Project 2

项目2

• 批准号: 10294713
• 负责人: Anna Devor
• 金额: $ 57.22万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294713
• 关键词: Acetylcholine; Address; Affect; BRAIN initiative; Behavioral; Blood; Blood Vessels; Brain; Caliber; Cell Nucleus; Collaborations; Dopamine; Electrodes; Ensure; Foundations; Functional Magnetic Resonance Imaging; Generations; Goals; Human; Image; Link; Measures; Modeling; Mus; Neuromodulator; Neurons; Neurotransmitters; Norepinephrine; Optics; Pattern; Performance; Physiological; Predictive Value; Research; Role; Serotonin; Signal Transduction; System; Testing; Time; Translating; Work; arteriole; awake; behavioral outcome; cognitive performance; experimental study; hemodynamics; mathematical model; member; neuronal patterning; neuroregulation; neurovascular; novel; optical imaging; optogenetics; phenomenological models; response; scale up; spatiotemporal; tool; vasomotion

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.

抽象的 我们建议研究神经调节在“全皮层”活性现象中的作用 伴有神经血管电路。该电路由整合神经元的小动脉网络组成 具有内在的动脉血管症的活性，产生动态振荡的动态模式 小动脉直径有效地塑造了皮质地幔。 先前的研究表明，上升神经调节系统可能会平行地影响大脑状态 和大规模皮质网络的处理能力。但是，在大多数研究中， 没有直接测量皮质中神经调节性神经递质的存在。相反，他们的释放 是根据刺激相应的皮层核或间接度量的刺激来推断的。克服这一点 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问题 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 在醒着的行为小鼠中的皮质地幔的空间和时间上。我们将将这些问题与 神经元Ca2+的光学成像，血液氧合，光学透明电极阵列，光遗传学 操纵和大胆的fMRI。使用这些工具，包括我们团队成员开创的工具，我们 将解决神经调节在（i）大规模赞助的皮质神经元活动中的作用 用广阔的Ca2+成像观察到（ii）暂时相干的血管舒张症模式 电路和（iii）血流动力学波动的最终空间时间模式。此外，我们问是否 可以无创测量的血管舒张和血液动力学的时空模式 用于推断特定神经调节系统的潜在内部大脑状态和/或活动。 我们将与项目1合作，以了解神经调节驱动器与本地的整合规则 神经元活性和内在的振荡动力学。我们还将合作 使用项目3，以确保我们的发现将从小鼠到人类的规模转化为。项目的关键链接 3将是清醒小鼠中简单的光学/fMRI研究。最后，我们将与项目4一起设计 现象学数学模型从脑状态捕获了脑状态的本质 血管积分物产生相干血管/血流动力学波动的大规模模式。 该项目将提供一种新颖的，前所未有的观点，说明神经调节在精心策划大型的角色中的作用 比例赞助神经元和血液动力学活性，探索潜在的机制，并提供强大的 解释大型fMRI信号的生理基础，并更好地理解 将赞助神经元活性与认知性能联系起来的机制。与其他 项目，我们将提供对PIAL的本地和全球控制的预测性，概念模型 神经血管电路和大脑状态的推断和人类特定的神经调节回路。