HORMONAL CONTROL OF CNS REORGANIZATION IN DROSOPHILA

激素对果蝇中枢神经系统重组的控制（PI, l.l. Restifo）本研究的重点是类固醇激素对中枢神经系统重构的控制。鉴于它们对人类神经发育和功能的广泛影响，我们必须更好地了解它们在细胞和分子水平上的作用。在黑腹果蝇模型系统中可用的遗传技术提供了这样一个机会。正在研究的假设是，类固醇激素20-羟基蜕皮激素（20E）控制蘑菇体的重组，这是学习和记忆所必需的大脑结构。在由激素波动调控的发育过程中，蘑菇体结构被轴突和树突的连续变性和再生以及神经发生和新生分化所改变。这种重塑可能促进突触连接的建立，而突触连接对成人的特定行为至关重要。Kenyon细胞对20E生理水平的反应是神经突生长增强，这与体内激素的作用一致。体外反应在女性和男性神经元中要大得多，这与成年女性大脑中较多的凯尼恩细胞轴突一致。在野生型和突变型样本中，体外的肯扬细胞特征与体内的肯扬细胞相似。我们建议结合细胞培养和全脑实验来确定三种Kenyon细胞亚型中哪一种对20E有反应，确定三种Kenyon细胞亚型中哪一种对20E有反应，并确定哪些皮质激素级联的调控基因是神经突生长增强的基础。基因性别反转实验将通过对表达绿色荧光蛋白的活培养蘑菇体神经元的连续观察来揭示20E对神经突生长的性别作用。Kenyon的形态学和激素反应特性预测揭示了细胞缺陷，这些缺陷破坏了对经验依赖的神经可塑性至关重要的功能回路的发育。从这些研究中获得的信息将产生治疗和预防与异常神经元结构和功能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.