Resting-state Neural Networks in Awake Rodents

描述（由申请人提供）：在过去的十年中，静息状态功能磁共振成像（rsfMRI）的新兴技术彻底改变了我们对人脑网络组织的理解。rsfMRI可用于在没有任何外界刺激的情况下测量静息状态功能连接（RSFC）。通过利用这项技术，RSFC在许多神经、神经精神和神经退行性疾病中的重要神经病理学相关性已被反复证实，这表明RSFC可能作为一种敏感的生物标志物，有助于诊断和评估人类脑部疾病的治疗。不幸的是，RSFC方法的全部潜力受到动物RSFC研究的关键空白的限制，主要是在RSFC动物实验中使用麻醉的混淆效应。缺乏临床前RSFC数据极大地阻碍了我们对动物基础大尺度功能性脑网络的理解。更重要的是，由于动物模型已被广泛用于研究脑部疾病的神经生物学和开发新的治疗方法，动物RSFC无法成像极大地阻碍了RSFC方法在神经病理学研究中的应用。因此，为了避免麻醉的干扰，填补动物RSFC研究的空白，有必要对清醒动物RSFC进行成像。在我们的实验室，我们已经“克服了对啮齿动物神经网络成像的技术障碍”（NIDA Notes， 2012年6月），并建立了一种rsfMRI方法，允许在清醒状态下获得动物的RSFC。基于这种方法，我们已经证明了在清醒大鼠不同神经生理条件下测量单个神经回路、全脑网络的内在组织以及脑网络重构的可行性。这些试点数据为我们进一步表征清醒大鼠大脑中的RSFC做好了准备。重要的是，我们将能够构建基于rsfc的大鼠脑连接组。此外，由于RSFC在动物体内的测量使得利用成熟的侵入性临床前工具来研究其详细的细胞和分子机制成为可能，我们将探索RSFC潜在的神经化学机制。这些研究目标将通过三个具体目标来实现：在Aim 1中，我们将系统地表征RSFC，以测试其可靠性，并获得清醒大鼠大脑中基础神经网络的知识。在Aim 2中，我们将使用图分析来构建和评估大鼠脑连接组，以了解大鼠脑组织。此外，在探索性目的中，我们将研究血清素系统与RSFC之间的关系，这被认为是RSFC的神经化学机制的关键。提出的工作是创新的，因为它将利用一种新的神经成像技术（清醒动物的RSFC）来研究啮齿动物的大规模神经网络。本研究的影响是非常重要的，因为它将填补RSFC研究的空白，并为研究各种脑部疾病的动物模型开辟新的途径。

DESCRIPTION (provided by applicant): In the past decade, our understanding of the organizations among human brain networks has been revolutionized by the emerging technique of resting-state functional magnetic resonance imaging (rsfMRI). rsfMRI can be used to measure resting-state functional connectivity (RSFC) in the absence of any external stimulation. By utilizing this technique, vital neuropathological relevance of RSFC has been repeatedly demonstrated in numerous neurological, neuropsychiatric and neurodegenerative disorders, suggesting that RSFC might serve as a sensitive biomarker for aiding diagnosis and evaluation of treatment for human brain diorders. Unfortunately, the full potential of RSFC methods is limited by a critical gap in animal RSFC research, mainly challenged by the confounding effects of anesthesia used in animal experiments on RSFC. Lack of preclinical RSFC data has considerably hindered our understanding of the basal large-scale functional brain networks in animals. More importantly, since animal models have been comprehensively used to investigate the neurobiology of brain diseases and develop new therapies, inability of imaging RSFC in animals has tremendously impeded the application of RSFC methods to studying neuropathology. Therefore, to avoid the confounder of anesthesia and bridge the gap of RSFC research in animals, it is essential to image RSFC in awake animals. In our laboratory, we have "surmounted a technical obstacle to imaging neural networks in rodents" (NIDA Notes, June 2012) and established a rsfMRI approach that allows RSFC in animals to be acquired at the awake condition. Based on this approach, we have demonstrated the feasibility of measuring individual neural circuitries, the intrinsic organization of the whole-brain networks, as well as brain network reconfigurations at different neurophysiological conditions in awake rats. These pilot data have prepared us for further characterizing RSFC in the awake rat brain. Importantly, we will be able to construct the RSFC-based rat brain connectome. In addition, since RSFC measurement in animals makes it feasible to investigate its detailed cellular and molecular mechanisms by taking advantage of well-established invasive preclinical tools, we will explore a potential neurochemical mechanism underlying RSFC. These research objectives will be achieved through three specific aims: In Aim 1, we will systematically characterize RSFC to test its reliability and gain the knowledge of basal neural networks in the awake rat brain. In Aim 2, we will construct and evaluate the rat brain connectome by using graph analysis to understand the rat brain organization. Also in an Exploratory Aim, we will examine the relationship between the serotonin system and RSFC, which has been suggested to be critical in the neurochemical mechanism of RSFC. The proposed work is innovative, because it will utilize a novel neuroimaging technique (RSFC in awake animals) to investigate large-scale neural networks in rodents. The impact of this research is highly significant because it will bridge the gap in RSFC research and open a new avenue to studying various animal models of brain disorders.