Simultaneous optical voltage imaging and fMRI in behaving mice

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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.