Resting-state Neural Networks in Awake Rodents

描述（由申请人提供）：在过去的十年中，我们对人脑网络中组织的理解已经被新兴的静息态功能磁共振成像（rsfMRI）技术彻底改变。rsfMRI可用于在没有任何外部刺激的情况下测量静息状态功能连接（RSFC）。通过利用这种技术，RSFC的重要神经病理学相关性已被反复证明在许多神经系统，神经精神和神经退行性疾病，这表明RSFC可能作为一个敏感的生物标志物，以帮助诊断和评价治疗人类大脑疾病。不幸的是，RSFC方法的全部潜力受到动物RSFC研究中的关键空白的限制，主要受到动物实验中使用的麻醉对RSFC的混淆作用的挑战。临床前RSFC数据的缺乏极大地阻碍了我们对动物基础大规模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疾病的神经生物学和开发新的治疗方法，无法在动物中成像RSFC极大地阻碍了RSFC方法在神经病理学研究中的应用。因此，为了避免麻醉的混淆和弥补动物RSFC研究的差距，有必要在清醒动物中成像RSFC。在我们的实验室中，我们已经“克服了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RSFC。基于这种方法，我们已经证明了测量个体神经回路的可行性，全脑网络的内在组织，以及在不同的神经生理条件下清醒大鼠的脑网络重构。这些试验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的大鼠脑连接体。此外，由于RSFC在动物中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，因此我们将探索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：在目标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。目的二：利用图形分析技术构建大鼠脑连接体，并对其进行评价，以了解大鼠脑组织结构。此外，在探索性目的中，我们将研究5-羟色胺系统和RSFC之间的关系，这被认为是RSFC的神经化学机制的关键。这项工作是创新的，因为它将利用一种新的神经成像技术（清醒动物中的RSFC）来研究啮齿动物的大规模神经网络。这项研究的影响是非常重要的，因为它将弥合RSFC研究的差距，并开辟了一条新的途径，研究各种动物模型的大脑疾病。

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.