It has been established that serotonin and S-100beta both function as trophic factors on CNS cortical neurons. Recently, 5-HT, acting at a 5- HT1A receptor, was found to stimulate astroglial cell to secrete a soluble trophic factor whose activity was blocked with anti-bodies against S- 100beta. Conversely, S-100beta was shown to stimulate the neurites of cultured serotonergic neurons. This neuronal/glial link to growth factor release is the basis of our project. We propose to study the effects of other unmyelinated (dopamine and acetylcholine) neurons on the regulation and action of S-100beta. There is evidence that in vivo these three systems have many cellular and functional interactions. It is proposed that competion for S-100beta may underlie their complimentary distribution in the CNS. ACTH and Substance-P have been demonstrated to increase the maturational rate of fetal 5-HT neurons. Enkephalin, on the other hand, leads to an inhibition. The synergistic actions of neuropeptides and S-100beta will be studied. Finally, there is good evidence that glucocorticoids are involved in brain aging. These steroids also have effects on 5-HT metabolism and plasticity. Glucocorticoids have been shown to have potent effects on astrocytic proliferation and on the molecular regulation of glial fibrillary acid protein (GFAP) transcription and translation. A final proposal of this project is to determine the effects of corticosterone on the neuronal and neuropeptide interactions on S-100beta transcription, translation and trophic activity. Our hypothesis is that glucocorticoids are an essential component for S- 100beta trophic actions on unmyelinated neurons, and, as a collorary, neuropeptides will have synergistic actions with S-100beta on neuronal sprouting. The results of our studies will have implications for understanding the role of hormones and neuronal interactions on growth regulatory factors during aging.
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