OPTICAL IMAGING AND FUNCTIONAL CONNECTIVITY MAPPING FOR MICE

描述(申请人提供)：静息状态功能连接(RSFC)分析是一种新的绘制脑功能组织图的方法，有望将认知科学与临床神经学相结合。在没有任务的情况下，与功能相关的大脑区域具有相关的自发神经和血流动力学活动，这一发现意味着，即使在严重脑损伤的患者中，包括昏迷、麻醉或非常年轻的患者，也可以研究大脑网络。除了无任务，功能连接磁共振成像(FcMRI)还具有时间效率高的特点，只需几分钟就能绘制出整个大脑的图谱。随着这些功能连接方法的进步，人类使用的非侵入性功能脑图方法与通常用于小鼠疾病模型的侵入性分子和遗传方法之间的差距继续扩大。一种适用于小鼠的有效功能连接方法可以在人类对疾病的评估与小鼠对疾病机制和治疗的研究之间提供关键联系。虽然功能磁共振成像已经扩展到一些动物模型(灵长类动物和较小程度的大鼠)，但到目前为止，由于对分辨率和信噪比的严格要求，功能磁共振成像在小鼠中仍然难以捉摸。最近，RSFC方法已经扩展到光学技术，在人类身上展示了功能连接性漫反射光学层析成像(FcDOT)。鼠标成像的一个优点是光学方法很容易扩展到较小的体积。在这笔赠款中，我们将把fcDOT扩展到鼠标-开发一种高性能的鼠标专用DOT仪器和互补的成像算法。小鼠大脑的小尺寸为DOT方法提供了远远超过人类获得的相对图像质量的机会。利用这一机会需要一种新的设计方法。我们建议使用多个摄像机视图与结构照明相结合来将基于摄像机的DOT的速度提高100倍。功能连通性方法，包括相关分析和皮质分割，将在小鼠模型中开发和建立，使用遗传、行为和手术操作的功能连通性，并对照刺激反应和组织学进行验证。为了在脑损伤模型中测试fcDOT，我们将检查缺血性中风。最近对缺血性中风患者的fcMRI研究表明，中风后2周内测量的双侧同位连接性是长期康复的预测因子。我们将使用fcDOT在中风恢复模型中连续测量小鼠的双侧连通性。缺乏对侧遗传连通性的小鼠品系将被用来确定是否通过膝盖骨连通性直接影响中风后的恢复。在这笔赠款中开发的小鼠fcDOT将使将人类神经科学与遗传小鼠模型联系起来的新范例成为可能。

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.