In-vivo imaging of the evolution of hemodynamic control in the developing brain

发育中大脑中血流动力学控制演变的体内成像

• 批准号: 8593772
• 负责人: Mariel Gailey Kozberg
• 金额: $ 4.72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593772
• 关键词: Accounting; Adult; Age; Alzheimer' s Disease; Architecture; Arteries; Attention Deficit Disorder; Autistic Disorder; Bilateral; Biological Markers; Birth; Blood Pressure; Blood Vessels; Blood flow; Brain; Brain imaging; Brain region; Calcium; Cells; Cellular Morphology; Cerebrum; Child; Child Development; Clinical Research; Coupling; Data; Development; Diagnosis; Dyes; Electrophysiology (science); Endothelium; Equilibrium; Evolution; Exhibits; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Hemoglobin; Homeostasis; Human; Hyperemia; Image; Imaging Techniques; Infant; Lead; Maps; Masks; Measures; Metabolic; Microscopy; Neonatal; Neurons; Newborn Infant; Optics; Oxygen Consumption; Pathology; Phase; Play; Population; Property; Rattus; Research; Rodent; Rodent Model; Role; Sensory; Signal Transduction; Stimulus; Stroke; Structure; System; Techniques; Uncertainty; Work; base; blood oxygen level dependent; cellular development; cerebrovascular; clinical application; constriction; deoxyhemoglobin; developmental disease; hemodynamics; improved; in vivo; insight; neonate; neuron development; neurovascular unit; novel; optical imaging; optogenetics; postnatal; public health relevance; pup; receptive field; research study; response; somatosensory; spatiotemporal; two-photon; vasoconstriction

DESCRIPTION (provided by applicant): In the adult brain, sensory stimulation leads to a localized increase in blood flow in a particular region of the brain. This blood flow increase causes a decrease in deoxy-hemoglobin that is detected by functional magnetic resonance imaging (fMRI) as the blood oxygen level dependent (BOLD) signal. However, prior studies in infants and children have revealed widely varying and sometimes inverted hemodynamic responses in the developing brain. Our preliminary data suggest that these differences are due, at least in part, to the immaturity of neurovascular coupling in the neonatal brain, potentially confounding interpretation of fMRI in young subjects. With fMRI increasingly being used for studies of brain development, and to understand developmental disorders such as autism and attention deficit disorder, an improved understanding of vascular control in the neonatal brain is urgently needed. This project will use in-vivo optical imaging and microscopy techniques to study the relationship between neuronal activity and blood flow in the neonatal rodent brain. We have already completed preliminary studies characterizing the evolution of the hemodynamic response to somatosensory stimulus in neonatal rat pups. This work confirmed the presence of 'inverted' responses in neonatal rats, and charted the progression of the response between postnatal days 12 - 23 via an intermediate bi-phasic response in which localized initial hyperemia gradually increased until the response was fully positive. Additionally, a strong vasoconstriction component was found to be present from birth, and clear signs of immature cerebral autoregulation were observed. To complete my dissertation, I propose to build upon this work to characterize the developing response at a cellular and vascular level through the use of both exposed-cortex optical imaging and in-vivo two-photon microscopy (aim 1). The goal of this aim will be to elucidate key components of the neurovascular unit by observing their assembly alongside maturation of functional hyperemia. I also plan to study the degree to which the neonatal hemodynamic response represents underlying neuronal activity using wide-field calcium sensitive dye imaging, electrophysiology, and optogenetics (aim 2). The goal of this aim will be to bring clarity to the interpretation of functional imaging results in infants and childre. The combination of wide-field optical imaging, in-vivo two-photon microscopy, and optogenetics that will be used in this study provides a unique approach to the examination of neonatal neurovascular coupling. We expect that the results of this work will have a significant impact on the field of neonatal brain imaging (both clinically and experimentally). Our results may also provide important insights into normal adult neurovascular coupling, and could potentially identify new biomarkers for normal and abnormal development of the brain's cerebrovascular, metabolic, and autoregulatory systems.

描述（由申请人提供）：在成年大脑中，感觉刺激导致大脑特定区域的血流局部增加。这种血流增加会导致脱氧 - 血红蛋白的降低，该脱氧血红蛋白被功能性磁共振成像（fMRI）检测到作为血氧水平依赖性（BOLD）信号。但是，对婴儿和儿童的先前研究表明，发育中的大脑中的血液动力学反应有时变化很大，有时是倒置的。我们的初步数据表明，这些差异至少部分归因于新生儿大脑中神经血管耦合的不成熟，这可能会混淆对年轻受试者中fMRI的解释。随着fMRI越来越多地用于大脑发育研究，并了解诸如自闭症和注意力缺陷障碍之类的发育障碍，因此迫切需要对新生儿大脑中血管控制的改善理解。 该项目将使用体内光学成像和显微镜技术来研究新生儿啮齿动物大脑中神经元活动与血流之间的关系。我们已经完成了表征新生儿大鼠幼犬体感刺激的血液动力学反应演变的初步研究。这项工作证实了新生大鼠中存在“反向”反应，并通过中间双重反应绘制了产后第12-23天之间反应的进展，在中间双重反应中，局部初始充血逐渐增加，直到反应完全阳性。此外，发现从出生开始就存在强大的血管收缩成分，并且观察到明显的脑自动调节的明显迹象。为了完成论文，我建议通过使用裸露的皮质光学成像和体内的两光子显微镜（AIM 1）来构建这项工作，以在细胞和血管水平上表征发育中的反应。该目标的目的是通过观察其组装与功能性充血的成熟来阐明神经血管单元的关键成分。我还计划研究新生儿血液动力学反应使用宽场钙敏感染料成像，电生理学和光遗传学（AIM 2）来代表潜在的神经元活性。这个目的的目的是使婴儿和Childre的功能成像结果清楚起见。 本研究中将使用的宽视野光学成像，体内两光子显微镜和光遗传学的组合为检查新生儿神经血管耦合提供了独特的方法。我们预计这项工作的结果将对新生儿脑成像（临床和实验性）产生重大影响。我们的结果还可以为正常的成人神经血管耦合提供重要的见解，并有可能识别出大脑脑血管，代谢和自动调节系统的正常和异常发育的新生物标志物。