CRCNS: US-French Research Proposal: Neurovascular coupling-democracy or oligarchy?

CRCNS：美法研究提案：神经血管耦合——民主还是寡头？

• 批准号: 9048044
• 负责人: Patrick James Drew
• 金额: $ 12.05万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9048044
• 关键词: Accounting; Blood Vessels; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Cognition Disorders; Collaborations; Computer Analysis; Computer Simulation; Coupled; Coupling; Data; Data Analyses; Democracy; Diagnosis; Diffusion; Educational process of instructing; Engineering; Excitatory Amino Acid Antagonists; Functional Magnetic Resonance Imaging; GABA-B Receptor; Generations; Human; Image; Laboratories; Life; Measurement; Measures; Mentors; Methods; Microscopy; Modeling; Neurons; Nitric Oxide; Odors; Organism; Pattern; Pharmaceutical Preparations; Physics; Population; Production; Property; Rattus; Reporting; Research; Research Project Grants; Research Proposals; Signal Transduction; Stimulus; Sum; Techniques; Testing; Time; Translating; Uncertainty; Underrepresented Minority; Vasodilator Agents; Woman; Work; biological systems; biophysical model; blood oxygen level dependent; computational neuroscience; design; hemodynamics; improved; in vivo; insight; nervous system disorder; neural patterning; neuroimaging; novel; olfactory bulb; relating to nervous system; research study; response; simulation; two-photon; undergraduate research

 DESCRIPTION (provided by applicant): Understanding the relationship between neural activity and cerebral blood flow is critical for interpreting hemodynamic signals, such as those measured with fMRI. It has long been assumed that blood flow to a brain region reported the average, or linear summation, of local neural activity. Recent work has cast this simplistic model into doubt. This proposal will use in vivo two-photon imaging, in close coordination with computational analysis methods, to distinguish between two alternative hypotheses of how neural activity is coupled to changes in blood flow. In one model, a 'democracy', blood flow is controlled by a linear sum of all neural activity. Alternatively, in an 'oligarchy', small groups o highly active neurons exert a disproportionate amount of control over blood flow, resulting in non-linear neurovascular coupling. Computational modeling will be used to test if the observed linear or non-linear coupling can be mechanistically explained by the production and diffusion of nitric oxide (NO). The proposed experiments will be performed in the olfactory bulb of rats, where discrete subpopulations of neurons (glomeruli) will be visualized and stimulated with odors. Two-photon microscopy will be used to simultaneously measure neural activity and blood flow in defined neural populations and single blood vessels. Targeted applications of drugs will be made to increase or decrease the neural activity in a single glomerulus. These experiments will be guided by real-time data analysis to determine the optimal stimulus or pharmacological perturbation in order to obtain a more accurate quantification of the linearity or nonlinearity of neurovascular coupling. In parallel, computational models will be constructed to test if the generation and diffusion of NO, a potent vasodilator, can account for the observed neurovascular coupling. This proposal is a collaboration between the labs of Dr. Serge Charpak, who has expertise using two-photon microscopy to simultaneously measure neural activity and blood flow changes in the olfactory bulb, and that of Dr. Patrick Drew, who has a background in computational neuroscience and has developed novel hemodynamic data analysis methods. The combination of these two approaches will yield a quantitative understanding of how blood flow changes relate to neural activity, and a determination of the mechanisms underlying neurovascular coupling. Hemodynamic signals, such as those measured by fMRI, are extensively used in inferring brain activity non-invasively, and being able to convert these hemodynamic signals into neural activity would be invaluable in diagnosing cognitive and neurological disorders. However, what specifically these changes in blood flow tell us about neural activity is not known. This proposal will result in a quantitative understanding of how neural activity is translated into hemodynamic signals, which will have immediate application to the interpretation of human imaging studies. This proposal will support undergraduates in mentored summer research projects, building on Dr. Drew's track record of mentoring women and underrepresented minorities in undergraduate research. The results will be incorporated into an interdisciplinary undergraduate class taught by Dr. Drew, "Physical principles of living organisms", which applies physics and engineering principles to the study of biological systems.

 描述（由申请人提供）：理解神经活动和脑血流量之间的关系对于解释血流动力学信号至关重要，例如通过功能磁共振成像测量的血流动力学信号。长期以来，人们一直认为流向大脑区域的血流量报告的是平均值或线性总和。最近的工作对这种简单化的模型提出了质疑，该提案将使用体内双光子成像，与计算分析方法密切配合，来区分神经活动如何与变化耦合的两种替代假设。血在一种“民主”模型中，血流由所有神经活动的线性总和控制；而在“寡头”模型中，小群体或高度活跃的神经元对血流施加不成比例的控制。非线性神经血管耦合将用于测试观察到的线性或非线性耦合是否可以通过一氧化氮（NO）的产生和扩散来机械地解释。 ，其中离散将使用双光子显微镜来观察和刺激神经元亚群（肾小球），以同时测量特定神经群和单个血管中的神经活动和血流量。这些实验将在实时数据分析的指导下确定最佳刺激或药理学扰动，以获得神经血管线性或非线性的更准确量化。同时，将构建计算模型来测试 NO（一种有效的血管舒张剂）的产生和扩散是否可以解释观察到的神经血管耦合。该提案是 Serge Charpak 博士实验室之间的合作，他拥有耦合方面的专业知识。双光子显微镜可同时测量嗅球中的神经活动和血流变化，帕特里克·德鲁博士拥有计算神经科学背景，并开发了新颖的血流动力学数据分析方法，这两种方法的结合将实现这一目标。定量了解血流变化如何与神经活动相关，并确定神经血管耦合的机制。 血流动力学信号，例如通过功能磁共振成像测量的信号，用于非侵入性地推断大脑活动，并且能够将这些血流动力学信号转化为神经活动对于诊断认知和神经疾病来说是非常有价值的。然而，血流的这些变化具体是什么。告诉我们关于神经活动的信息尚不清楚。该提案将导致对神经活动如何转化为血流动力学信号的定量理解，这将立即应用于人类成像研究的解释。 该提案将基于德鲁博士在本科生研究中指导女性和代表性不足的少数族裔的记录，支持本科生开展受指导的夏季研究项目。该研究成果将纳入德鲁博士教授的跨学科本科生课程“生物体的物理原理”中。 ”，它将物理和工程学原理应用于生物系统的研究。