CELLULAR CORRELATES OF AXONAL SPROUTING

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The neurons of the mammalian hypothalamic magnocellular neurosecretory system (MNS) exhibit unusually vigorous regenerative capabilities. It has been known for many years that they can regenerate axons severed by pituitary stalk section, and this laboratory has recently demonstrated that the axon terminals of uninjured MNS neurons will also undergo robust compensatory sprouting in the adult rat. Following destruction of one half of the hypothalamo-neurohypophysial tract via a unilateral hypothalamic lesions, axons of intact contralateral MNS neurons grow sprouts which return the axon population of the neural lobe (NL) to near normal levels within 90 days. The long-term objective of this project is to determine what special characteristics of the MNS provide the basis for this plasticity. The NL is a greatly simplified peptidergic terminal field, composed primarily of neurosecretory axons, pituicytes (a form of astrocyte), and microglia. Thus the organization of this system especially lends itself to investigation of two aspects of compensatory sprouting: the role of neuronal activity, and the influence of glial cells. Fulfillment of the specific aims of this project will provide a detailed comparison between the cellular events which accompany axonal degeneration and sprouting in this new model with those know to occur in response to brain injury. This is being accomplished using morphometric and immunocytochemical techniques to: (1) quantify the extent of glial hyperplasia and hypertrophy in the NL during the sprouting response; (2) determine the pattern of expression of macrophage-specific antigens by glial cells of the NL; (3) determine if altered expression of glial fibrillary acidic protein, vimentin, and glial hyaluronate-binding protein by vasopressin neurons, and investigate the expression of Growth Associated Protein GAP-43 by these neurons during sprouting. Results of these studies will establish the necessary data base for future efforts to alter the course of the sprouting response by administration of peptide hormones and antibodies to cell surface receptors, adhesion molecules, etc. Since virtually all neural disorders involve some degree of tissue degeneration, increased knowledge of the cell biology underlying compensatory responses to injury of the CNS is crucial for the ultimate design of effective therapies.