The long term goal of this project is to understand at the cellular level how hormones (steroids and peptides) regulate nervous system development and function. These classes of hormones have profound effects on the nervous system of most animals ranging from lower invertebrates up to humans. The metamorphosis of the nervous system of the moth Manduca sexta is a useful model system in which steroid and peptide hormone action can be studied in relation to identifiable, individual neurons. The action of these hormones can therefore be followed with greater precision in this invertebrate system than in any present vertebrate model of the CNS. Hormones control the proliferation, dendritic growth and programmed death of specific neurons in the insect. One part of the proposal will examine the steroid related death of differentiated neurons in the CNS. Autoradiographic localization of radiolabeled steroid in the CNS will provide information as to the relationship of steroid target cells to the cells that die. Also a study using a series of inhibitors of macromolecular synthesis will provide an initial test of the hypothesis that the onset of neuronal degeneration requires the activation of new genetic information. The steroids also affect other aspects of CNS development. A series of endocrinological studies in conjunction with 3H-thymidine birth-dating of cells will be used to establish the endocrine regulation of postembryonic neuronal proliferation and differentiation. Also, the biochemical basis of the steroid-regulated induction of sensitivity to the peptide eclosion hormone will be examined. The latter studies will involve a biochemical examination of the steroid's effect on molecules in the pathway that mediate eclosion hormone action (i.e. receptors, guanylate cyclase, protein kinase, and cellular substrates). Lastly, the action of eclosion hormone will be studied from an electrophysical point of view in the contex of identified circuits that change their properties in response to the peptide.
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