Dynamic regulation of whole brain circuit function by basal ganglia pathways

 描述（由申请人提供）：神经刺激疗法（如深部脑刺激（DBS））治疗帕金森病（PD）的近期成功支持了解特定局部神经元群体的活动如何影响整个大脑网络以驱动行为（如逆转帕金森病中的震颤）的重要性。考虑到由此产生的复杂行为输出，大脑刺激的影响可能不仅限于简单地改变局部神经元活动。局部变化正在驱动大脑许多区域的神经活动，从而产生治疗效果。然而，这个重要的神经生物学问题，即大规模网络活动与行为的关系，在很大程度上仍然是难以捉摸的。了解特定神经元群体在功能上如何与整个大脑相关，使我们能够根据我们对行为背后的电路功能的具体知识，系统地设计神经系统疾病的治疗方法。神经系统疾病的主要治疗目标在于逆转行为表型，例如原发性震颤，其是适当回路功能丧失的直接后果。如果电路功能 潜在的行为可以直接可视化，治疗干预的潜力是无限的。因此，在这个提议中，我们的目标是开始逆向工程与基底神经节回路相关的全球大脑动力学，并了解它们如何与运动行为相关。新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中特定的神经元群体，同时监测活动如何 大脑中的某些区域会因为这种刺激而改变。光遗传学使细胞类型特异性，毫秒级，活动调制使用光，而高场功能磁共振成像跟踪 导致活体受试者的整个大脑产生反应。在最初的研究中，研究人员发现，特定细胞类型触发的功能磁共振成像反应可以在整个大脑中以时间精度测量。自从我们首次开发ofMRI技术以来，我们开发了先进的成像技术，以实现活体受试者的高通量，高分辨率图像。随着这些进展的到位，我们获得了初步的ofMRI数据集，通过这些数据集，我们有证据表明，多巴胺D1和D2受体表达中型多刺神经元（MSN）驱动的整个大脑的动态相互作用可以在多个突触上可靠地测量。电生理记录也显示出强有力的证据表明ofMRI信号的时间过程与潜在的电活动模式密切匹配。利用这种前所未有的获得与细胞类型特异性调节相关的全局脑动力学的能力，我们的目标是确定全局直接和间接通路功能。然后将这些测量值进行计算建模，以提供机械的理解。此外，静息状态的功能磁共振成像测量将在系统增加和减少兴奋性的D1或D2 MSN。这将使我们能够评估直接和间接途径的不平衡是如何反映在静息状态的功能磁共振成像测量，并允许直接翻译的结果到临床神经影像学。

 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.