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

苍白球外谷氨酸能神经元在进行性多巴胺耗竭动物模型行为缺陷中的作用

• 批准号: 10317493
• 负责人: Stefan Leutgeb
• 金额: $ 48.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-02 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317493
• 关键词: Address; Affect; Anatomy; Animal Model; Animals; Attention; Basal Ganglia; Basal Ganglia Diseases; Behavior; Behavioral; Behavioral Symptoms; Brain region; Cell Nucleus; Corpus striatum structure; Data; Disease; Dopamine; Dose; Electrophysiology (science); Functional disorder; Genetic; Globus Pallidus; Glutamates; Heterogeneity; Human; Individual; Investigation; Mediating; Methods; Modeling; Molecular; Motor; Movement; Movement Disorders; Mus; Nature; Neurons; Neurotoxins; Output; Oxidopamine; Parkinson Disease; Pathway interactions; Patients; Population; Positioning Attribute; Progressive Disease; Reporting; Research; Role; Signal Transduction; Synapses; Techniques; Time; Viral; associated symptom; base; behavioral impairment; cell type; cognitive function; dopaminergic neuron; field study; flexibility; improved; in vivo; mitopark mouse; molecular marker; motor behavior; motor control; motor deficit; mouse model; neural circuit; neuroadaptation; neuromechanism; neuron loss; novel; optogenetics; parkinsonian animal; population based; relating to nervous system

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.

概括 基底神经节是调节运动和认知功能的一组皮层核。最近的 基底神经节中神经元异质性的鉴定表明功能上不同的神经回路 即使在同一核内也存在其分子身份和传出投影所定义的。这种区别 可能会说明与基底神经节疾病（如帕金森氏病）相关的多种症状 （PD）。但是，我们对基底神经节功能组织的不完全理解进一步阻碍了 调查可能是不同疾病状态下不同行为症状的单个电路。 外部球粒（GPE）是一种中央基底神经节核，可以影响许多下游 地区。虽然盛行的电路模型假设GPE是神经元的均匀种群 在基底神经节的间接途径中转移信号，积累的证据表明神经元 在GPE中，GPE比以前所欣赏的要多。尽管已知GPE是一个核 GABA能神经元，我们已经确定了表达vglut2的新型细胞类型，谷氨酸能神经元标记，在 GPE的外层。在我们仔细的解剖学和分子检查中，表明vglut2gpe神经元 主要针对GPE的内部项目，将突触接触在其他神经元种群上进行。最近的证据 表明GPE中不同细胞类型可能在调节基底神经节电路和 相关行为。因此，阐明VGLUT2GPE神经元的解剖和功能组织将 提供新颖的细胞和电路信息以了解基底神经节功能。 与PD相关的行为缺陷的渐进性在人类患者中有很好的证明。 但是，在PD不同阶段与行为缺陷相关的神经适应性尚未完全 理解。在此应用程序中，我们尝试使用两种不同的动物模型来解决这一问题。首先，就像我们的初步 结果和最近的报告，我们将管理不同剂量的神经毒素给药以诱导不同的 DA神经元损失的程度，引起不同的行为缺陷。其次，我们将确认神经毒素 - 在Mitopark小鼠中诱导了与PD相关的行为，显示出DA神经元的逐渐丧失。检查 两个动物模型中的电路适应将提供有关神经机制的重要信息 PD的进步性质的基础。因此，使用包括光学遗传的遗传学在内的尖端技术 和病毒介导的操作，体内多单元记录等等，我们将破译vglut2gpe的角色 PD的这两个动物模型中的行为缺陷中的神经元。