Simultaneous optical voltage imaging and fMRI in behaving mice

摘要 在大脑研究的各个领域中，大脑成像是最受普通观众欢迎的。由于 随着成像技术的进步，我们可以“看到”大脑的活动。最有前途的， 广泛使用的非侵入性成像技术是功能性磁共振成像（fMRI），其基于 血氧水平依赖（BOLD）对比。然而，这种技术的生理基础是 仍然知之甚少。电记录和体内双光子钙成像使我们能够 了解已识别神经元群体的功能。今天的一个主要挑战是将这些 微观神经科学的见解，这需要侵入性成像和记录工具，与宏观 非侵入性功能磁共振成像信号。 为了应对这一挑战，我建议将联合收割机与电神经元活动的光学成像结合起来， 与清醒行为小鼠的BOLD fMRI测量同时进行。这些实验将利用 一个兼容MRI的光学成像仪，我已经设计并集成到一个动物保持器， 第一个目标（Aim 1）。在新的目标1中，我将探讨细胞类型特异性神经元 电压和BOLD fMRI信号在自发和任务诱导的神经元活动。BOLD信号可以 积极和消极的，从我的实验室以前的发现表明，一个特定的重要性， 皮质抑制性神经元群释放信号分子神经肽Y（NPY），导致 通过Y1受体的血管收缩。在新的目标2中，我将讨论NPY阳性神经元在 BOLD信号的产生。为此，我将结合联合收割机电压成像和BOLD功能磁共振成像与光遗传学 沉默NPY阳性神经元和拮抗NPY-Y1通路。 从技术的角度来看，我的研究将是第一个在MRI扫描仪内进行电压成像的研究。 在生物学方面，我的研究将提供经验数据，解决细胞类型之间的关系， 特定的神经元活动和BOLD信号，并评估特定的宏观成像的依赖性 信号负BOLD -具体的细胞/分子途径。在我的论文项目中，我 我将扩大我的科学知识基础，制作高知名度的出版物，并为我的研究奠定基础。 未来的职业是独立调查员。

Abstract Among the various areas in brain research, brain imaging is the most appreciated by a general audience. Due to recent advances in imaging technologies, we can “see” brain in action. One of the most promising and widely used noninvasive imaging technologies is functional Magnetic Resonance Imaging (fMRI) based on the Blood Oxygenation Level Dependent (BOLD) contrast. However, the physiological basis of this technique is still poorly understood. Electrical recordings and in vivo 2-photon calcium imaging have enabled us to understand functions of identified neuronal populations. A major challenge of today is to connect these microscopic neuroscience insights, which require invasive imaging and recording tools, with macroscopic noninvasive fMRI signals. To address this challenge, I propose to combine optical imaging of electrical neuronal activity simultaneously with BOLD fMRI measurements in awake behaving mice. These experiments will leverage an MRI-compatible optical imager that I have engineered and integrated into an animal holder since the first submission (the old Aim 1). In the new Aim 1, I will explore the relationship of cell-type-specific neuronal voltage and BOLD fMRI signals during spontaneous and task-induced neuronal activity. The BOLD signal can be both positive and negative, and previous findings from my lab demonstrate the importance of a specific population of cortical inhibitory neurons that release a signaling molecule Neuropeptide Y (NPY) causing vasoconstriction via Y1 receptors. In the new Aim 2, I will address the role of NPY-positive neurons in generation of BOLD signals. To this end, I will combine voltage imaging and BOLD fMRI with optogenetic silencing of NPY-positive neurons and antagonizing the NPY-Y1 pathway. From a technological perspective, my study will be the first to perform voltage imaging inside an MRI scanner. On the biological side, my study will provide empirical data addressing the relationship between cell-type- specific neuronal activity and the BOLD signal and evaluate the dependence of a specific macroscopic imaging signal – negative BOLD – on a concrete cellular/molecular pathway. While working on my dissertation project, I will expand my scientific knowledge base, produce high-profile publications, and build a foundation for my future career as an independent investigator.