操纵、体内多单位记录等，我们将破译VGLUT2GPe的作用 在这两种帕金森病动物模型中，神经元存在行为缺陷。

SUMMARY The basal ganglia are a group of subcortical nuclei that regulates motor and cognitive functions. Recent identification of neuronal heterogeneity in the basal ganglia suggests that functionally distinct neural circuits defined by their molecular identity and efferent projections exist even within the same nuclei. This distinction may account for a multitude of symptoms associated with basal ganglia disorders such as Parkinson's disease (PD). However, our incomplete understanding of the basal ganglia functional organization has hindered further investigation of individual circuits that may underlie distinct behavioral symptoms in different disease states. The external globus pallidus (GPe) is a central basal ganglia nucleus that can influence numerous downstream regions. While the prevailing circuit model assumes that the GPe is a homogeneous population of neurons transferring the signal in the indirect pathway of the basal ganglia, accumulating evidence suggests that neurons in the GPe are more heterogeneous than previously appreciated. Although GPe is known to be a nucleus with GABAergic neurons, we have identified novel cell types expressing VGLUT2, glutamatergic neuronal marker, at the outer layer of GPe. In our careful anatomical and molecular examination showed that VGLUT2GPe neurons project mainly to inner part of GPe, making synaptic contacts onto other neuronal populations. Recent evidence showed that the distinct cell types in GPe may have different roles in modulating basal ganglia circuitry and associated behaviors. Thus, elucidating the anatomical and functional organization of VGLUT2GPe neurons will provide novel cellular and circuit information to understand basal ganglia function. The progressive nature of behavioral deficits associated with PD is very well documented in human patients. However, what neural adaptations associated with behavioral deficits at different stages of PD are not fully understood. In this application, we try to address this with two different animal models. First, as in our preliminary results and recent reports, we will administer different doses of neurotoxin administration to induce different degrees of DA neuronal loss, which elicit the different behavioral deficits. Second, we will confirm the neurotoxin- induced PD-related behaviors in MitoPark mice which show the progressive loss of DA neurons. Examining the circuit adaptation in two animal models will provide an important information on the neural mechanisms underlying the progressive nature of PD. Therefore, using cutting-edge techniques including optogenetic, genetic and viral-mediated manipulation, in vivo multi-unit recording, and so on, we will decipher roles of VGLUT2GPe neurons in behavioral deficits in these two animal models for PD.