In-vivo optical imaging of neurovascular coupling and cerebral metabolism

 描述（由申请人提供）：在健康大脑中，几乎所有神经元活动的增加都伴随着局部血流量的增加。这些局部血流的动态变化对正常的大脑功能至关重要，同时也提供了功能性磁共振成像（fMRI）中检测到的对比度。因此，了解神经血管耦合对于功能磁共振成像数据的解释以及了解大脑如何调节健康和疾病的能量供应都很重要。虽然已经提出了许多不同的神经血管耦合的细胞模型，但我们在R 01项目的第一个资助期的工作揭示了一个参与大脑神经血管耦合的新成分：血管内皮。我们的实验表明，血管内皮细胞用于传播刺激诱发的扩张信号沿着血管在大脑中，使其成为健康的神经血管耦合的重要组成部分。根据我们的研究结果，我们建议，血管内皮细胞的参与可以解释异常早期星形胶质细胞和/或周细胞为基础的模型的神经血管耦合，以及时空的非线性fMRI BOLD响应中观察到的。此外，由于内皮功能障碍涉及从心血管疾病到糖尿病的一系列全身性病理，我们的研究结果表明，这些相同的条件可以直接影响大脑中的动态神经血管耦合，从而提供全身微血管功能障碍和神经退行性变之间的可能直接联系。在这个更新的应用程序中，我们建议建立在我们最近的研究结果，并进一步探讨内皮信号在神经血管耦合的作用。在目标1中，我们将研究如何在完整的体内脑中启动内皮信号。通过分离内皮细胞信号传导起始的位置和性质，我们将探索神经元活动可能通过的新途径。 驱动血管舒张，同时也定义了星形胶质细胞和周细胞在我们新模型中的作用。在目标2中，我们将确定参与脑血管舒张传播的内皮信号通路的类型。这些研究将确定神经血管耦合的敏感性 由疾病或药物引起的内皮功能障碍。数学建模将用于吸收机制发现并验证它们是否预测血流动力学反应的时空非线性，从而预测fMRI BOLD信号。最后，我们将进行研究，以评估内皮功能受损对神经元功能，行为和长期神经退行性变的影响。虽然受损的神经血管耦合和神经退行性变之间的因果关系是可以预期的，这些影响从来没有被量化，无论是急性或纵向，如果全身性内皮功能障碍是一个危险因素，是高度的意义。所有实验将涉及创新的新的体内光学成像，显微镜和光操作技术的共同发展，沿着数学建模，图像分析和神经血管控制和功能障碍的新型转基因模型。

 DESCRIPTION (provided by applicant): Increases in local blood flow accompany almost all increases in neuronal activity in the healthy brain. These dynamic changes in local blood flow are essential for normal brain function, while also providing the contrast detected in functional magnetic resonance imaging (fMRI). Understanding neurovascular coupling is therefore important both for interpretation of fMRI data, and to understand how the brain regulates its energy supplies in health and disease. While a number of different cellular models of neurovascular coupling have been proposed, our work during the first funded period of this R01 project revealed a new component involved in neurovascular coupling in the brain: the vascular endothelium. Our experiments demonstrated that the vascular endothelium serves to propagate stimulus-evoked dilatory signals along blood vessels in the brain, making it an essential part of healthy neurovascular coupling. Based on our findings to date, we propose that involvement of the vascular endothelium could explain anomalies in earlier astrocyte and / or pericyte-based models of neurovascular coupling, as well as spatiotemporal non-linearities observed in the fMRI BOLD response. In addition, since endothelial dysfunction is involved in a range of systemic pathologies, from cardiovascular disease to diabetes, our findings suggest that these same conditions could directly affect dynamic neurovascular coupling in the brain, providing a possible direct link between systemic microvascular dysfunction and neurodegeneration. In this renewal application we propose to build upon our recent findings, and further explore the role of endothelial signaling in neurovascular coupling. In aim 1 we will investigate how endothelial signaling is initiated in the intact, in-vivo brain. By isolating the location and properties of initiation of endothelial signaling we will explore novel pathways by which neuronal activity could drive vasodilation, while also defining the role of astrocytes and pericytes in our new model. In aim 2 we will determine the types of endothelial signaling pathways involved in the propagation of vasodilation in the brain. These studies will define the sensitivities of neurovascular coupling to endothelial dysfunction caused by disease or pharmacological agents. Mathematical modeling will be used to assimilate mechanistic findings and validate whether they predict the spatiotemporal non-linearities of the hemodynamic response, and thus the fMRI BOLD signal. Finally, we will perform studies to assess the impact of impaired endothelial function on neuronal function, behavior and long-term neurodegeneration. While a causal link between impaired neurovascular coupling and neurodegeneration is to be expected, these effects have never been quantified either acutely or longitudinally, and are of heightened significance if systemic endothelial dysfunction is a risk factor. All experiments will involve the co-development of innovative new in-vivo optical imaging, microscopy and photo-manipulation techniques along with mathematical modeling, image analysis and novel transgenic models of neurovascular control and dysfunction.