A novel neuroimaging approach to mapping the neural circuits underlying behavior

描述(申请人提供)：神经回路是神经系统的功能和结构单位。神经回路功能和发育缺陷会导致多种神经功能障碍。我们感兴趣的是了解信息是如何被神经回路处理的，基因是如何调节这种处理的，以及这最终是如何产生和重塑行为输出的。由于许多神经机制被发现在系统发育中是保守的，遗传模式生物，如线虫和果蝇，已被广泛用于研究神经生物学中的各种现象。大约三分之二的人类疾病基因在这些生物体中有同源基因。然而，某些技术缺陷极大地阻碍了将这些遗传有机体用作神经生物学研究的模型。特别是，没有可用的技术来记录蠕虫或苍蝇行为时的神经活动。因此，目前所有的研究都局限于记录固定或半固定的神经活动，而不是在行为自由的动物身上，这使得很难可靠地将神经活动和行为联系起来。在这里，我们首次开发了一种新型的非侵入性神经成像系统，它可以在单个神经元分辨率下记录自由行为蠕虫的神经元活动，从而能够绘制出行为背后的神经回路。在目前的提案中，通过利用这种新的神经成像系统，结合激光显微外科手术和分子遗传学工具，我们将定义一些经典蠕虫行为背后的神经回路。此外，我们还将通过引入更先进的功能来进一步开发该系统。这项拟议的工作将为神经系统和基因如何控制哺乳动物的行为提供新的见解。许多类型的神经疾病(如癫痫、运动障碍和双相情感障碍)都表现为神经回路功能和发育缺陷导致的行为异常。我们的工作将为神经回路和基因如何控制正常行为以及这一过程中的缺陷如何导致神经障碍提供新的见解。

DESCRIPTION (provided by applicant): Neural circuits are the functional and structural units of the nervous system. Defects in neural circuit function and development lead to a variety of neurological disorders. We are interested in understanding how information is processed by neural circuits and how genes regulate such processing, and how this ultimately produces and reshapes behavioral output. As numerous neural mechanisms are found to be conserved across phylogeny, genetic model organisms, such as C. elegans and Drosophila, have been widely utilized to study various phenomena in neurobiology. About two-third of human disease genes have homologs in these organisms. However, certain technological shortfalls have greatly hampered the use of these genetic organisms as a model for neurobiology research. In particular, there is no technology available that allows one to record neural activity in behaving worms or flies. Consequently, all current studies have been limited to recording neural activity in immobilized or semi-immobilized, but not in freely-behaving animals, making it difficult to reliably correlate neural activity and behavior. Here we have, for the first time, developed a novel noninvasive neuroimaging system that can record neuronal activity in freely-behaving worms at single neuron resolution, thus allowing for mapping the neural circuits underlying behavior. In the current proposal, by taking advantage of this novel neuroimaging system in conjunction with laser microsurgery and molecular genetic tools, we will define the neural circuits underlying some classic worm behaviors. In addition, we will further develop the system by introducing more advanced functionalities. The proposed work will provide novel insights into how the nervous system and genes control behavior in mammals. Many types of neurological disorders (e.g., epilepsy, movement disorders and bipolar disorder) are manifested by behavioral abnormalities that result from defective neural circuit function and development. Our work will provide novel insights into how neural circuits and genes control normal behavior and how defects in this process lead to those neurological disorders.