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

摘要，项目3 睡眠伴随着神经活动、调节状态和血流动力学的巨大变化。大的 睡眠中动脉的扩张和收缩可以促使血管周围的脑脊液泵出，这将有助于清除 大脑中的液体和溶质。我们假设，在NREM睡眠期间，动脉的大幅振荡 直径由局部神经活动驱动，并由去甲肾上腺素(NE)和 胆碱能(ACh)神经调节驱动。我们将通过对大脑皮质血管系统进行光学成像来测试这一想法 在扰乱神经活动和神经调节的同时让小鼠睡着。在目标1中，我们将更改定义的活动 使用光和化学发生工具确定局部神经活动在睡眠期间的神经元数量 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层血管中的作用 睡眠时的动态变化。我们将测量ACH和NE调制之间的时间关系，并剖析 它们在睡眠中控制血流动力学的各自作用。在目标3中，我们将使用多平面双光子 显示动脉收缩和扩张的传播方向的成像和宽视野成像 神经和血管信号，可视化血管活动是如何在多个空间尺度上协调的 睡吧。 项目3将通过解剖神经控制机制来为整个U19提案做出贡献 NREM睡眠期间的动脉扩张和收缩。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。我们使用鼠标模型 将补充项目2中的测量。它还将有助于弥合详细的机械研究 方案2与其他方案相对应的脑脊液运动的动脉内径变化 动态测量睡眠时的状态。我们对神经调节、神经元之间因果关系的确定 亚型活动性和血管动力学将被应用于理解同时进行的脑电和神经成像 项目4中的数据。

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.