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)：了解神经活动和脑血流之间的关系对于解释血流动力学信号至关重要，例如用fMRI测量的信号。长期以来，人们一直认为，流向大脑区域的血液报告了局部神经活动的平均值或线性总和。最近的研究让这个过于简单化的模型受到了质疑。这项提议将使用体内双光子成像，并与计算分析方法密切协调，以区分关于神经活动如何与血流变化相耦合的两种替代假说。在一个“民主”模型中，血液流动是由所有神经活动的线性总和控制的。或者，在“寡头政治”中，由高度活跃的神经元组成的小群体对血流施加了不成比例的控制，导致了非线性的神经血管耦合。计算模型将被用来检验观察到的线性或非线性耦合是否可以用一氧化氮(NO)的产生和扩散来力学解释。拟议的实验将在大鼠的嗅球中进行，在那里离散的神经元亚群(肾小球)将被可视化并被气味刺激。双光子显微镜将被用来同时测量确定的神经群体和单个血管中的神经活动和血流量。将进行有针对性的药物应用，以增加或减少单个肾小球的神经活动。这些实验将由实时数据分析指导，以确定最佳刺激或药物扰动，以便更准确地量化神经血管耦合的线性或非线性。同时，将构建计算模型来测试有效的血管扩张剂NO的产生和扩散是否可以解释观察到的神经血管耦合。这项建议是Serge Charpak博士和Patrick Drew博士实验室的合作成果。Serge Charpak博士擅长使用双光子显微镜同时测量嗅球的神经活动和血流变化，Patrick Drew博士具有计算神经科学背景，并开发了新的血液动力学数据分析方法。这两种方法的结合将产生对血流变化如何与神经活动相关的定量理解，并确定神经血管耦合的潜在机制。 血流动力学信号，如功能磁共振成像测量的信号，被广泛用于非侵入性推断大脑活动，能够将这些血流动力学信号转换为神经活动，将在诊断认知和神经疾病方面具有非常重要的价值。然而，关于神经活动，这些血流变化具体告诉了我们什么还不清楚。这一建议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，这将立即应用于解释人类成像研究。 这项提案将在德鲁博士指导女性和在本科研究中代表不足的少数族裔方面的记录的基础上，支持本科生进行有指导的暑期研究项目。研究结果将被纳入德鲁教授的一门跨学科本科课程--《生物有机体的物理原理》，该课程将物理学和工程学原理应用于生物系统的研究。