Elucidating the synaptic and cellular basis of cerebral hemodynamics

血流动力学和代谢成像方法被用于研究哺乳动物大脑的认知和网络功能，但这些宏观或中观尺度的功能成像信号与神经元活动之间的确切关系尚不完全清楚。在大脑中，当神经元激活时，局部血流量增加，然而，血流动力学信号与局部脑激活之间的空间、时间和数量关系尚不清楚。我假设，为了最终了解血液流动是如何在复杂的血管网络中调节的，我们需要调查和辨别整个血管树上的神经元-血管相互作用。在NSERC发现基金的支持下，我将建立一个研究项目，旨在阐明功能成像信号背后的血液动力学信号的突触和细胞基础。在短期内，我们将重点描述不同空间尺度下脑血流调节的生理机制。这项工作将通过结合不同的成像方式来在微观和介观分辨率下成像感官反应来实现。具体地说，我们将在清醒和行为正常的转基因小鼠中结合体内双光子成像和超快功能超声(FUS)。通过利用细胞和分子操纵，我们将描绘血流动力学成像信号背后的生理机制。在短期内，这项工作将分为3个项目：1)确定与局部突触激活有关的大脑皮层不同层血液流动的调节机制。2)建立微电路可塑性过程中神经元和血管反应之间的定量关系。3)研究在体周细胞和平滑肌细胞钙信号的细胞机制及其对血流动力学信号的调节。这项研究计划将发现脑血管网络中血液流动调节的基本生理机制。通过在所有尺度上研究功能性充血，从介观FUS信号到其背后的细胞机制，我们将开始全面了解复杂的细胞相互作用如何调节血流动力学成像信号，从而提高我们对人脑成像的理解和解释。

Hemodynamic and metabolic imaging approaches are used to study cognitive and network function in the mammalian brain, yet the precise relationship between these macro- or meso-scale functional imaging signals and neuronal activity is not fully understood. In the brain, blood flow increases locally upon neuronal activation, however, the spatial, temporal, and quantitative relationship between hemodynamic signals and local brain activation remain unclear. I hypothesize that in order to ultimately understand how blood flow is regulated in complex vascular networks we need to investigate and discern neuronal-vascular interactions across the entire vascular tree. With the support of a NSERC discovery grant, I will establish a research program that aims to elucidate the synaptic and cellular basis of hemodynamic signals underlying functional imaging signals. Over the short term, we will focus on delineating the physiological mechanisms underlying cerebral blood flow regulation at different spatial scales. This work will be achieved by combining different imaging modalities to image sensory responses at both microscopic and mesoscopic resolution. Specifically, we will combine in vivo 2-photon imaging, with ultrafast functional ultrasound (fUS) in awake and behaving transgenic mice. By utilizing cellular and molecular manipulations we will delineate the physiological mechanisms underlying hemodynamic imaging signals. Over the short-term this work will be divided into 3 projects: 1) Determine the mechanisms regulating blood flow across different layers of the cerebral cortex in relation with local synaptic activation. 2) Establish quantitative relationships between neuronal and vascular responses during microcircuit plasticity. 3) Investigate cellular mechanisms underlying pericyte and smooth muscle cell Ca2+ signaling and their regulation of hemodynamic signals in vivo. This research program will discover basic physiological mechanisms underlying the regulation of blood flow in cerebral-vascular networks. By studying functional hyperemia at all scales, from mesoscopic fUS signals to the cellular mechanisms underlying them, we will begin to gain a complete picture of how complex cellular interactions mediate hemodynamic imaging signals, and thereby improve our understanding and interpretation of human brain imaging.