Dynamic regulation of whole brain circuit function by basal ganglia pathways

基底神经节通路对全脑回路功能的动态调节

• 批准号: 8996739
• 负责人: Jin Hyung Lee
• 金额: $ 48.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996739
• 关键词: Accelerometer; Affect; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Beryllium; Biological Models; Brain; Brain region; Cells; Clinical; Complex; Computer Simulation; Corpus striatum structure; Data; Data Set; Decision Making; Deep Brain Stimulation; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Elements; Engineering; Essential Tremor; Functional Magnetic Resonance Imaging; Goals; Health; Image; Imaging technology; Indium; Knowledge; Life; Light; Location; Measurement; Measures; Modeling; Motor; Network-based; Neurobiology; Neurons; Output; Parkinson Disease; Pathway interactions; Pattern; Phenotype; Population; Process; Regulation; Resolution; Rest; Signal Transduction; Source; Staging; Synapses; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Translations; Tremor; Work; base; behavior measurement; behavior test; brain cell; cell type; design; driving behavior; millisecond; nervous system disorder; neuroimaging; new technology; novel; optogenetics; predicting response; relating to nervous system; response; success; temporal measurement; therapy design

 DESCRIPTION (provided by applicant): Recent success of neurostimulation therapies such as deep brain stimulation (DBS) for Parkinson's disease (PD) support the importance of understanding how activity of specific local neuronal population influence the overall brain network to drive behaviors such as reversing tremors in Parkinson's disease. Given the resulting complex behavioral output, it is likely that the effects of brain stimulations are not limited to simply changing local neuronal activity. The local change is driving neural activity in many regions of the brain to give rise to the therapeutic effects. However, this important neurobiological question of how large-scale network activity relates to behavior still remains largely elusive. Understanding of how specific neuronal population functionally relates to the overall brain enables us to systematically design therapeutics for neurological diseases based on our concrete knowledge of the circuit function underlying behavior. The main therapeutic goal for neurological diseases lies in reversing the behavioral phenotype such as essential tremors, which are a direct consequence of loss of proper circuit function. If the circuit function underlying behavior can be directly visualized, the potential for therapeutic intervention is limitless. Therefore, in this proposal, we aim to start reverse- engineering global brain dynamics associated with the basal ganglia circuit and to understand how they relate to motor behavior. The novel optogenetic functional magnetic resonance imaging (ofMRI) technology, enables us to selectively trigger specific neuronal populations within the brain while monitoring how activity in regions across the brain are altered as a result of such stimulations. Optogenetics enables cell-type specific, millisecond-scale, activity modulation using light while high-field fMRI tracks resulting responses in live subjects across the whole brain. In the initial study, it was shown tha specific cell-type triggered fMRI responses could be measured throughout the brain with temporal precision. Since we first developed the ofMRI technology, we developed advanced imaging technologies to enable high-throughput, high-resolution images in live subjects. With these advances in place, we acquired preliminary ofMRI datasets, through which we have evidence that dopamine D1 and D2 receptor expressing medium spiny neuron (MSN)-driven dynamic interactions across the whole brain can be reliably measured across multiple synapses. Electrophysiological recordings also show strong evidence that the time course of the ofMRI signal closely matches underlying electrical activity patterns. With this unprecedented ability to obtain global brain dynamics associated with cell- type specific modulations, we aim to determine the global direct and indirect pathway functions. These measurements will then be computationally modeled to provide a mechanistic understanding. In addition, resting-state fMRI measurements will be made during systematically increased and decreased excitability of D1 or D2 MSN. This will enable us to evaluate how the direct and indirect pathway imbalance is reflected in resting-state fMRI measurements, and allow direct translation of the findings into clinical neuroimaging.

 描述（由适用提供）：神经刺激疗法的最新成功，例如深脑刺激（DBS）对帕金森氏病（PD）（PD）支持了解特定局部神经元种群的活动的重要性，以使整个脑网络的活动如何影响诸如驱动诸如帕金森氏病的震颤之类的行为。鉴于由此产生的复杂行为输出，大脑刺激的影响可能不限于简单地改变局部神经元活动。局部变化是在大脑的许多地区推动神经元活动，从而引起治疗作用。然而，这个重要的神经生物学问题关于大规模网络活动与行为的关系如何仍然很大程度上仍然是弹性。了解特定的神经元与整体大脑之间的关系如何使我们能够根据我们对我们对电路功能的具体知识的知识来系统地设计神经系统疾病的治疗剂。神经疾病的主要理论目标在于逆转行为表型，例如基本震颤，这是丧失适当电路功能的直接结果。如果电路函数 可以直接看到潜在的行为，热干预的潜力受到限制。因此，在此提案中，我们旨在启动与巴萨神经节电路相关的反向工程全球脑动力学，并了解它们与运动行为的关系。新型的光遗传学功能磁共振成像（OFMRI）技术使我们能够选择性地触发大脑内的特定神经元种群，同时监测活动的方式 由于这种刺激，整个大脑的区域都会改变。光遗传学可实现特异性细胞类型，毫秒尺度的活动调制，而高场fMRI轨道则可以调制 在整个大脑的现场受试者中产生的反应。在最初的研究中，可以以暂时的精度在整个大脑中测量触发fMRI反应的特定细胞类型。自从我们首次开发MRI技术以来，我们开发了高级成像技术，以实现现场主题中的高通量，高分辨率图像。有了这些进步，我们获得了MRI数据集的初步，我们有证据表明多巴胺D1和D2受体表达培养基神经元（MSN）驱动的整个大脑中的动态相互作用可以可靠地测量多个突触。电生理记录还显示了有力的证据表明，MRI信号的时间过程与电活动模式的潜在性匹配密切匹配。凭借这种前所未有的能力，可以获得与细胞类型特定调制相关的全局脑动力学，我们旨在确定全局直接和间接途径函数。然后，将对这些测量值进行计算建模，以提供机械理解。此外，在系统地增加和减少D1或D2 MSN的兴奋期间，将进行静止状态fMRI测量。这将使我们能够评估如何在静止状态fMRI测量中反映直接和间接途径的不平衡，并允许将发现直接转换为临床神经影像学。