Project 2

项目2

• 批准号: 10649646
• 负责人: Anna Devor
• 金额: $ 85.78万
• 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/10649646
• 关键词: Acetylcholine; Affect; BRAIN initiative; Behavioral; Blood; Blood Vessels; Brain; Cell Nucleus; Collaborations; Diameter; Dopamine; Electrodes; 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“全皮质”活动现象中的作用 软脑膜神经血管回路。该回路由软脑膜小动脉网络组成，该网络整合了神经元 与内在小动脉血管舒缩的活动产生相干振荡的动态模式 小动脉直径有效地分割皮质套。 先前的研究表明，上行神经调节系统可能同时影响大脑状态 和大规模皮质网络的处理能力。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 通过刺激相应的皮层下核团或间接测量来推断。为了克服这个 限制，在拟议的项目中，我们将使用直接、选择性和灵敏的光学探针 乙酰胆碱、去甲肾上腺素、多巴胺和血清素并追踪这些神经递质的存在 在清醒行为小鼠的空间和时间上穿越皮质地幔。我们将把这些探针与 神经元 Ca2+ 光学成像、血氧、光学透明电极阵列、光遗传学 操作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 将解决神经调节在产生（i）大规模自发皮质神经元活动中的作用 通过宽视野 Ca2+ 成像观察到，(ii) 软脑膜神经血管中血管运动的时间相干模式 电路，以及（iii）由此产生的血流动力学波动的时空模式。进一步，我们问是否 这些可以无创测量的血管舒缩和血流动力学的时空模式可以 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，了解神经调节驱动与局部神经调节的整合规则。 软脑膜神经血管回路内的神经元活动和内在振荡动力学。我们也将合作 与项目 3 合作，确保我们的发现能够从小鼠扩展到人类。项目的关键链接 3 将在清醒小鼠中同时进行光学/功能磁共振成像研究。最后，我们将与项目 4 合作设计一个 从现象学的角度捕捉大脑状态本质的数学模型 血管积分器产生大规模的连贯血管/血流动力学波动模式。 该项目将为神经调节在协调大规模神经调节中的作用提供一种新颖的、前所未有的观点。 衡量自发神经元和血流动力学活动，探索潜在机制，并提供强大的 为解释大规模功能磁共振信号和更好地理解功能奠定了生理基础 将自发神经元活动与认知表现联系起来的机制。与其他人合作 在项目中，我们将提供局部和全局控制脑膜的预测性概念模型 神经血管回路以及人类大脑状态和特定神经调节回路的推断。