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

神经元、神经胶质和 BOLD fMRI 信号：从 BOLD 到 2 光子显微镜

• 批准号: 7729143
• 负责人: Anna Devor
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729143
• 关键词: Address; Application procedure; Astrocytes; Basic Science; Blood; Blood Flow Velocity; Blood Vessels; Blood flow; Brain; Calcium; Calcium Signaling; Caliber; Cells; Communication; Complex; Coupled; Coupling; Data; Development; Diagnostic; Dilatation - action; Disease; Dyes; Emotions; Exhibits; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Hematocrit procedure; Human; Image; Lasers; Maps; Measurement; Measures; Metabolism; Methods; Microscopic; Microscopy; Molecular; Monitor; Neurons; Optical Methods; Optics; Oxygen; Photons; Physiological Processes; Physiology; Process; Rattus; Relative (related person); Role; Second Messenger Systems; Sensory; Signal Transduction; Signal Transduction Pathway; Somatosensory Cortex; Stimulus; Surface; System; Veins; arteriole; base; blood oxygenation level dependent response; calcium indicator; cerebrovascular; clinical application; constriction; design; hemodynamics; improved; neuroimaging; neurovascular unit; novel therapeutics; optical imaging; public health relevance; response; second messenger; stroke rehabilitation; tool; venule; voltage

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The relationship between functional MRI (fMRI) signals and the underlying microscopic neurovascular unit (NVU) physiology is a central unresolved issue in the interpretation of human functional neuroimaging data. The main goal of this proposal is to combine quantitative optical measurements of hemodynamic and neuroglial signals directly with BOLD fMRI aiming for a mechanistic interpretation of BOLD signals in terms of activity of the underlying single cells and single blood vessels. The proposed project will provide a mechanistic framework for understanding of fMRI signals and ultimately will guide the development of novel therapeutic, preventative, and diagnostic approaches.

描述（由申请人提供）：功能性磁共振成像（fMRI）已成为人类功能性神经成像研究的首选方法，并开始进入临床应用，如监测中风康复。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血流动力学反应的潜在神经胶质细胞的活动和定量血流动力学参数。对疾病状态下的fMRI研究的解释更加模糊，因为它不仅需要了解神经血管耦合的机制，而且需要了解在神经血管缺陷的条件下改变的脑血管动力学对BOLD信号的影响。因此，到目前为止，功能磁共振成像数据的分析主要是相关性和描述性的。为了获得BOLD对比度和潜在的神经胶质细胞活性之间的关系的机械理解，必须考虑多个生理过程，从宏观的血液动力学变化到微观的神经血管通信。为此，我们将结合联合收割机直接和定量测量的血流动力学和神经元参数，同时与功能磁共振成像，旨在了解BOLD反应和潜在的神经胶质细胞活动之间的关系。然后，我们将建立大规模（人口）血流动力学和神经胶质细胞信号的微观相关性，并将整合宏观和微观测量。具体而言，在Aim1中，我们将通过采用血氧和血流的同时光学成像来表征血液动力学方面的BOLD信号。在Aim2中，我们将通过同时进行钙成像（使用荧光钙指示剂）和电压敏感染料成像，建立刺激诱导的BOLD反应与潜在的神经元和星形胶质细胞活性之间的相关性。我们选择钙作为神经胶质细胞活性的指标是基于其公认的作用，作为一个重要的第二信使在多个分子信号转导途径，包括那些密切参与神经血管通信。最后，我们将通过使用双光子显微镜建立大规模血流动力学和钙信号的显微相关性（目标3）。宏观功能磁共振成像和钙测量与双光子数据的整合将允许BOLD信号的潜在的单细胞和单血管的活动方面的机械解释。公共卫生关系：功能磁共振成像（fMRI）信号和潜在的微观神经血管单位（NVU）生理之间的关系是一个中心的未解决的问题，在人类功能神经影像数据的解释。该建议的主要目标是将血液动力学和神经胶质信号的定量光学测量直接与BOLD fMRI结合联合收割机，旨在根据潜在的单细胞和单血管的活性对BOLD信号进行机械解释。该项目将为理解fMRI信号提供一个机制框架，并最终指导新的治疗，预防和诊断方法的开发。