Project 3: Dissecting the neural and neuromodulatory control mechanisms of arterial dynamics during sleep

项目3：剖析睡眠期间动脉动力学的神经和神经调节控制机制

• 批准号: 10673165
• 负责人: Patrick James Drew
• 金额: $ 45.49万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673165
• 关键词: Area; Arteries; Astrocytes; Biosensor; Blood Vessels; Blood Volume; Brain; Calcium Signaling; Cerebrospinal Fluid; Complement; Data; Diameter; Electroencephalography; Fiber; Genetic; Goals; Human; Image; Link; Liquid substance; Measurement; Measures; Microscopic; Microspheres; Modeling; Motion; Movement; Mus; Neuroglia; Neurons; Nitric Oxide Synthase Type I; Parvalbumins; Pattern; Photometry; Population; Pump; Role; Sensory; Signal Transduction; Sleep; Somatostatin; Speed; Testing; Transgenic Mice; Vascular Smooth Muscle; Vasodilation; Visualization; Work; awake; basal forebrain; cell type; cerebrospinal fluid flow; cholinergic; comparative; constriction; experimental study; fluorescence imaging; hemodynamics; hippocampal pyramidal neuron; locus ceruleus structure; mouse model; neural; neural circuit; neuroimaging; neuromechanism; neuroregulation; neurovascular coupling; neurovascular unit; non rapid eye movement; noradrenergic; optical imaging; optogenetics; response; solute; spatiotemporal; tool; two photon microscopy; two-photon; vasoconstriction

Abstract, Project 3 Sleep is accompanied by large changes in neural activity, modulatory state, and hemodynamics. The large arterial dilations and contractions during sleep could drive perivascular pumping of CSF, which would help clear fluid and solutes from the brain. We hypothesize that during NREM sleep, the large oscillations of arterial diameter are driven by local neural activity and coordinated globally across the cortex by noradrenergic (NE) and cholinergic (ACh) neuromodulatory drive. We will test this idea by optically imaging the cortical vasculature of sleeping mice while perturbing neural activity and neuromodulation. In Aim 1, we will alter the activity of defined neuronal populations during sleep using opto-and chemogenetic tools to determine the role of local neural activity in controlling vascular dynamics. In Aim 2, we will use fluorescent biosensors, optogenetics, and chemogenetics to understand the role of cholinergic and noradrenergic modulation in coordinating the global cortical vascular dynamics during sleep. We will measure the temporal relationship between ACh and NE modulation, and dissect their respective roles in controlling hemodynamics during sleep. In Aim 3, we will use multiplane two-photon imaging to visualize the directions of propagation of arterial constrictions and dilations and widefield imaging of neural and vascular signals to visualize how vascular activity is coordinated across multiple spatial scales during sleep. Project 3 will contribute to the overall U19 proposal by dissecting the neural mechanisms controlling arterial dilations and constrictions during NREM sleep. Our measures of arterial dynamics at both the local and global scales during sleep will provide important data for the modeling in Project 1. Our use of the mouse model will complement the measurements in Project 2. It will also help bridge the detailed mechanistic studies relating arterial diameter changes of CSF movement in Project 2 with the other Projects by making corresponding arterial dynamics measures during sleep. Our determination of causal relationships among neuromodulation, neuronal subtype activity, and vascular dynamics will be applied to understand the simultaneous EEG and neuroimaging data in Project 4.

摘要，项目3 睡眠伴随着神经活动、调节状态和血液动力学的巨大变化。大 睡眠期间的动脉扩张和收缩可以驱动CSF的血管周围泵送，这将有助于清除 液体和溶质。我们假设，在NREM睡眠期间，动脉的大振荡， 直径由局部神经活动驱动，并通过去甲肾上腺素能（NE）和 胆碱能（ACh）神经调节驱动。我们将通过光学成像来测试这个想法， 睡眠的小鼠，同时扰乱神经活动和神经调节。在目标1中，我们将改变定义的活动 使用光和化学发生学工具确定局部神经活动的作用 在控制血管动力学方面。在目标2中，我们将使用荧光生物传感器、光遗传学和化学遗传学 了解胆碱能和去甲肾上腺素能调节在协调大脑皮质血管 睡眠中的动态我们将测量ACh和NE调制之间的时间关系，并解剖 它们各自在睡眠期间控制血液动力学中的作用。在目标3中，我们将使用多平面双光子 成像以使动脉收缩和扩张的传播方向可视化， 神经和血管信号，以可视化血管活动如何在多个空间尺度上协调， 睡吧 项目3将有助于通过解剖控制神经机制的整体U19提案 在NREM睡眠期间动脉扩张和收缩。我们对局部和局部动脉动力学的测量 睡眠期间的全局尺度将为项目1中的建模提供重要数据。我们使用的小鼠模型 将补充项目2中的测量。它还将有助于连接详细的机制研究， 通过制作相应的动脉，将项目2中CSF运动的动脉直径变化与其他项目进行比较 睡眠时的动态测量。我们确定了神经调节、神经元 亚型活动和血管动力学将被应用于了解同步脑电图和神经影像学 项目4中的数据。