OPTICAL IMAGING AND FUNCTIONAL CONNECTIVITY MAPPING FOR MICE

描述（由申请人提供）：静息状态功能连接（RSFC）分析是一种用于映射功能性脑组织的新方法，其承诺将认知科学与临床神经学相结合。在没有任务的情况下，功能相关的脑区域具有相关的自发神经和血液动力学活动的发现意味着即使在具有严重脑损伤的患者中也可以研究脑网络，包括无意识的、麻醉的或非常年轻的患者。除了无任务外，功能连接磁共振成像（fcMRI）在时间上也很有效，可以在几分钟内绘制整个大脑。 随着这些功能连接方法的发展，在人类中使用的非侵入性功能性脑映射方法与通常在小鼠疾病模型中使用的侵入性分子和遗传方法之间的差距继续增长。一种适用于小鼠的有效功能连接方法可以在人类疾病评估与小鼠疾病机制和治疗研究之间提供关键联系。虽然fMRI已经扩展到一些动物模型（灵长类动物和较小程度的大鼠），但由于分辨率和信噪比的严格要求，迄今为止fcMRI在小鼠中仍然难以捉摸。最近，RSFC方法已扩展到光学技术与功能连接扩散光学断层扫描（fcDOT）在人类中证明。小鼠成像的一个优点是光学方法容易扩展到更小的体积。 在这项资助中，我们将fcDOT扩展到小鼠-开发高性能小鼠特异性DOT仪器和互补成像算法。小鼠大脑的小尺寸为DOT方法提供了远远超过在人类中获得的相对图像质量的机会。利用这个机会需要一种新的设计方法。我们建议使用多个相机视图与结构化照明相结合，以将基于相机的DOT的速度提高> 100倍。功能连接方法，包括相关性分析和皮质包裹将开发和建立在小鼠模型中使用遗传，行为和手术操作的功能连接，并验证刺激反应和组织学。为了在脑损伤模型中测试fcDOT，我们将检查缺血性中风。最近在缺血性卒中患者中的fcMRI研究表明，在卒中后2周内测量的双侧同源连接是长期恢复的预测因子。我们将使用fcDOT在中风恢复模型中连续测量小鼠的双侧连接。将使用遗传上缺乏对侧连接的小鼠品系来确定经胼胝体连接是否直接影响中风后恢复。在这项资助下开发的小鼠fcDOT将使人类神经科学与遗传小鼠模型联系起来的新范式成为可能。

DESCRIPTION (provided by applicant): Resting state functional connectivity (RSFC) analysis is a novel approach for mapping functional brain organization that promises integration of the cognitive sciences with clinical neurology. The discovery that functionally-related brain regions have correlated spontaneous neural and hemodynamic activity in absence of tasks means that brain networks can be studied even in patients with severe brain- injury, including unconscious, anesthetized, or very young patients. In addition to being task-less, functional connectivity Magnetic Resonance Imaging (fcMRI) is also efficient in time, mapping the entire brain in as little as several minutes. As these functional connectivity methods advance, a gap continues to grow between the non- invasive functional brain mapping methodologies used in humans and the invasive molecular and genetic methodologies commonly used in mouse models of disease. An efficient functional connectivity method applicable in the mouse could provide a critical link between human evaluation of disease and mouse studies of disease mechanisms and therapies. While fMRI has been extended to some animal models (primates and to a lesser extent rats), thus far fcMRI remains elusive in the mouse due to stringent demands in resolution and signal-to-noise. Recently the RSFC methods have been extended to optical technology with functional connectivity diffuse optical tomography (fcDOT) demonstrated in humans. An advantage for mouse imaging is that optical methods readily scale to smaller volumes. In this grant we will extend fcDOT to the mouse - developing both a high-performance mouse specific DOT instrument and complementary imaging algorithms. The small size of the mouse brain provides an opportunity for DOT methods to far exceed the relative image quality of that obtained in humans. Leveraging this opportunity requires a new design approach. We propose using multiple camera views combined with structured illumination to increase the speed of camera based DOT by >100x. Functional connectivity methods, including correlation analysis and cortical parcellation will be developed and established in mouse models using genetic, behavioral and surgical manipulations of functional connectivity, and validation against stimulated responses and histology. To test fcDOT in a brain injury model, we will examine ischemic stroke. Recent fcMRI studies in ischemic stroke patients have demonstrated that bilateral homotopic connectivity, measured within 2 weeks after stroke, was a predictor of long-term recovery. We will serially measure bilateral connectivity in mice in a model of stroke recovery using fcDOT. Mice strains genetically lacking contralateral connectivity will be used to determine if transcallosal connectivity directly influences post-stroke recovery. The mouse fcDOT developed in this grant will enable new paradigms linking human neuroscience to genetic mouse models.