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

 描述（由申请人提供）：了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（例如使用fMRI测量的信号）至关重要。长期以来，人们一直认为，流向大脑区域的血液是局部神经活动的平均值或线性总和。最近的研究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，以区分神经活动如何与血流变化耦合的两种替代假设。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”中，高度活跃的神经元的小群体对血流施加不成比例的控制，导致非线性神经血管耦合。计算建模将用于测试所观察到的线性或非线性耦合是否可以通过一氧化氮（NO）的产生和扩散进行机械解释。 拟议的实验将在大鼠的嗅球中进行，其中离散的神经元亚群（肾小球）将被可视化并用气味刺激。双光子显微镜将用于同时测量定义的神经群体和单个血管中的神经活动和血流量。药物的靶向应用将增加或减少单个肾小球中的神经活动。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学扰动，从而获得神经血管耦合的线性或非线性的更准确定量。同时，将构建计算模型来测试是否NO（一种有效的血管扩张剂）的产生和扩散可以解释所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，他拥有使用双光子显微镜同时测量嗅球神经活动和血流变化的专业知识，帕特里克Drew博士拥有计算神经科学背景，并开发了新颖的血液动力学数据分析方法。这两种方法的结合将产生一个定量的了解如何血流变化与神经活动，并确定神经血管耦合的机制。 血流动力学信号，如通过功能磁共振成像测量的那些，被广泛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换为神经活动，这在诊断认知和神经障碍方面将是非常宝贵的。然而，这些血液流动的变化具体告诉我们什么是神经活动尚不清楚。这一建议将导致神经活动如何转化为血液动力学信号的定量理解，这将直接应用于人类成像研究的解释。 该提案将支持本科生参加暑期研究项目，建立在德鲁博士在本科生研究中指导妇女和代表性不足的少数民族的记录基础上。研究结果将被纳入由德鲁博士教授的跨学科本科课程“生物体的物理原理”，该课程将物理学和工程学原理应用于生物系统的研究。

 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.