TARGET FACULTY/THE ROLE OF NOTCH IN ADULT NEUROPLASTICITY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在之前的工作中，我们已经确定了Notch功能在果蝇成年神经系统完整性中的作用。Notch有条件受损的果蝇表现出神经退行性缺陷，包括寿命缩短、飞行不协调和长期记忆受损。实验是在神经系统完全发育和非有丝分裂后进行的。我们的假设是Notch对于分化神经元的神经可塑性是必要的。在这方面，可塑性被定义为神经结构（树突、轴突、突触）的获取或维持，以便在功能上处理个体生物独特的生活经历。大脑的可塑区域可能具有动态的神经结构，这取决于来自丰富刺激环境的感觉输入、未使用的神经连接的磨损或损伤等条件。果蝇是这些研究的理想模型系统，有两个原因。首先，可以使用强大的遗传工具来分析果蝇发育和衰老的分子途径，以分析重要的功能基因。其次，从昆虫到脊椎动物的进化过程中，许多关键的信号通路都是保守的，果蝇对我们目前对人类信号通路和疾病病理的理解做出了重大贡献。因此，我们建议研究Notch信号在成人神经系统中的主要作用是促进包括记忆在内的可塑性功能的假设，并且我们可以使用果蝇来模拟阿尔茨海默病的重要方面。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In previous work, we have defined a role for Notch function in the integrity of the adult nervous system of Drosophila. Flies in which Notch is conditionally compromised display neurodegenerative defects that included a reduced life span, uncoordinated flight, and an impairment of long-term memory. Experiments were performed in adult flies after the nervous system was fully developed and non-mitotic. Our hypothesis is that Notch is necessary for neuroplasticity in differentiated neurons. Plasticity in this context is defined as the acquisition or maintenance of neural structures (dendrites, axons, synapses) in order to functionally deal with the individual organism's unique set of life experiences. Plastic regions of the brain would be expected to have a dynamic neuroarchitecture depending on such conditions as sensory inputs from environments rich in stimuli, attrition of unused neural connections, or injury. Drosophila is an ideal model system for these investigations for two reasons. First, the molecular pathways contributing to Drosophila development and aging can be dissected using powerful genetic tools to assay the important functional genes. Second, many of these critical pathways are conserved through evolution from insects to vertebrates, and Drosophila has made substantial contributions to our current understanding of signaling pathways and disease pathologies in humans. Thus, we propose to investigate the hypothesis that the major role of Notch signaling in the adult nervous system is to contribute to plastic functions that include memory, and that we can use Drosophila to model important aspects of Alzheimer¿s disease.