Neuronal, glial and BOLD fMRI signals: From BOLD to 2-photon microscopy

摘要 功能性磁共振成像（fMRI）已成为人类功能成像的首选方法。 神经影像学研究，并开始进入临床应用，如监测中风 康复活动.然而，在目前的实践中，功能磁共振成像遭受的不确定关系的成像 对潜在神经胶质细胞活性的血流动力学反应和定量血流动力学参数。 对疾病状态下的功能磁共振成像研究的解释甚至更加模糊，因为它不仅需要 了解神经血管耦合的机制，但改变脑血管动力学的影响 在神经血管缺陷的情况下，BOLD信号。因此，迄今为止，对功能磁共振成像数据的分析 在很大程度上是相关的和描述性的。为了获得一个机械的理解的关系 在BOLD对比和潜在的神经胶质细胞活动之间，必须考虑多种生理学因素。 从宏观的血液动力学变化到微观的神经血管通信。本 最后，我们将联合收割机直接定量测量血流动力学和神经元参数相结合， 同时进行fMRI，旨在了解BOLD反应与 潜在的神经胶质活动然后，我们将建立大规模（人口） 血液动力学和神经胶质信号，并将整合宏观和微观测量。具体到 目的1我们将通过采用同步光学成像来表征血液动力学方面的BOLD信号， 血液氧合和血液流动。在目标2中，我们将建立刺激诱导的BOLD之间的相关性。 反应和潜在的神经元和星形胶质细胞的活动，通过执行同步钙成像 （使用荧光钙指示剂）和电压敏感染料成像。我们选择钙作为 神经胶质细胞活性的指标是基于其作为多个神经细胞中重要的第二信使的公认作用。 分子信号转导途径，包括那些密切参与神经血管通讯。 最后，我们将建立大规模血流动力学和钙信号的微观相关性， 2-光子显微术（Aim 3）。宏观fMRI和钙测量与双光子数据的整合 将允许BOLD信号在潜在的单细胞和单个细胞的活性方面的机械解释。 血管 1

Abstract Functional Magnetic Resonance Imaging (fMRI) has become a method of choice for human functional neuroimaging studies, and is beginning to make inroads into clinical applications such as monitoring of stroke rehabilitation. However, in current practice, fMRI suffers from the uncertain relation of the imaged hemodynamic responses to the underlying neuroglial activity and quantitative hemodynamic parameters. Interpretation of fMRI studies in disease states are even more ambiguous since it requires not only understanding the mechanisms of neurovascular coupling but the impact of altered cerebrovascular dynamics on the BOLD signal under conditions of neurovascular deficit. As a result, the analysis of fMRI data has so far been largely correlational and descriptive. In order to gain a mechanistic understanding of the relationship between BOLD contrast and the underlying neuroglial activity, one has to consider multiple physiological processes, from macroscopic hemodynamic changes to the microscopic neurovascular communication. To this end, we will combine direct and quantitative measurement of hemodynamic and neuronal parameters simultaneously with fMRI aiming to understand the relationship between the BOLD response and the underlying neuroglial activity. We then will establish microscopic correlates of large-scale (populational) hemodynamic and neuroglial signals and will integrate macro- and microscopic measurements. Specifically, in Aim1 we will characterize BOLD signals in hemodynamic terms by employing simultaneous optical imaging of blood oxygenation and blood flow. In Aim2 we will establish a correlation between stimulus-induced BOLD response and the underlying neuronal and astrocytic activity by performing simultaneous calcium imaging (using fluorescent calcium indicators) and voltage-sensitive dyes imaging. Our choice of calcium as an indicator of neuroglial activity is based on its recognized role as an important second messenger in multiple molecular signal transduction pathways, including those intimately involved in neurovascular communication. Finally, we will establish microscopic correlates of the large-scale hemodynamic and calcium signals by using 2-photon microscopy (Aim 3). Integration of macroscopic fMRI and calcium measurements with 2-photon data will allow a mechanistic interpretation of BOLD signals in terms of activity of underlying single cells and single blood vessels. 1