Microscopic imaging of neuro-capillary coupling in brain cortex

描述（由申请人提供）：光学相干断层扫描（OCT）能够实现组织结构的um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。通过提出的K99/R00计划，候选人将开发新的基于oct的组织动力学的um分辨率成像技术，特别是在活体动物的大脑皮层。具体而言，候选人将开发三种技术来成像啮齿动物大脑皮层中发生的各种血管和细胞动力学：单细胞分辨率神经元胞内细胞器运动的体内成像（Specific Aim 1a），单毛细血管1-s分辨率血流量速度的同时成像（Specific Aim 1b），单细胞和ms分辨率神经元活动的快速光信号成像（Specific Aim 2）。这些技术将对一系列神经科学和病理生理学研究普遍有用，这些研究受益于这些组织动态的高时空分辨率的直接可视化。拟议的K99/R00计划将侧重于使用这些技术提出和演示神经-毛细血管耦合的概念。这一概念将挑战当前的范式，即神经血管耦合，以理解大脑的能量供应调节和解释基于血流动力学的人类大脑图谱数据。最近，在毛细血管水平上的血流调节被认为是由外周细胞介导的，但尚未在体内得到证实。此外，皮层毛细血管流动动力学也被认为与病理生理有关。因此，提出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。具体而言，使用在Specific Aims 1和2中开发的技术，候选人将测试三个假设，以证明和表征体内神经-毛细血管耦合（Specific Aim 3）：（H1）毛细血管根据体感觉皮层的神经元激活调节血流，直接证明毛细血管控制血流；（H2）神经-毛细血管耦合导致早期毛细血管网络流动均质化，确定了毛细血管流动调节的作用；（H3）神经-毛细血管耦合表现出兴奋神经元与响应毛细血管之间的微观空间相关性，揭示了神经-毛细血管耦合的特征。该研究项目将使候选人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。与研究项目一起，建议的职业发展计划包括课程工作和研讨会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项目。

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.