HORMONAL CONTROL OF CNS REORGANIZATION IN DROSOPHILA

果蝇中枢神经系统重组的激素调控Restifo)拟议研究的重点是类固醇激素对中枢神经系统重塑的控制。鉴于它们对人类神经发育和功能的广泛影响，我们必须在细胞和分子水平上更好地了解它们的作用。果蝇黑腹果蝇模型系统中的基因技术提供了这样的机会。研究中的假设是类固醇激素20-羟基蜕皮激素(20E)控制蘑菇体的重组，蘑菇体是学习和记忆必不可少的大脑结构。在变态过程中，菌体结构通过轴突和树突的顺序退化和再生以及神经发生和新生分化来改变，这是由激素波动控制的发育间隔。这种重塑可能会促进突触连接的建立，这些突触连接对成人特有的行为至关重要。Kenyon细胞，在那里它们通过促进轴突生长对20E的生理水平做出反应，这与激素在体内的作用一致。女性和男性神经元的体外反应要大得多，这与成年女性大脑中更多的Kenyon细胞轴突是一致的。在野生型和突变型样本中，体外培养的Kenyon细胞的一些特征与体内的同类细胞相似。建议采用细胞培养和全脑实验相结合的方法来确定三种Kenyon细胞亚型中的哪一种对20E有反应，并确定三种Kenyon细胞亚型中的哪一种对20E有反应，并确定哪些蜕皮激素级联的调控基因支持轴突生长促进。遗传性逆转实验将揭示20E对轴突生长的性别作用是否将通过对表达绿色荧光蛋白的活培养蘑菇体神经元的系列观察来确定。Kenyon的形态和激素反应特性预测揭示了细胞缺陷，这些缺陷扰乱了对经验依赖性神经可塑性至关重要的功能电路的发展。从这些研究中获得的信息将产生治疗和预防与神经元结构和功能异常相关的获得性和先天性疾病的新策略。

Hormonal control of CNS reorganization in Drosophila (PI, L.l. Restifo) The focus of the proposed research is the control of central nervous system remodeling by steroid hormones. Given their widespread impact on human neural development and function, it is imperative that we achieve a better understanding of their action at cellular and molecular levels. The genetic technology available in the Drosophila melanogaster model system provides such an opportunity. The hypothesis under investigation is that the steroid hormone 20-hydroxyecdysone (20E) controls the reorganization of the mushroom bodies, brain structures that are essential for learning and memory. During metamorphosis, a developmental interval orchestrated by hormonal fluctuations, mushroom body structure is modified by sequential degeneration and regeneration of axons and dendrites, as well as neurogenesis and do novo differentiation. This remodeling is likely to promote the establish of synaptic connections critical for adult-specific behaviors. Kenyon cells, where they respond to physiological levels of 20E by enhanced neurite outgrowth, consistent with an in vivo role of the hormone. The in vitro response is much greater in females and in male neurons, consistent with the larger number of Kenyon cell axons in adult female brains. In both wild-type and mutant samples, a number of Kenyon cell characteristics in vitro are similar to their in vivo counterparts. A combination of cell culture and whole-brain experiments are proposed to determine which of the three Kenyon cell subtypes is responsive to 20E, and to determine which of the three Kenyon cell subtypes is responsive to 20E, and to determine which regulatory genes of the ecdysone cascade underlie neurite outgrowth enhancement. Genetic sex reversal experiments will reveal whether the sex action of 20E on neurite outgrowth will be determined by serial observations of live cultured mushroom body neurons expressing Green Fluorescent Protein. The morphology and hormone-response properties of Kenyon predicted to reveal cellular defects that disrupt the development of functional circuitry critical to experience-dependent neural plasticity. Information obtained from these studies will produce the generation of new strategies for treating and preventing acquired and congenital disorders associated with abnormal neuronal structure and function.