CRCNS: Dynamics and mechanisms of rhythmic activity in basal ganglia

描述(申请人提供)：基底节(BG)是一组皮质下核团，从皮质接受广泛的投射，并向丘脑发送广泛的投射，除其他外，参与神经运动控制。对BG生理学的兴趣也受到BG相关疾病的推动，特别是帕金森氏病(PD)--一种以慢性多巴胺(DA)缺乏为特征的主要神经退行性疾病，导致一系列主要与运动相关的症状。尽管BG在帕金森病的运动控制和运动缺陷中起着重要作用，但这种控制和帕金森病运动缺陷的生理机制仍然知之甚少。最近的研究表明，BG中振荡同步活动的模式虽然非常可变，但与BG生理学和BG疾病(如帕金森病)密切相关。这些振荡的动力学及其机制是本研究的主题。将从人类患者的BG中记录尖峰单位和局部场电位(LFP)中的同步振荡行为模式，并使用同步发作检测的方法进行分析。模型将被患者记录的同步活动的不同模式的分析结果充分约束。该模型将被用作研究间歇性同步行为起源的机制的工具，从而确定体内可能的机制。在全模型的数值实验和简化系统的分析方法中，将研究生理上真实的动力学发生的基础分叉。因此，无论是在“生物语言”(突触、细胞和连接性的特征，它们产生间歇同步)和“数学语言”(系统中的分叉，表现出现实的节律性)中，BG的间歇同步活动的机制都将被理解。基于对这些机制的理解，将提出可能的方法来调节和抑制这种节律性(据信是病理性的)。公共卫生相关性：该项目将加强对帕金森氏症(一种主要的神经退行性疾病)人脑生理学的理解。该项目的结果可能有助于开发治疗这种疾病和相关疾病的新疗法。

DESCRIPTION (provided by applicant): The basal ganglia (BG) are a group of subcortical nuclei receiving extensive projections from cortex and sending extensive projections to thalamus and which are, among other things, involved in neural control of movement. Interest in BG physiology is also motivated by BG-related disorders, especially Parkinson's disease (PD) - a major neurodegenerative disorder characterized by chronic dopamine (DA) deficiency resulting in a set of primarily movement-related symptoms. Although BG plays a significant role in motor control and in motor deficits of PD, the physiological mechanisms responsible for this control and for PD motor deficits remain poorly understood. Recent studies indicate that patterns of oscillatory synchronous activity in BG, although very variable, are strongly relevant to BG physiology and BG disorders, such as PD. The dynamics of these oscillations and their mechanisms are the subjects of this study. Patterns of synchronous oscillatory behavior in spiking units and local field potentials (LFP) will be recorded from BG of human patients and analyzed using a method of synchronous episodes detection. Models, which are adequately constrained by the results of analysis of the variable patterns of synchronous activity recorded from the patients, will be developed. This model will be used as a tool to investigate the mechanisms responsible for the origin of intermittent synchronous behavior and thus identify possible mechanisms in vivo. Bifurcations underlying the occurrence of physiologically realistic dynamics in numerical experiments with the full model and in an analytical approach to a reduced system will be studies. As a result, the mechanisms of the intermittent synchronous activity in BG both in the "biological language" (features of synapses, cells, and connectivity, which give birth to intermittent synchrony) and in "mathematical language" (bifurcations in the system, exhibiting realistic rhythmicity) will be understood. Based on the understanding of the mechanisms, potential methods for modulation and suppression of this rhythmicity (which is believed to be pathological) will be suggested. PUBLIC HEALTH RELEVANCE: The project will enhance understanding of physiology of human brain in Parkinson's disease, a major neurodegenerative disorder. The results of the project may assist in development of new therapies for this disease and related disorders.