Simultaneous optical voltage imaging and fMRI in behaving mice

摘要 在脑研究的各个领域中，脑成像是最受普通观众欣赏的。到期 到了最近成像技术的进步，我们才能看到大脑的活动。最有希望和最有希望的 得到广泛应用的非侵入性成像技术是基于 血氧水平依赖(BOLD)对比。然而，这项技术的生理基础是 人们对此仍知之甚少。电子记录和活体双光子钙成像使我们能够 了解已确定的神经元群体的功能。当今的一个主要挑战是将这些 需要侵入性成像和记录工具的微观神经科学洞察力，以及宏观 无创功能磁共振信号。 为了应对这一挑战，我建议将神经电活动的光学成像 同时对清醒行为的小鼠进行大胆的fMRI测量。这些实验将利用 一个MRI兼容的光学成像器，我从第一个开始就设计并集成到了一个动物支架上 提交(旧目标1)。在新的目标1中，我将探索细胞类型特定的神经元之间的关系 自发和任务诱导的神经元活动期间的电压和BOLD fMRI信号。大胆的信号可以 既是积极的，也是消极的，我的实验室之前的发现证明了特定的 释放信号分子神经肽Y(NPY)的皮质抑制神经元群体，导致 通过Y1受体收缩血管。在新的目标2中，我将讨论NPY阳性神经元在 产生大胆的信号。为此，我将把电压成像和BOLD功能磁共振与光遗传学相结合 沉默NPY阳性神经元并拮抗NPY-Y1通路。 从技术角度来看，我的研究将是第一个在核磁共振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性数据，解决细胞类型- 特定神经元活动和BOLD信号并评估特定宏观成像的依赖性 信号-负BOLD-在具体的细胞/分子途径上。在写论文的时候，我 我将扩大我的科学知识基础，出版备受瞩目的出版物，并为我的 未来的职业生涯是独立调查员。

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.