Microscopic imaging of neuro-capillary coupling in brain cortex

大脑皮层神经毛细血管耦合的显微成像

• 批准号: 9172247
• 负责人: Jonghwan Lee
• 金额: $ 24.89万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172247
• 关键词: Algorithms; Alzheimer' s Disease; Animals; Area; Biological; Biomedical Engineering; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Diseases; Brain Mapping; Caliber; Cancer Biology; Cardiac; Cells; Cerebral cortex; Characteristics; Clinical Research; Coupling; Data; Data Analyses; Energy Supply; Exhibits; Functional disorder; Goals; Health; Human; Image; Imagery; Imaging technology; In Vitro; Knowledge; Lead; Learning; Life; Measures; Mediating; Mentors; Microscopic; Morphologic artifacts; Motion; Neurons; Neurosciences; Ophthalmology; Optical Coherence Tomography; Optics; Organelles; Pericytes; Phase; Physics; Regulation; Research; Research Project Grants; Resolution; Rodent; Role; Signal Transduction; Somatosensory Cortex; Speed; Stroke; Structure; Techniques; Technology; Testing; Therapeutic; Tissue imaging; Tissues; Validation; Variant; Work; arteriole; base; capillary; career; career development; experience; hemodynamics; improved; in vivo; in vivo imaging; light scattering; microscopic imaging; neuroimaging; neuronal cell body; neurotransmission; neurovascular coupling; novel; programs; research study; respiratory; response; skills; somatosensory; spatiotemporal

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.

描述（由申请人提供）：光学相干断层扫描（OCT）能够对组织结构进行微米分辨率和高速成像，促进眼科、癌症生物学和神经科学领域的许多基础和临床研究。通过拟议的 K99/R00 计划，候选人将开发基于 OCT 的新型技术，用于组织动力学（尤其是活体动物的大脑皮层）的微米分辨率成像。具体来说，候选人将开发三种技术，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：以单细胞分辨率对神经元细胞内细胞器的运动进行体内成像（具体目标1a），对血流速度进行同步成像以单毛细管和 1 秒分辨率对数百个毛细血管进行成像（具体目标 1b），并以单细胞和毫秒分辨率对神经元活动的快速光学信号进行成像（具体目标 2）。这些技术通常可用于一系列神经科学和病理生理学研究，这些研究受益于高时空分辨率的组织动力学的直接可视化。 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，以理解大脑的能量供应调节和解释基于血流动力学的人脑绘图数据。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，但在体内尚未得到证实。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，所提出的概念将提高我们对血流调节的理解，从而为开发治疗一系列脑部疾病（包括中风和阿尔茨海默病）的治疗方法提供新的机会。具体来说，使用特定目标 1 和 2 中开发的技术，考生将测试三个假设，以证明和表征体内神经毛细血管耦合（特定目标 3）： (H1) 毛细血管响应于神经元激活而调节血流。体感皮层，直接证明毛细血管对血流的控制； (H2) 神经-毛细血管耦合导致早期毛细血管网络血流均质化，确定毛细血管血流调节的作用； (H3)神经毛细血管耦合表现出兴奋神经元和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。 拟议的研究项目将使候选人能够在生物医学光学和神经影像领域获得进一步的研究经验和科学知识。除了研究项目之外，拟议的职业发展计划（包括课程工作和研讨会）将帮助他实现职业目标：在生物医学工程或应用物理系建立独立的研究计划。