Functional connectivity and spatiotemporal dynamics in unanesthetized rodents

描述（由申请人提供）：功能连接MRI （fcMRI）是一种强大的工具，用于解密大脑内的自发网络活动。在阿尔茨海默病、精神分裂症和自闭症患者中观察到功能连接的变化，这表明fcMRI对大脑临床相关的改变很敏感。尽管这项技术越来越受欢迎，但我们对用于绘制功能连接图的血氧依赖（BOLD） MRI信号变化背后的自发神经和血流动力学波动的理解还远远不够完整。我们的实验室率先开发了同时功能磁共振成像和多位点微电极记录啮齿动物，以确定功能连接的神经基础和在BOLD信号中观察到的时空模式。我们的初步结果表明，神经活动和BOLD波动之间的关系强烈依赖于所用麻醉的类型和深度。除了它们对神经活动的主要作用外，大多数麻醉剂还直接影响血液动力学，并且很难解除这种影响。在这项研究中，我们将比较麻醉和未麻醉大鼠的功能连接和BOLD时空动态与微电极记录。这项工作将验证麻醉的啮齿动物作为未来多模态研究的模型，以阐明支持fcMRI的神经血管过程，或者作为进一步在未麻醉的啮齿动物中进行实验的垫脚石。本研究的具体目的是：1。对未麻醉的大鼠实施功能磁共振成像，并确定功能连通性和时空动态与麻醉动物的测量结果相比较。使用目前市售的用于未麻醉大鼠的专用支架，大鼠将在几天内适应扫描仪，以尽量减少压力。将在醒着的大鼠、异氟醚和美托咪定下获得fcMRI数据。在四个功能网络连接之间的差异将被检查。BOLD波动的时空动态也将使用我们实验室开发的模板创建算法进行映射，并且大鼠体内模板之间的关系将用于表征每种条件下的时空动态。2. 利用电生理学确定清醒大鼠与麻醉大鼠的功能连接差异的神经来源。为了将麻醉药对血管的影响与神经的影响分开，将首先在清醒的动物身上进行同步微电极记录/功能磁共振成像研究，然后将其过渡到麻醉状态。我们将比较带限局部场电位（LFP）信号相干性和BOLD信号相关性，以确定每种状态下哪些神经特性是fcMRI的基础。我们还将计算传递函数，直接比较LFPs和fMRI在每种条件下的变化。

DESCRIPTION (provided by applicant): Functional connectivity MRI (fcMRI) is a powerful tool for deciphering spontaneous network activity within the brain. Changes in functional connectivity have been observed in patients with Alzheimer's disease, schizophrenia, and autism, suggesting that fcMRI is sensitive to clinically relevant alterations in the brain. Despite the growing popularity of this technique, our understanding of the spontaneous neural and hemodynamic fluctuations underlying the variations in the blood oxygenation dependent (BOLD) MRI signal used to map functional connectivity is far from complete. Our lab has pioneered the development of simultaneous fcMRI and multisite microelectrode recording in the rodent in order to determine the neural basis for functional connectivity and the spatiotemporal patterns observed in the BOLD signal. Our preliminary results indicate that the relationship between neural activity and BOLD fluctuations is strongly dependent upon the type and depth of anesthesia used. In addition to their primary action on neural activity, most anesthetics also directly impact hemodynamics, and it can be difficult to uncouple the effects. In this study, we will compare functional connectivity and BOLD spatiotemporal dynamics to microelectrode recordings in both anesthetized and unanesthetized rats. This work will either validate the anesthetized rodent as a model for future multimodality studies to elucidate the neurovascular processes underpinnings fcMRI, or serve as a stepping stone for further experiments in unanesthetized rodents. The specific aims of this study are: 1. Implement fcMRI for unanesthetized rats and determine how functional connectivity and spatiotemporal dynamics compare to measurements in anesthetized animals. Using a specialized holder for unanesthetized rats now commercially available, rats will be acclimatized to the scanner over several days to minimize stress. fcMRI data will be acquired in the awake rat, under isoflurane, and under medetomidine. Differences between connectivity in four functional networks will be examined. The spatiotemporal dynamics of the BOLD fluctuations will also be mapped using a template-creation algorithm developed by our lab, and the relationship between the templates within rats will be used to characterize the spatiotemporal dynamics for each condition. 2. Determine the neural sources of functional connectivity differences in awake compared to anesthetized rats using electrophysiology. To separate the vascular effects of the anesthetics from neural effects, simultaneous microelectrode recording/fcMRI studies will be first obtained from awake animals, and then they will be transitioned to anesthesia. We will compare band-limited local field potential (LFP) signal coherence to BOLD signal correlation to determine which neural properties are the basis of fcMRI in each state. We will also calculate the transfer function for comparing LFPs and fMRI directly under each condition to identify changes.