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: 9278168
• 负责人: Patrick James Drew
• 金额: $ 11.39万
• 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/9278168
• 关键词: Blood Vessels; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Cognition Disorders; Collaborations; Computer Analysis; Computer Simulation; Coupled; Coupling; Data; Data Analyses; Democracy; Diagnosis; Diffusion; Engineering; Excitatory Amino Acid Antagonists; Functional Magnetic Resonance Imaging; GABA-B Receptor; Generations; Image; Laboratories; Measurement; Measures; Mentors; Methods; Microscopy; Modeling; Neurons; Nitric Oxide; Odors; Organism; Pattern; Pharmaceutical Preparations; Pharmacology; 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; experimental study; hemodynamics; human imaging; imaging study; improved; in vivo two-photon imaging; insight; nervous system disorder; neural patterning; neuroimaging; neurovascular; neurovascular coupling; novel; olfactory bulb; parallel computer; relating to nervous system; response; simulation; summer research; two-photon; undergraduate research; undergraduate student

 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（应用程序提供）：了解神经元活动与脑血流量之间的关系对于解释血液动力学信号至关重要，例如用fMRI测量的血液动力学信号。长期以来，人们一直认为，流向大脑区域的血流报告了局部神经元活性的平均值或线性求和。最近的工作使这个简单的模型陷入了怀疑。该建议将在与计算分析方法密切协调下使用体内两光子成像，以区分两个替代假设，即如何与血液流动的变化结合使用。在一种模型中，“民主”，血流由所有神经元活动的线性总和控制。另外，在“寡头”中，小组o高度活性神经元对血流的控制不成比例，导致非线性神经血管耦合。计算建模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的产生和扩散（NO）来机械解释。提出的实验将在大鼠的嗅球中进行，其中神经元的离散亚群（glomerulli）将被可视化并用气味刺激。两光子显微镜将用于轻松测量定义的神经元群体和单血管中的神经元活性和血流。将对药物的靶向应用增加或减少单个肾小球中的神经元活性。这些实验将通过实时数据分析来指导，以确定最佳刺激或药理扰动，以获得更准确的神经血管偶联的线性或非线性。同时，将构建计算模型以测试潜在的血管扩张剂NO的产生和扩散是否可以解释观察到的神经血管耦合。 Serge Charpak博士实验室之间的合作是使用两光子显微镜的专业知识，同时衡量嗅球的神经元活动和血流变化，以及帕特里克·德鲁（Patrick Drew）博士，他在计算神经科学方面具有背景，并开发了新颖的血液动力学数据分析方法。这两种方法的组合将对血流变化的方式产生定量理解，与神经元活性有关，并确定神经血管偶联的机制。 血液动力学信号（例如通过fMRI测量的信号）广泛用于非侵入性推断大脑活性，并且能够将这些血液动力学信号转化为神经元活性，在诊断性认知和神经系统疾病中是无价的。但是，这些血流中这些具体的变化告诉我们有关神经元活性的原因尚不清楚。该建议将导致对神经元活性如何转化为血液动力学信号的定量理解，该信号将立即应用于人类影像学研究的解释。 该提案将支持修改夏季研究项目的本科生，这是基于Drew博士的记录，该记录是修订妇女和代表性不足的本科研究。结果将纳入由Drew博士（“生物的物理原理”）教授的跨学科本科班级，该课程将物理和工程原理应用于生物系统研究。