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.

总结 基底神经节是一组调节运动和认知功能的皮质下核团。最近 基底神经节神经元异质性的鉴定表明，功能不同的神经回路 由它们的分子身份和传出投射定义，甚至存在于相同的核内。这种区别 可以解释与基底神经节疾病如帕金森病相关的多种症状 （PD）。然而，我们对基底神经节功能组织的不完全理解阻碍了进一步的研究， 研究可能构成不同疾病状态下不同行为症状基础的个体回路。 外侧苍白球（GPe）是基底神经节中央核团，可影响许多下游神经元， 地区虽然流行的电路模型假设GPe是一个均匀的神经元群体， 在基底神经节的间接通路中传递信号，积累的证据表明，神经元 在GPe中，它们比以前认识到的更加异质。虽然已知GPe是一个核， GABA能神经元，我们已经确定了新的细胞类型表达VGLUT 2，多巴胺能神经元标记物， GPe的外层。在我们仔细的解剖学和分子学检查中发现，VGLUT 2GPe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中不同的细胞类型可能在调节基底神经节回路中具有不同的作用， 相关的行为。因此，阐明VGLUT2GPe神经元的解剖学和功能组织将 提供新的细胞和电路信息，以了解基底神经节的功能。 与PD相关的行为缺陷的进行性在人类患者中有很好的记录。 然而，在PD的不同阶段，与行为缺陷相关的神经适应并不完全 明白在本申请中，我们尝试用两种不同的动物模型来解决这个问题。首先，在我们的初步调查中 结果和最近的报告，我们将管理不同剂量的神经毒素管理，以诱导不同的 程度的DA神经元损失，这引起不同的行为缺陷。其次我们要确认神经毒素 在MitoPark小鼠中诱导PD相关行为，其显示DA神经元的进行性损失。检查 在两种动物模型中的回路适应将提供关于神经机制的重要信息 这是帕金森病渐进性的基础。因此，使用尖端技术，包括光遗传学，遗传学， 以及病毒介导的操纵、体内多单位记录等，我们将破译VGLUT 2GPe的作用 神经元在这两种PD动物模型中的行为缺陷。