In Vivo Properties of Spontaneous Waves in the Retina and Developing Visual Syste

描述（由申请人提供）：模式自发活动的显示是未成熟神经系统的一种紧急特性，被认为在许多发育中的神经回路中介导突触竞争并指导自组织。在视觉系统中，发育中的视网膜的分离（体外）制备在邻近的视网膜神经节细胞（RGCs）之间表现出传播性的电活动，称为“视网膜波”。由于RGCs将视觉信息传递到中枢神经系统的高阶结构，因此视网膜波被认为在上丘（SC）、外侧膝状核（LGN）和视觉皮层（VCtx）的活动依赖性神经地形图的细化中起着关键作用。然而，视网膜波在神经回路发育中的作用仍然存在很大的争议，部分原因是它们的存在从未在体内得到证实。先前在体内使用细胞外微电极记录技术的工作表明，胚胎大鼠RGCs对之间存在有限的局部相关尖峰，但尚未在体内进行波活动评估，可能是因为在新生动物中大量RGCs记录的方法上存在挑战。在这项提议中，我们使用一种高度新颖的成像方法来检查和表征新生小鼠体内整个视觉神经轴的自发活动，包括RGCs， SC和VCtx。我们试图确定自发性活动的行波是否发生在清醒、行为正常的新生小鼠身上，并在出生后的头两周内检查波在整个视觉系统发育中的时空特性。我们的初步数据表明，自发视网膜波在体内发育至少一周，并表现出与先前在体外描述的时空特性相似的特征。此外，视网膜波在中脑和视觉皮层产生匹配的活动模式。考虑到我们在小鼠睁眼前的一段时间内视网膜波的显著保真度，以及之前的研究表明猕猴视网膜内的自发波在出生前就存在，在人类胎儿发育过程中，视觉系统可能在相当长的妊娠期经历了视网膜波的模式激活，这可能是在感觉体验开始之前形成神经回路功能成熟的关键。总之，这些实验旨在研究哺乳动物视觉系统中神经回路发育中模式自发活动的性质和作用。

DESCRIPTION (provided by applicant): The display of patterned spontaneous activity is an emergent property of the immature nervous system that is thought to mediate synaptic competition and instruct self- organization in many developing neural circuits. In the visual system, isolated (in vitro) preparations of developing retina exhibit propagating electrical activiy amongst neighboring retinal ganglion cells (RGCs), termed 'retinal waves'. Since RGCs relay visual information to higher order structures in the central nervous system, retinal waves are thought to play a key role in activity-dependent refinement of topographic neural maps in the superior colliculus (SC), lateral geniculate nucleus (LGN), and visual cortex (VCtx). However, the role of retinal waves in neural circuit development remains remarkably controversial, in part because their existence has never been demonstrated in vivo. Previous work using extracellular microelectrode recording techniques in vivo demonstrated limited and local correlated spiking between pairs of embryonic rat RGCs, but no assessment of wave activity has been undertaken in vivo, likely because of the methodological challenges associated with recording from a large cohort of RGCs in neonatal animals. In this proposal, we use a highly novel imaging approach to examine and characterize spontaneous activity throughout the visual neuraxis, including RGCs, the SC and VCtx, in neonatal mice in vivo. We seek to establish whether traveling waves of spontaneous activity occur in awake, behaving neonatal mice, and examine the spatiotemporal properties of waves throughout the developing visual system during the first two weeks after birth. Our preliminary data indicates that spontaneous retinal waves are present for at least a week of development in vivo and exhibit a similar profile of spatiotemporal properties as those described previously in vitro. Moreover, retinal waves generate matched activity patterns in the midbrain and visual cortex. Given the remarkable fidelity of retinal waves during the period prior to eye opening in mice we report here in vivo, together with previous work demonstrating that spontaneous waves within macaque retina are present in vitro before birth, it seems likely that the visual system experiences patterned activation by retinal waves for a substantial gestational period during human fetal development that may be crucial for shaping the functional maturation of neural circuits before the onset of sensory experience. In all, these experiments are designed to investigate the properties and role of patterned spontaneous activity in vivo in the development of neural circuits in the mammalian visual system.