The long term objectives of this project are: 1) to determine the mechanisms that link neuronal activity to axonal sprouting in the adult CNS; 2) to discover the cause of maturational decrements in axonal sprouting; and 3) to examine potential means of compensating for these decrements. These objectives will be addressed using a model neuroendocrine system that displays unusually vigorous axonal plasticity, the hypothalamic magnocellular neurosecretory system, or MNS. Uninjured neurons in the MNS of young adult (35 day-old) rats undergo robust collateral axonal sprouting in response to a lesion that destroys the contralateral side of this bilateral system. This sprouting response is activity-dependent. MNS neurons are hyperactive during axonal sprouting, secreting more of the neuropeptides oxytocin and vasopressin, while simultaneously sprouting new axon collaterals that reestablish the neurosecretory axon population within the neurohypophysis. Sprouting does not occur if activity of MNS neurons is inhibited by establishment of a chronic hyposmolar state, and MNS neurons in more mature (125 day-old) rats do not become hyperactive in response to the lesion and do not sprout.
The specific aims of the proposal are: 1) to determine if it is the initiation and/or the maintenance of the growth process that is activity-dependent, and to examine the role of glutamatergic and noradrenergic afferents in stimulating sprouting; 2) to determine if activity-dependent axonal sprouting is mediated by the growth factors IGF-I, CNTF, and BDNF and the cytokine IL-1beta, synthesized by and acting upon the neurons and glia of the MNS; and 3) to identify mechanisms responsible for the maturational decline in collateral sprouting and to determine if chronic hyperosmotic stimulation of MNS neurons can reverse this decline.
These aims will be accomplished by altering MNS activity by receptor blockade or through chronic osmostimulation and correlating changes in the expression, cellular localization, and activity of the above factors and their receptors with the extent of axonal sprouting in animals of different ages. Fulfillment of these aims will provide new insights regarding the cellular mechanisms involved in reestablishment of axon populations in the injured brain and the alterations that occur in these mechanisms during brain maturation.
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