MAPPING FUNCTIONAL CONNECTIVITY WITH FLUORESCENCE MOLECULAR TOMOGRAPHY

项目摘要： 静息态功能连接分析的自发脑活动功能映射 功能磁共振成像数据最近已成为绘制人类大脑功能的主要方法，并继续 来获得动力然而，功能磁共振成像是基于脑血流动力学， 耦合到神经元活动，并且慢得多（~0.3 Hz）。进一步阐明FC的生理基础 相对未解决的，这样的机制和影响改变FC往往不清楚。为 例如，在缺血性中风中，众所周知，缺血核心周围的半暗带已经改变 神经血管耦合（NVC），使FC缺陷的解释复杂化。由于FC措施 进一步扩展到大脑发育，衰老和疾病的研究，了解 FC的基础将得到发展。我们最近开发了功能性心脏瓣膜的血流动力学标测， 使用光学固有信号成像（fcOIS）在小鼠中进行了连接，并发现fcOIS对几种 神经系统疾病，包括中风和阿尔茨海默病的小鼠模型。但随着 随着小鼠基因工程技术的出现，有新的机会来扩展光学 对钙活动的宽场成像，速度快10倍以上，与神经活动的耦合更直接 血红蛋白。通过结合钙和血流动力学成像，有可能量化 细胞特异性钙动力学与整个脑区血流动力学之间的关系。 进一步的钙和血红蛋白同步成像可能有助于解决以下问题： 在中风等疾病和早期大脑发育中改变NVC。然而，到目前为止， 已经开发了一个系统来检查整个小鼠皮层的这些丰富的关系。在这 项目，我们将开发光学成像硬件和软件，用于表征钙动力学， 基因编码钙指示剂（GECI's）的小鼠。对于示例应用， 功能网络正在迅速变化，我们将在中风恢复期间量化FC， 发展，跟踪功能连接和神经血管耦合（NVC）的进展。 目标一：发展荧光分子断层成像（FMT）和扩散光学断层成像（DOT） 用于小鼠中钙和血红蛋白的同时绘图的仪器。目标2将优化系统 用于小鼠脑功能的高速FMT/DOT的性能。目标3将建立FMT/DOT， 用GECIs绘制小鼠细胞特异性钙信号的功能网络。同时成像 将能够绘制神经血管耦合。在目标4中，确立了 FMT/DOT在中风恢复和脑发育中的作用在这两个应用程序中，我们将量化钙- FC和改变NVC对血红蛋白FC的影响。

Project Summary: Functional mapping of spontaneous brain activity with resting-state functional connectivity (FC) analysis of fMRI data has recently become a dominant approach to mapping human brain function and continues to gain momentum. However fMRI is based on cerebral hemodynamics that is relatively indirectly coupled to neuronal activity and much slower (~0.3 Hz). Further the physiological underpinnings of FC are relatively un-resolved, such that the mechanisms and implications altered FC are often unclear. For example in ischemic stroke, it is well known that the penumbra surrounding the ischemic core has altered neurovascular coupling (NVC), complicating the interpretation of the FC deficits. As FC measures are extended further into studies of brain development, aging and disease, the importance of understanding the fundamental basis for FC will grow. We recently developed hemodynamic mapping of functional connectivity in mice using optical intrinsic signal imaging (fcOIS), and found fcOIS sensitive to several neurological diseases, including mouse models of stroke and Alzheimer's disease. However, with the advent of genetic engineering techniques for mice, there are new opportunities for extending optical wide-field imaging to calcium activity, which is >10x faster and more directly coupled to neural activity than hemoglobin. By combining calcium and hemodynamic imaging, there is the potential to quantify the relationship between cell-specific calcium dynamics and hemodynamics throughout brain regions. Further concurrent calcium and hemoglobin imaging could help resolve questions about the impact of altered NVC in diseases such as stroke, and in early brain development. However, as yet, no imaging system has been developed to examine these rich relationships throughout the mouse cortex. In this project, we will develop optical imaging hardware and software for characterizing calcium dynamics in mice engineered for genetically encoded calcium indicators (GECI's). For exemplar applications where the functional networks are changing quickly, we will quantify FC during stroke recovery and brain development, tracking the progression of both functional connectivity and neurovascular coupling (NVC). Aim 1 will develop fluorescence molecular tomography (FMT) and diffuse optical tomography (DOT) instrumentation for concurrent mapping of calcium and hemoglobin in mice. Aim 2 will optimize system performance for high speed FMT/DOT of mouse brain function. Aim 3 will establish FMT/DOT for mapping the functional networks of cell-specific calcium signals in mice with GECIs. Concurrent imaging with hemoglobin will enable mapping of neurovascular coupling. In aim 4, with establish feasibility of FMT/DOT in both stroke recovery and brain developmental. In both applications we will quantify calcium- FC and the influence of altered NVC on hemoglobin-FC.