Presynaptic Regulation of Dendritic Structural Dynamics

描述(申请人提供)：发育神经科学的一个中心目标是阐明神经回路形成、完善和维持背后的细胞机制，研究这些机制的一个实验策略是树突形态变化的时移成像；虽然成像研究表明突触前神经活动影响树突结构，但影响突触后形态的突触前活动参数仍不清楚。例如，在非洲爪哇蝌蚪的视顶盖中，视觉刺激促进了顶盖细胞树突的生长；然而，尚不清楚是视网膜神经节细胞活性增加还是刺激诱导的视网膜神经节细胞之间的相互关系导致了额外的生长。通过表征神经节细胞的自发活动及其对各种视觉刺激的反应，将有可能开发出系统地操纵它们的放电率和相互关系的视觉刺激。在向蝌蚪播放这些刺激的同时，监测单个顶盖细胞树突的结构动力学，将直接测试突触前活动水平和相关性对调节突触后形态的重要性。此外，通过关联一些视网膜神经节细胞的活动，而不是其他具有类似活动水平的细胞的活动，可以确定顶盖细胞是否更喜欢启动和/或稳定与相关输入的接触。最后，对顶盖细胞突触能力因遗传而降低的树突进行成像，将区分顶盖细胞动作电位是否是顶盖树突突触前调节所必需的。更深入地了解与树突结构可塑性相关的突触前活动的特征，从而进一步了解神经回路的形成，将揭示更多关于潜在的细胞机制。特别是，将测试依赖于棘波时序的突触可塑性和树突结构可塑性的兼容性。这些研究将帮助我们了解视网膜活动如何影响大脑深处视觉回路的连接。这些知识将使我们能够更好地预测一些影响视网膜活动的眼病是否也会导致这些电路中以前未被检测到的布线缺陷，并设计策略来预防、改善或补偿这些缺陷。

DESCRIPTION (provided by applicant): A central goal in developmental neuroscience is to elucidate the cellular mechanisms behind the formation, refinement, and maintenance of neural circuits, An experimental strategy for studying these mechanisms is time lapse imaging of morphological changes in dendritic arbors; while imaging studies have shown that presynaptic neural activity influences dendritic structure, the parameters of presynaptic activity that influence postsynaptic morphology remain unclear. For example, in the optic tectum of Xenopus tadpoles, visual stimulation enhances tectal cell dendritic growth; however, it is unknown whether elevated retinal ganglion cell activity or stimulus induced correlations amongst retinal ganglion cells are responsible for the additional growth. By characterizing ganglion cells' spontaneous activity and their responses to a variety of visual stimuli, it will be possible to develop visual stimuli that systematically manipulate their firing rates and correlations. Playing these stimuli to tadpoles while monitoring the structural dynamics of individual tectal cell dendritic arbors, will directly test the importance of presynaptic activity levels and correlations for regulating postsynaptic morphology. In addition, by correlating the activity of some retinal ganglion cells, but not others with comparable activity levels, it is possible to determine whether or not tectal cells prefer initiating and/or stabilizing contacts with correlated inputs. Finally, imaging the dendritic arbors of tectal cells whose ability to spike has been genetically reduced, will distinguish whether or not tectal cell action potentials are required for presynaptic regulation of tectal dendrites. Greater understanding of the features of presynaptic activity relevant to dendritic structural plasticity, and therefore neural circuit formation, will reveal much about the underlying cellular mechanisms. In particular, the compatibility of spike timing dependent synaptic plasticity and dendritic structural plasticity will be tested. These studies will help us understand how retinal activity impacts wiring in visual circuits deeper in the brain. This knowledge will allow us to better predict whether some eye diseases that impact retinal activity might also cause previously undetected wiring defects in these circuits and design strategies to prevent, ameliorate, or compensate for these defects.