Project 2

摘要 我们建议研究神经调节在“全皮质”活动现象中的作用。 软脑膜神经血管回路。这个回路是由软膜小动脉组成的网络，它整合了神经元。 内源性小动脉血管运动的活动产生相干振荡的动态模式 小动脉直径有效分离皮质外套膜。 先前的研究表明，上升的神经调节系统可能并行工作，影响大脑状态。 以及大规模大脑皮层网络的处理能力。然而，在大多数这些研究中， 大脑皮层中神经调节性神经递质的存在没有被直接测量到。相反，他们的释放 是从刺激相应的皮质下核团或间接措施推断出来的。要克服这一点 限制，在提议的项目中，我们将使用直接、选择性和灵敏的光学探头来 乙酰胆碱、去甲肾上腺素、多巴胺和5-羟色胺并跟踪这些神经递质的存在 在清醒行为的小鼠的大脑皮层外套层的空间和时间上。我们将把这些探测器与 神经元钙离子光学成像，血液氧合，光学透明电极阵列，光发生 手法和大胆的功能磁共振成像。使用这些工具，包括我们团队成员首创的工具，我们 将讨论神经调节在产生(I)大规模自发皮质神经元活动中的作用 用广视场钙成像观察(II)软脑膜神经血管运动的时间相关模式 以及(Iii)血流动力学波动的时空模式。此外，我们问是否 这些血管运动和血流动力学的时空模式，可以无创地测量，可以 用于推断潜在的大脑内部状态和/或特定神经调节系统的活动。 我们将与项目1合作，了解神经调节驱动与局部整合的规则 软脑膜神经血管环路内的神经元活动和本征振荡动力学。我们还将合作 与项目3合作，以确保我们的发现从老鼠到人类的规模向上转换。到项目的关键链接 3将在清醒的小鼠中同时进行光学/功能磁共振研究。最后，我们将与项目4一起设计一个 现象学数学模型，从大脑状态的角度捕捉大脑状态的本质 血管积分器，产生连贯的血管/血流动力学波动的大规模模式。 该项目将提供一种新的、史无前例的观点，即神经调节在协调大型- 衡量自发的神经元和血流动力学活动，探索潜在的机制，并提供强大的 解释大规模fMRI信号的生理学基础和更好地理解 将自发神经元活动与认知能力联系起来的机制。与其他人合作 项目，我们将提供一个预测性的、概念性的Pial局部和全球控制模型。 人类的神经血管回路和大脑状态的推断以及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.