Excitatory and Inhibitory Activity Contributions to Hemodynamic Signals

项目摘要/摘要 评估大脑功能和连接性的大多数方法，包括功能磁共振成像 (功能磁共振成像)和内在信号的光学成像(OIS)，依赖于活动诱发的脑血流变化， 血容量和/或血氧饱和度作为神经活动的间接测量。而这些血流动力学 方法对于绘制人类和动物的大脑功能和连接性图是非常有价值的，基本 由于其复杂性和方法学的原因，我们对神经血管机制的理解仍然存在差距 困难。这种知识上的差距极大地阻碍了我们对驱动神经过程的理解。 在大胆的脑功能、功能障碍和发育的fMRI结果背后。这项提议的目标是 确定兴奋性和抑制性神经元活动的作用，包括谷氨酸能和GABA能 突触活动，在血管调节中及其在血流动力学信号中的表现。要激活特定的 体内神经元亚群，表达通道视紫红质-2(ChR2)的新型光遗传小鼠模型 将使用皮质兴奋性或抑制性神经元。这些光遗传模型将与一种 一种在药理学条件下同时记录神经和血管信号的创新方法 旨在调节谷氨酸和氨基丁酸能突触传递。神经活动将通过以下方式来衡量 电生理学和双光子钙成像。血管血流信号将通过激光获得 多普勒血流计，而OIS将用于成像脑血容量和血氧饱和度的变化 (直接类似于功能磁共振成像)。这些数据将被用来模拟和整合兴奋性和抑制性 活动对血流动力学信号的贡献。这项工作将产生巨大的影响，推动我们的 了解相关的神经血管机制，并建立一个更具体的框架， 可以更深入地了解大脑血流动力学变化背后的神经过程 发育和功能障碍。

PROJECT SUMMARY/ABSTRACT Most approaches to assess brain function and connectivity, including functional magnetic resonance imaging (fMRI) and optical imaging of intrinsic signals (OIS), rely on activity-evoked changes in cerebral blood flow, blood volume and/or blood oxygenation as indirect measures of neural activity. While these hemodynamic methods are immensely valuable to map brain function and connectivity in humans and animals, fundamental gaps remain in our understanding of neuro-vascular mechanisms due to its complexity and methodological difficulties. This gap in knowledge greatly impedes our understanding of the driving neuronal processes behind BOLD fMRI findings of brain function, dysfunction and development. The goal of this proposal is to determine the role of excitatory and inhibitory neuronal activity, including glutamatergic and GABAergic synaptic activity, in vascular regulation and their representation in hemodynamic signals. To activate specific neuronal sub-populations in vivo, novel optogenetic mouse models expressing Channelrhodopsin-2 (ChR2) in cortical excitatory or inhibitory neurons will be used. These optogenetic models will be combined with an innovative approach to concurrently record neural and vascular signals under pharmacological conditions designed to modulate glutamatergic and GABAergic synaptic transmission. Neural activity will be measured by electrophysiology and two-photon calcium imaging. Vascular signals of blood flow will be obtained by laser Doppler flowmetry, while OIS will be used to image changes in cerebral blood volume and blood oxygenation (directly analogous to fMRI). These data will then be used to model and integrate excitatory and inhibitory activity contributions to hemodynamic signals. This work will have a tremendous impact by advancing our understanding of relevant neuro-vascular mechanisms as well as establish a more concrete framework that can allow for a deeper understanding of the neuronal processes behind hemodynamic alterations in brain development and dysfunction.