Microscopic imaging of neuro-capillary coupling in brain cortex

描述(申请人提供)：光学相干断层扫描(OCT)能够实现组织结构的超分辨率和高速成像，促进眼科、癌症生物学和神经科学的一些基础和临床研究。通过拟议的K99/R00计划，候选人将开发基于OCT的新技术，用于组织动力学的超分辨率成像，特别是在活体动物的大脑皮层中。具体来说，候选人将开发三种成像技术，用于对啮齿动物大脑皮层中发生的各种血管和细胞动力学进行成像：单细胞分辨率的神经元细胞内细胞器运动的活体成像(特定目标1a)；单毛细血管和1-S分辨率的数百条毛细血管上血流速度的同时成像(特定目标1b)；以及单细胞和ms分辨率的神经元活动的快速光学信号的成像(特定目标2)。这些技术通常对一系列神经科学和病理生理学研究有用，这些研究受益于以高时空分辨率直接可视化这些组织动力学。拟议的K99/R00计划将侧重于使用这些技术来提出和演示神经-毛细血管耦合的概念。这一概念将挑战当前的范式--神经血管耦合，以了解大脑的能量供应调节，并解释基于血流动力学的人脑映射数据。最近，毛细血管水平的血流调节在体外被认为是由周细胞介导的，但在体内还没有得到证实。此外，皮质毛细血管血流动力学也被认为与病理生理学有关。因此，拟议的概念将提高我们对血流调节的理解，从而为开发包括中风和阿尔茨海默病在内的一系列脑部疾病的治疗方法提供新的机会。具体来说，利用在特定目标1和2中开发的技术，候选人将在体内测试三个假说，以演示和表征神经-毛细血管耦合(特定目标3)：(H1)毛细血管响应于躯体感觉皮质中的神经元激活而调节血流，直接证明毛细管控制流动；(H2)神经-毛细血管耦合导致早期的毛细血管网络流动均质化，识别毛细管流动调节的作用；(H3)神经-毛细血管耦合显示兴奋的神经元和反应的毛细血管之间的微观空间关联，揭示神经-毛细管耦合的特征。拟议的研究项目将使应聘者在生物医学光学和神经成像领域获得进一步的研究经验和科学知识。除了研究项目，包括课程工作和研讨会在内的拟议职业发展计划将帮助他实现他的职业目标：在生物医学工程或应用物理系建立一个独立的研究计划。

DESCRIPTION (provided by applicant): Optical coherence tomography (OCT) enables um-resolution and high-speed imaging of tissue structure, facilitating a number of basic and clinical studies in ophthalmology, cancer biology, and neuroscience. Through the proposed K99/R00 program, the candidate will develop novel OCT-based technologies for um-resolution imaging of tissue dynamics, especially in the brain cortex of a living animal. In detail, the candidate will develop three technologies for imaging various vascular and cellular dynamics occurring in the rodent cerebral cortex: in vivo imaging of the motion of neuronal intracellular organelles with single-cell resolution (Specific Aim 1a), simultaneous imaging of blood flow speed over hundreds of capillaries with single-capillary and 1-s resolution (Specific Aim 1b), and imaging of fast optical signals of neuronal activity with single-cell and ms resolution (Specific Aim 2). Thes technologies will be generally useful for a range of neuroscience and pathophysiology studies that benefit from direct visualization of those tissue dynamics with high spatiotemporal resolution. The proposed K99/R00 program will focus on using the technologies to propose and demonstrate the concept of neuro-capillary coupling. This concept will challenge the current paradigm, neurovascular coupling, for understanding the brain's energy supply regulation and for interpreting hemodynamics-based human brain mapping data. Recently, blood flow regulation at the capillary level has been suggested in vitro as mediated by pericytes, but not demonstrated in vivo. Further, cortical capillary flow dynamics is also suggested to relate with pathophysiology. Therefore, the proposed concept will improve our understanding of blood flow regulation and thus offer new opportunities for developing therapeutic approaches to a range of disorders of the brain including stroke and Alzheimer's disease. In detail, using the technologies developed in Specific Aims 1 and 2, the candidate will test three hypotheses for demonstrating and characterizing neuro-capillary coupling in vivo (Specific Aim 3): (H1) Capillaries regulate blood flow in response to neuronal activation in the somatosensory cortex, directly proving the capillary control of flow; (H2) Neuro-capillary coupling leads to an early capillary network flow homogenization, identifying the role of the capillary flow regulation; and (H3) Neuro-capillary coupling exhibits a microscopic spatial correlation between excited neurons and responding capillaries, revealing the characteristics of neuro-capillary coupling. The proposed research project will enable the candidate to gain further research experience and scientific knowledge in the field of biomedical optics and neuroimaging. Along with the research project, the proposed career development programs including course work and seminars will assist him in achieving his career goal: to establish an independent research program in a biomedical engineering or applied physics department.