Dynamic regulation of whole brain circuit function by basal ganglia pathways

 描述(申请人提供)：最近深部脑刺激(DBS)治疗帕金森病(PD)等神经刺激疗法的成功支持了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(如帕金森病的逆转震颤)的重要性。考虑到由此产生的复杂的行为输出，大脑刺激的影响很可能不仅仅限于改变局部神经元的活动。这种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，大规模网络活动与行为之间的关系这个重要的神经生物学问题在很大程度上仍然难以捉摸。了解特定的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潜在行为的电路功能的具体知识，系统地设计神经疾病的治疗方法。神经系统疾病的主要治疗目标在于逆转行为表型，如特发性震颤，这些表型是丧失正常电路功能的直接结果。如果电路运行正常 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，在这项提议中，我们的目标是开始对与基底节回路相关的全球脑动力学进行反向工程，并了解它们与运动行为的关系。新的光遗传功能磁共振成像(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，同时监控 在这种刺激下，大脑的各个区域都会发生变化。光遗传学实现了在高场fMRI跟踪时，利用光对细胞类型进行毫秒级的活动调制 从而在整个大脑的活体受试者中产生反应。在最初的研究中，研究表明，特定细胞类型触发的fMRI反应可以在整个大脑中以时间精度进行测量。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，以实现在活体受试者中进行高通量、高分辨率的图像。有了这些进展，我们获得了初步的MRI数据集，通过这些数据集，我们有证据表明，可以可靠地跨多个突触测量整个大脑中由中棘神经元(MSN)驱动的动态相互作用。电生理记录也显示出强有力的证据表明，ofMRI信号的时间进程与潜在的电活动模式密切匹配。有了这种前所未有的能力来获得与细胞类型特定调制相关的全球脑动力学，我们的目标是确定全球直接和间接途径功能。然后，将对这些测量进行计算建模，以提供机械上的理解。此外，在D1MSN或D2MSN兴奋性的系统性增加和降低期间，进行静息状态的fMRI测量。这将使我们能够评估直接和间接通路失衡如何反映在静息状态的fMRI测量中，并允许将发现直接转化为临床神经成像。

 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.