CIRCUIT MECHANISMS UNDERLYING LONG-LASTING RECOVERY OF MOVEMENT IN DOPAMINE DPELETED MICE INDUCED BY OPTOGENETIC INTERVENTION IN THE GPe

GPe 光遗传学干预引起的多巴胺缺乏小鼠运动持久恢复的电路机制

• 批准号: 10316994
• 负责人: Aryn Hilary Gittis
• 金额: $ 33.68万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316994
• 关键词: Acute; Address; Affect; American; Anatomy; Anxiety; Axon; Basal Ganglia; Behavior; Behavioral; Cell Nucleus; Cells; Chronic; Complement; Corpus striatum structure; Coupled; Data; Diffuse; Disease; Dopamine; Electrophysiology (science); Environment; Food; Functional disorder; Genetic; Globus Pallidus; Goals; Heterogeneity; Hour; Intervention; Knowledge; Lead; Location; Maps; Mediating; Methodology; Modeling; Motor; Movement; Mus; Nature; Neurodegenerative Disorders; Neurons; Opsin; Output; Parkinson Disease; Parvalbumins; Pathologic; Pathway interactions; Pattern; Play; Population; Positioning Attribute; Property; Recovery; Resources; Rest; Rodent; Role; Site; Social Interaction; Structure of subthalamic nucleus; Substantia nigra structure; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Viral; Work; base; cell type; experimental study; improved; in vivo; insight; motor disorder; motor symptom; mouse model; nervous system disorder; neural circuit; novel; optogenetics; restoration; tool; treatment strategy

Abstract A major challenge in the treatment of neurological diseases is the elaborate and diffuse nature of neural circuits, where physically proximal neurons are engaged in functionally different pathways. The ability to target neurons based on function, rather than location, is critical to improving treatments for disease. In Parkinson's disease, improved treatments have been driven by the discovery of cell type diversity in the striatum, providing access to functionally opposing circuits: the direct and indirect pathways. However, with the exception of neuronal diversity in the striatum, all other downstream nuclei in the basal ganglia are depicted as homogeneous relay nuclei, an oversimplification whose limits are increasingly apparent as techniques to study circuit function become more sophisticated. Recently, my lab has pioneered the use of transgenic mouse lines to subdivide neurons in the external globus pallidus (GPe) into subpopulations that differ in anatomy and electrophysiological properties. Leveraging tools to optogenetically manipulate these genetic subpopulations, we are now in position to discover their contributions to behavior. In a recent study, we found that optogenetic interventions targeted to particular subpopulations in the GPe (but not global stimulation of the entire nucleus) restores motor function in acutely dopamine depleted mice, and the effects persisted for hours after stimulation. This finding challenges long-standing models of circuit organization in the basal ganglia and has relevance for PD, where current interventions provide only transient relief of motor symptoms that rapidly return once stimulation stops. Experiments in this proposal will test the ability of GPe interventions to rescue movement in a chronic dopamine depletion model (Aim 1) and will elucidate the pathways through which GPe subpopulations mediate their effects (Aim 2). Aim 1, will use optogenetics and in vivo recordings to assess the impact of modulating genetically-defined neuronal subpopulations on local circuit dynamics in the GPe and their effects on behavior. Specifically, we will test the hypothesis that recovered movements following optogenetic stimulation are goal-directed and restore the ability of mice to seek out food, social interactions, and avoid anxiety-provoking environments. In Aim 2, we will use in vivo recordings, coupled with viral-assisted circuit mapping, to elucidate the pathways through which neuronal subpopulations in the GPe exert their prokinetic effects on movement. Our preliminary data suggest that therapeutic interventions share a common mechanism of reversing pathological firing patterns in the substantia nigra reticulata (SNr), the primary basal ganglia output nucleus in rodents. Our proposed experiments will determine whether this effect is mediated by direct projections of GPe neurons to the SNr, or whether it is mediated through a disynaptic pathway involving the subthalamic nucleus (STN). Combined, results from these studies will elucidate the pathways and circuit mechanisms responsible for long-lasting motor rescue in dopamine depleted mice and will revise long-standing models of indirect pathway dysfunction in disease.

抽象的 神经系统疾病治疗的一个主要挑战是神经系统的复杂性和弥散性。 电路，其中物理上邻近的神经元参与功能上不同的通路。瞄准目标的能力 基于功能而不是位置的神经元对于改善疾病治疗至关重要。在帕金森病中 纹状体细胞类型多样性的发现推动了治疗方法的改进，提供了 进入功能相反的回路：直接和间接途径。然而，除了 纹状体中的神经元多样性，基底神经节中的所有其他下游核被描述为 均质中继核，一种过度简化，其局限性随着研究技术的发展而日益明显 电路功能变得更加复杂。最近，我的实验室率先使用转基因小鼠品系 将外部苍白球 (GPe) 中的神经元细分为解剖结构和结构不同的亚群 电生理特性。利用光遗传学工具来操纵这些遗传亚群， 我们现在能够发现它们对行为的贡献。在最近的一项研究中，我们发现光遗传学 针对 GPe 中特定亚群的干预措施（但不是对整个细胞核的全局刺激） 恢复严重多巴胺耗竭小鼠的运动功能，并且效果持续数小时 刺激。这一发现挑战了基底神经节中长期存在的电路组织模型，并已 与 PD 的相关性，目前的干预措施只能暂时缓解运动症状，但很快就会缓解 一旦刺激停止就返回。该提案中的实验将测试 GPe 干预措施的救援能力 慢性多巴胺耗竭模型中的运动（目标 1），并将阐明 GPe 的途径 亚群体介导其影响（目标 2）。目标 1，将使用光遗传学和体内记录来评估 调节基因定义的神经元亚群对 GPe 和局部回路动态的影响 他们对行为的影响。具体来说，我们将测试以下假设：恢复运动 光遗传学刺激是有目标的，可以恢复小鼠寻找食物、社交互动、 并避免引起焦虑的环境。在目标 2 中，我们将使用体内记录，并结合病毒辅助 电路图谱，以阐明 GPe 中的神经元亚群发挥其作用的途径 对运动的促动力作用。我们的初步数据表明，治疗干预措施有一个共同点 逆转黑质网状结构（SNr）病理性放电模式的机制，这是初级基底 啮齿动物的神经节输出核。我们提出的实验将确定这种效应是否是由 GPe 神经元直接投射到 SNr，或者是否通过涉及的突触通路介导 丘脑底核（STN）。结合起来，这些研究的结果将阐明通路和回路 负责多巴胺耗尽小鼠的长期运动救援的机制，并将修改长期存在的机制 疾病中间接途径功能障碍的模型。