In-vivo optical imaging of neurovascular coupling and cerebral metabolism

描述（由申请人提供）：皮质血流量的局部增加被广泛接受来报告大脑中神经元活动的存在和位置。这种血流动力学反应是功能性脑成像方法的基础，如功能性磁共振成像（fMRI）。然而，大脑控制这些血液流动的方式发生了变化，甚至血液动力学反应的潜在目的仍然未知。越来越多的证据表明，血液动力学反应的调节受损可能是与年龄相关的神经变性的基础，并可能与阿尔茨海默氏症等疾病的进展有关。目前迫切需要一个全面的模型来解释大脑中神经元和血流动力学反应之间耦合的机制。迄今为止，缺乏一个结论性的模型，部分原因是在对正常、功能完整的活体大脑进行成像时面临的困难。单独研究潜在机制的体外研究都难以与其他体外结果进行比较，也难以与体内观察结果相一致。然而，开发能够获得足够分辨率、灵敏度和对比度的体内成像范式是极具挑战性的，以获得神经元、代谢和血管过程的完整图像，这些过程共同产生对激活的血流动力学反应。我们开发了一套先进的光学成像和显微镜工具，用于体内检查神经血管耦合。我们计划利用广泛的光学对比，包括氧和脱氧血红蛋白，钙敏感染料，细胞特异性染料，表达荧光蛋白的转基因小鼠，以及能量代谢的内在荧光底物，如NADH和FAD。我们建议改进和应用我们的成像工具来解决以下两个基本的重要问题：“皮层血管系统是如何被物理调节的？”和“为什么会发生血流动力学反应？”我们的多尺度和多参数成像方法提供了充分表征调节和控制血流动力学反应的物理机制的机会，并在细胞水平上研究反应的代谢基础及其与能量供需的关系。我们相信，这些研究将导致神经血管耦合的综合模型。我们还预计，我们开发的成像技术，以及我们对健康大脑的仔细表征，将为未来对疾病的细胞、代谢和神经血管基础的体内研究扫清道路。

DESCRIPTION (provided by applicant): A local increase in cortical blood flow is widely accepted to report the presence and location of neuronal activity in the brain. This hemodynamic response is the basis of functional brain imaging methods such as functional Magnetic Resonance Imaging (fMRI). Yet the way that the brain controls these blood flow changes, and even the underlying purpose of the hemodynamic response are still unknown. There is growing evidence that impairments in regulation of the hemodynamic response may underlie age-related neurodegeneration, and can be linked to the progression of diseases such as Alzheimer's. A comprehensive model of the mechanisms underlying the coupling between neuronal and hemodynamic responses in the brain is urgently needed. The lack of a conclusive model to date is due, in part, to the difficulties faced in imaging the normal, functioning, intact brain in-vivo. In-vitro studies which investigate potential mechanisms in isolation are uniformly difficult to compare with other in-vitro results, and to reconcile with in-vivo observations. However, it is highly challenging to develop in-vivo imaging paradigms capable of achieving sufficient resolution, sensitivity and contrast to gain a complete picture of the neuronal, metabolic and vascular processes which together generate the hemodynamic response to activation. We have developed a suite of advanced optical imaging and microscopy tools for in-vivo examination of neurovascular coupling. We plan to exploit a wide range of optical contrasts including oxy- and deoxyhemoglobin, calcium sensitive dyes, cell-specific dyes, transgenic mice expressing fluorescent proteins, and intrinsically fluorescent substrates of energy metabolism such as NADH and FAD. We propose to refine and apply our imaging tools to address the following two fundamentally important questions: 'How is the cortical vasculature physically modulated?' and 'Why does the hemodynamic response happen?' Our multi-scale and multi-parametric imaging approaches offer the chance to both fully characterize the physical mechanisms which modulate and control the hemodynamic response, and to investigate the metabolic basis of the response and its relation to energy supply and demand at a cellular level. We believe that these studies will lead to a comprehensive model of neurovascular coupling. We also anticipate that the imaging techniques that we develop, and our careful characterization of the healthy brain, will clear the way for future in-vivo research into the cellular, metabolic and neurovascular underpinnings of disease.