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

基底节是皮质下核团的集合，研究它们对运动、动作的贡献。 运动障碍中的选择、习惯养成、奖赏学习及其功能障碍。而当 皮层输入的基底节处理与直接和间接通路的出现 纹状体内的沟通渠道一直是广泛调查的对象， 这些通道在包括黑质在内的基底节输出核水平上的整合 网纹夜蛾(SNR)的研究相对较少。这种不平衡对我们理解 基底节功能，因为基底节影响神经系统的其他区域，因此 行为是通过基底节输出核传递的，并取决于它们如何处理信号 他们收到了。该项目将建立在并测试最近提出的基于计算和 私人投资机构小组的实验工作，以弥补这一知识差距的方式调查SNR活动。 具体地说，这项工作将促进我们对以下方面的了解：SNR神经元如何对GABA能输入做出反应 在间接途径中，苍白球外段(GPE)的主要来源依赖于 SNR神经元特征、受试者的运动状态和多巴胺水平；它们是如何被预期的 在SNR网络及其产出层面上影响动态；氯动态的程度 以及它对GABA逆转潜力的影响导致了这些行为；以及这些因素是如何起作用的 特别是在多巴胺耗竭的情况下，SNR中出现的增量带振荡。这些进展 将通过模型开发、模拟和分析的跨学科方法实现 与小鼠切片和活体实验的协同作用涉及光遗传学、神经记录、 药物操作，以及在控制和多巴胺耗尽条件下的行为。 相关性(请参阅说明)： 基底节功能障碍导致包括帕金森氏病在内的一系列疾病，帕金森氏症的特点是显著 多巴胺耗尽。这项拟议的研究将为多巴胺枯竭如何改变沟通提供新的见解。 在基底节内的关键神经群之间，以及来自基底节的输出信号，这可能会影响 运动行为。这些发现将提供直接有用的信息，用于寻找治疗靶点和 开发高效、有效的脑刺激范例，以减少帕金森氏病的运动并发症。

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.