CRCNS: Diverse effects of GABAergic inputs on a basal ganglia output center

CRCNS：GABA 能输入对基底神经节输出中心的多种影响

• 批准号: 10395793
• 负责人: Aryn Hilary Gittis
• 金额: $ 37.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395793
• 关键词: Affect; Animals; Area; Basal Ganglia; Behavior; Behavioral; Brain; Cell Nucleus; Characteristics; Chlorides; Collection; Communication; Complement; Computer Models; Corpus striatum structure; Development; Disease; Distal; Dopamine; Functional disorder; Gatekeeping; Generations; Globus Pallidus; Goals; Habits; Heterogeneity; Homeostasis; Instruction; Investigation; Knowledge; Learning; Link; Maps; Modeling; Motor; Motor output; Movement; Movement Disorders; Mus; Nervous system structure; Neurons; Outcome; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathway interactions; Pharmacology; Physiological; Play; Population; Process; Property; Recording of previous events; Regulation; Research; Rewards; Rodent; Route; Shapes; Signal Pathway; Signal Transduction; Slice; Source; Substantia nigra structure; Synapses; Testing; Work; base; behavior test; experimental study; gamma-Aminobutyric Acid; in vivo; insight; interdisciplinary approach; model development; motor behavior; neural stimulation; optogenetics; predicting response; protein biomarkers; relating to nervous system; response; simulation; synergism; theories; therapeutic target

The basal ganglia are a collection of subcortical nuclei studied for their contributions to movement, action selection, habit formation, and reward learning as well as their dysfunction in movement disorders. While basal ganglia processing of cortical inputs and the emergence of the direct and indirect pathway communication channels within the striatum have been the subject of extensive investigation, the integration of these channels at the level of basal ganglia output nuclei including the substantia nigra pars reticulata (SNr) has been relatively understudied. This imbalance is problematic for our understanding of basal ganglia function, because basal ganglia impacts on other areas of the nervous system, and hence on behavior, are funneled through basal ganglia output nuclei and depend on how they process the signals they receive. This project will build on and test ideas recently proposed based on computational and experimental work from the PIs’ groups to investigate SNr activity in ways that redress this knowledge gap. Specifically, this work will advance our knowledge about: how SNr neuron responses to GABAergic inputs from a major source, the external segment of the globus pallidus (GPe) in the indirect pathway depend on SNr neuron characteristics, the locomotor state of the subject, and dopamine levels; how they are expected to impact dynamics at the level of the SNr network and its outputs; the extent to which chloride dynamics and its effect on the GABA reversal potential give rise to these behaviors; and how these factors contribute to the delta band oscillations that emerge in SNr specifically under dopamine depletion. These advances will be achieved via an interdisciplinary approach of model development, simulations, and analysis done in synergy with experiments in slice and in vivo in mice involving optogenetics, neural recording, pharmacological manipulations, and behavior across control and dopamine-depleted conditions. RELEVANCE (See instructions): Basal ganglia dysfunction contributes to a range of disorders including Parkinson’s disease, which is characterized by significant dopamine depletion. The proposed research will provide new insights about how dopamine depletion alters communication among key neural populations within the basal ganglia, as well as output signaling from the basal ganglia, which can impact motor behavior. These findings will supply information that is of direct utility in the search for therapeutic targets and the development of efficient, effective brain stimulation paradigms to reduce the motor complications of Parkinson’s disease.

基底神经节是皮质下核团的集合，研究它们对运动、动作 选择、习惯形成和奖励学习以及它们在运动障碍中的功能障碍。而 基底神经节对皮层输入的处理以及直接和间接通路的出现 纹状体内的沟通渠道一直是广泛研究的主题， 这些通道在包括黑质部的基底神经节输出核水平的整合 网织红细胞（SNr）的研究相对不足。这种不平衡对于我们理解 基底神经节功能，因为基底神经节影响神经系统的其他区域，因此， 行为，通过基底神经节输出核团，并取决于他们如何处理信号 他们收到。该项目将建立在最近提出的基于计算和 PI小组的实验工作，以弥补这一知识差距的方式调查SNr活动。 具体来说，这项工作将推进我们的知识：SNr神经元如何响应GABA能输入 从一个主要来源，苍白球（GPe）的间接途径的外部部分依赖于 SNr神经元特征、受试者的运动状态和多巴胺水平;它们是如何预期的 影响SNr网络及其输出水平的动态;氯化物动态 及其对GABA逆转电位的影响引起了这些行为;以及这些因素如何促成 特别是在多巴胺耗尽的情况下，SNr中出现的δ带振荡。这些进步 将通过跨学科的模型开发、模拟和分析方法来实现， 与切片和小鼠体内实验协同作用，涉及光遗传学、神经记录 药理学操作，以及在对照和多巴胺耗尽条件下的行为。 相关性（参见说明）： 基底神经节功能障碍导致包括帕金森病在内的一系列疾病，其特征在于显著的神经功能障碍。 多巴胺耗竭这项拟议中的研究将为多巴胺耗尽如何改变交流提供新的见解 在基底神经节内的关键神经群体之间，以及来自基底神经节的输出信号，这可以影响 运动行为这些发现将为寻找治疗靶点提供直接有用的信息， 开发高效，有效的脑刺激范例，以减少帕金森病的运动并发症。