HORMONAL CONTROL OF CNS REORGANIZATION IN DROSOPHILA

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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.