Neural circuit basis for neurovascular coupling

神经血管耦合的神经回路基础

• 批准号: 10549806
• 负责人: Sarah Elizabeth Ross
• 金额: $ 51.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549806
• 关键词: Alleles; Alzheimer' s Disease; Blood Vessels; Blood flow; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Clinical; Communication; Correlative Study; Data; Diameter; Etiology; Genetic; Goals; Homeostasis; Image; Ischemia; Knowledge; Laser-Doppler Flowmetry; Mediating; Methods; Microscopy; Monitor; Mus; Myoepithelial cell; Neurodegenerative Disorders; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Output; Parvalbumins; Pathogenesis; Perfusion; Pericytes; Population; Positioning Attribute; Process; Regulation; Relaxation; Research; Signal Transduction; Stroke; Structure; Testing; Time; Tissues; Traumatic Brain Injury; Vasodilation; Vasodilator Agents; Vibrissae; Visualization; awake; cerebrovascular; experimental study; hemodynamics; inhibitory neuron; insight; neural; neural circuit; neuromechanism; neurovascular coupling; novel therapeutics; optogenetics; photoactivation; response; tool; two-photon

Abstract Neurovascular coupling (NVC) is the temporal relationship between neural activity and cerebral blood flow (CBF). This neural-evoked hemodynamic response is fundamental to local cerebrovascular homeostasis and is disrupted in cerebrovascular diseases, such as stroke, cerebral amyloid angiopathy, traumatic brain injury, as well as Alzheimer's Disease. The neurons that express neuronal nitric oxide synthase (Nos1) are ideal candidates for the regulation of NVC since nitric oxide (NO) is a very potent vasodilator. Our group has recently developed a Tacr1CreER allele that enables the visualization and manipulation of these neurons. We now have exciting preliminary data supporting the hypothesis that Tacr1 neurons mediate vasodilation. Here, we propose to test this idea through a set of experiments that will: determine the relationship between Tacr1 neurons and blood vessels; examine causality in the regulation of NVC by Tacr1 neurons; and investigate the underlying circuitry. These experiments include correlative studies that will establish whether the structure (place) and function (activity) of Tacr1 neurons positions them to regulate CBF. We will also use optogenetic approaches and laser Doppler flowmetry (LDF) to record CBF in awake behaving mice to test whether Tacr1 neurons necessary and sufficient for vasodilation. Finally, we will use a combination of optogenetic manipulation, GCaMP6f-, and 2P-imaging to elucidate the underlying circuitry of NVC. Overall, our proposal will address a critical gap in knowledge with respect to the specific neural mechanisms that underlie the BOLD signal, which is a widely used, but poorly understood research and clinical tool. Moreover, this insight into NVC is fundamental to our understanding of the pathogenesis of common cerebrovascular diseases and the advancement of pharmacotherapeutics targeting cerebral perfusion.

摘要 神经血管耦合是神经活动与脑血流之间的时间关系 （CBF）.这种神经诱发的血流动力学反应是局部脑血管稳态的基础， 在脑血管疾病如中风、脑淀粉样血管病、创伤性脑损伤 以及老年痴呆症。表达神经元型一氧化氮合酶（Nos 1）的神经元是理想的 因为一氧化氮（NO）是一种非常有效的血管扩张剂，所以NVC是调节NVC的候选物。我们集团 最近开发了一种Tacr 1CreER等位基因，使这些神经元的可视化和操作成为可能。我们 现在有令人兴奋的初步数据支持Tacr 1神经元介导血管舒张的假设。在这里， 我们建议通过一系列实验来测试这一想法，这些实验将：确定Tacr 1 神经元和血管;检查Tacr 1神经元调节NVC的因果关系;并研究 底层电路这些实验包括相关的研究，将确定结构是否 Tacr 1神经元的位置和功能（活性）使其定位于调节CBF。我们还将使用光遗传学 方法和激光多普勒血流仪（LDF）记录清醒行为小鼠的CBF，以测试Tacr 1是否 神经元是血管舒张所必需的和足够的。最后，我们将使用光遗传学和 操作，GCaMP 6 f-和2 P-成像，以阐明NVC的潜在电路。总的来说，我们的建议 将解决一个关键的知识差距方面的具体神经机制的基础BOLD 信号，这是一个广泛使用，但了解甚少的研究和临床工具。此外，这种对 NVC是我们了解常见脑血管病发病机制的基础， 以脑灌注为靶点的药物治疗研究进展。