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.