Project 2

摘要 我们建议研究神经调节在大脑皮层“全皮层”活动现象中的作用， 软膜神经血管回路该回路由整合神经元的软脑膜小动脉网络组成 活动与内在的小动脉血管运动产生动态模式的连贯振荡，在 小动脉直径有效地分隔皮质套。 先前的研究表明，提升的神经调节系统可能会并行工作，影响大脑状态 和大规模皮层网络的处理能力。然而，在大多数这些研究中， 没有直接测量皮质中神经调节神经递质的存在。相反，他们的释放 是从刺激相应的皮层下核团或间接措施推断。为了克服这个 限制，在拟议的项目中，我们将使用直接，选择性和敏感的光学探针， 乙酰胆碱，去甲肾上腺素，多巴胺和血清素，并跟踪这些神经递质的存在 在空间和时间上穿越大脑皮层。我们将联合收割机与 神经元钙离子光学成像，血氧，光学透明电极阵列，光遗传学 操作和BOLD功能磁共振成像。使用这些工具，包括我们团队成员开创的工具，我们 将讨论神经调节在产生（i）大规模自发皮层神经元活动中的作用 观察宽场钙离子成像，（ii）在软膜神经血管的血管运动的时间相干模式 电路，和（iii）由此产生的血流动力学波动的时空模式。此外，我们还问， 血管运动和血液动力学的这些时空模式可以被无创地测量， 用于推断特定神经调节系统的潜在内部脑状态和/或活动。 我们将与项目1合作，以了解神经调节驱动与局部神经元整合的规则。 软膜神经血管回路内的神经元活动和内在振荡动力学。我们还将合作 与项目3合作，以确保我们的发现从小鼠到人类的规模。项目的关键链接 3将在清醒小鼠中同时进行光学/fMRI研究。最后，我们将与项目4合作， 现象学的数学模型，捕捉大脑状态的本质，从的立场， 血管积分器产生相干血管/血液动力学波动的大规模模式。 该项目将提供一个新的，前所未有的观点，神经调节的作用，在编排大- 规模自发神经元和血流动力学活动，探索潜在的机制，并提供了一个强大的 解释大规模fMRI信号和更好地理解 将自发神经元活动与认知表现联系起来的机制。协同其他 项目，我们将提供一个预测性的，概念模型的本地和全球控制软脑膜 神经血管回路和大脑状态的推断以及人类中特定的神经调节回路。

Abstract We propose to investigate the role of neuromodulation in the phenomenon of “whole-cortex” activity of the pial neurovascular circuit. This circuit is composed of a network of pial arterioles that integrate neuronal activity with the intrinsic arteriolar vasomotion producing dynamic patterns of coherent oscillations in the arteriolar diameter effectively parcellating the cortical mantle. Prior research suggests that ascending neuromodulatory systems may work in parallel affecting the brain state and processing capacity of large-scale cortical networks. In the majority of these studies, however, the presence of neuromodulatory neurotransmitters in the cortex was not directly measured. Rather, their release was inferred from stimulation of the corresponding subcortical nuclei or indirect measures. To overcome this limitation, in the proposed project we will use direct, selective and sensitive optical probes for acetylcholine, norepinephrine, dopamine and serotonin and track the presence of these neurotransmitters in space and time across the cortical mantle in awake behaving mice. We will combine these probes with optical imaging of neuronal Ca2+, blood oxygenation, optically transparent electrode arrays, optogenetic manipulations and BOLD fMRI. Using these tools, including those pioneered by the members of our team, we will address the role of neuromodulation in generation of (i) large-scale spontaneous cortical neuronal activity observed with wide-field Ca2+ imaging, (ii) temporally coherent patterns of vasomotion in the pial neurovascular circuit, and (iii) the resultant spatiotemporal pattern of hemodynamic fluctuations. Further, we ask whether these spatiotemporal patterns of vasomotion and hemodynamics, which can be measured noninvasively, can be used to infer the underlying internal brain state and/or activity of specific neuromodulatory systems. We will collaborate with Project 1 to understand the rules of integration of the neuromodulatory drive with local neuronal activity and intrinsic oscillatory dynamics within the pial neurovascular circuit. We will also collaborate with Project 3 to ensure that our findings translate up the scale from mice to humans. A critical link to Project 3 will be simultaneous optical/fMRI studies in awake mice. Finally, we will work with Project 4 to devise a phenomenological mathematical model that captures the essence of a brain state from the standpoint of the vascular integrator producing large-scale patterns of coherent vascular/hemodynamic fluctuations. This Project will provide a novel, unprecedented view on the role of neuromodulation in orchestrating large- scale spontaneous neuronal and hemodynamic activity, explore the underlying mechanisms, and offer a strong physiological foundation for the interpretation of large-scale fMRI signals and better understanding of the mechanisms linking spontaneous neuronal activity to cognitive performance. In collaboration with other Projects, we will deliver a predictive, conceptual model of local and global control of the pial neurovascular circuit and inference of brain states and specific neuromodulatory circuits in humans.