Synaptic Structural Plasticity in the Drosophila Brain

描述（由申请人提供）：我们的目标是开发一个新的系统，用于研究成熟大脑中的突触结构可塑性。使用长期多光子成像，我们发现成年果蝇大脑中的突触连接是动态的，在几个小时内经历形成和消除。该系统提供了将果蝇遗传分析的力量应用于CNS内突触结构可塑性的问题，并且可以应用于直接参与学习和记忆等过程的大脑区域。我们寻求支持，以发展这一系统成为一个重要的范式突触可塑性的遗传分析。我们将利用多光子共聚焦成像和图像分析方法研究这种结构可塑性的机制。动态突触的结构将通过研究其超微结构和功能来详细研究。将开发一种用于活体动物的长期成像方案。我们的初步研究表明，过度激活的神经元或过度表达功能获得性Raf等位基因可以诱导成年CNS中突触结构的变化。神经活动是否调节突触结构动力学将通过成像个体突触而进一步解决，同时过度激活或抑制成年动物的活动。为了进一步探索调节突触结构的分子机制，我们将启动一个大规模的遗传筛选突触结构的调节剂。在本提案的期限之后，将对这些调节剂进行分子表征和详细研究。我们的最终目标是操纵神经系统的可塑性，以便为脑损伤或疾病后恢复神经功能提供途径。通过了解哪些分子可以调节正常CNS中的突触动力学，我们可能能够在因疾病或中风而受损的大脑中诱导特定的变化，或者在行为障碍中发生功能障碍。

DESCRIPTION (provided by applicant): Our objective is to develop a new system for the study of synaptic structural plasticity in the mature brain. Using long term multi-photon imaging, we have found that synaptic connections in the adult Drosophila brain are dynamic, undergoing both formation and elimination over a period of several hours. This system offers to bring the power of Drosophila genetic analysis to bear on the question of synaptic structural plasticity within the CNS, and can be applied to regions of the brain with direct involvement in processes such as learning and memory. We seek support to develop this system into an important paradigm for the genetic analysis of synaptic plasticity. We will investigate the mechanism of this structural plasticity using multi- photon confocal imaging and image analysis methods. The structure of dynamic synapses will be investigated in detail by investigating their ultrastructure and function. A long-term imaging protocol for live behaving animals will be developed. Our initial studies indicate that hyper-activating neurons or over- expressing a gain-of-function Raf allele can induce changes in synapse architecture in the adult CNS. Whether neural activity regulates synaptic structural dynamics will be further addressed by imaging individual synapses while hyper-activating or suppressing activity in adult animals. To further explore the molecular mechanisms that regulate synaptic structure, we will initiate a large-scale genetic screen for regulators of synaptic architecture. Beyond the term of this proposal, these regulators will be characterized molecularly and studied in detail. Our ultimate goal is to manipulate the plasticity of the nervous system in order to provide avenues for restoring neural function after brain injury or disease. By understanding what molecules may regulate synaptic dynamics in a normal CNS, we may be able to induce specific changes in a brain damaged by disease or stroke, or that malfunctions in behavioral disorders.