Oscillations and Resonance in Basal Ganglia Circuits

长期以来，基底神经节功能和功能障碍的模型都是基于描绘通过核团的电活动流的电路图。这些模型指导了基底神经节神经退行性疾病治疗的发展，并继续用于设计和改进新的治疗方法。功能模型的有效性及其对新治疗设计的预测价值与每个细胞核中电路的准确信息紧密相关。我们对基底神经节核神经元之间的解剖连接的了解是好的，并迅速提高，但我们对电路对电活动流动的影响的理解还处于起步阶段。本文分析了基底神经节的主要输入核团（纹状体）和主要输出核团（黑质）的神经回路的功能特点。实验使用正弦输入和正弦曲线的组合在一定的频率范围内，以表征局部电路对神经元反应的影响。这些输入参与了神经元和突触的已知共振特性，它们将揭示电路相互作用产生的其他共振。在一些实验中，输入在细胞内或光遗传学上被递送到电路中的一些或所有细胞类型，而在其他实验中，到电路的周期性输入信号通过连续控制上游神经元的激发而被突触地递送。这些实验将揭示放大或抑制基底神经节节律活动的电路机制，包括帕金森病的主要病理生理组成部分β振荡和DBS期间产生的治疗周期信号。

Models of basal ganglia function and dysfunction have long been based on a circuit diagram sketching the flow of electrical activity through the nuclei. These models have guided the development of treatments for neurodegenerative diseases of the basal ganglia, and continue to be useful for design and refinement of new treatments. The validity of the functional models and their predictive value for design of new treatments is tightly linked to accurate information on the circuitry in each of the nuclei. Our knowledge of the anatomical connectivity among neurons in basal ganglia nuclei is good and improving rapidly, but our understanding of circuit effect on the flow of electrical activity is in its infancy. In this proposal, the functional characteristics of circuits in the main input nucleus of the basal ganglia (the striatum) and that in the main output nucleus (the substantia nigra) are analyzed. The experiments use sinusoidal inputs and combinations of sinusoids over a range of frequencies to characterize the effects of local circuits on neuronal responses. These inputs engage the known resonance properties of the neurons and synapses, and they will reveal other resonances that arise from circuit interactions. In some experiments, the input is intracellularly or optogenetically delivered to some or all cell-types in the circuit, whereas in others the periodic input signal to the circuit is delivered synaptically by continuously controlling firing of upstream neurons. These experiments will reveal the circuit mechanisms that amplify or suppress rhythmic activity in the basal ganglia, including both the beta oscillations that are a principal pathophysiological component of Parkinson's disease, and the therapeutic periodic signal generated during DBS.