The proposed studies are aimed at the characterization of functionally important responses of basal forebrain cholinergic neurons to NGF. During the previous funding period it was established that NGF promotes survival, neurite growth, and biochemical differentiation of cholinergic neurons developing in vitro. In adult rats with partial fimbrial transections, it was shown that intraventricular administration of NGF prevents the lesion-induced disappearance of cholinergic cell bodies in the septal area, that single injections or administration for up to five months does not result in permanent rescue of the cells, and that NGF is equally effective in middle-aged as in young adult rats. The first part of this proposal addresses specific remaining questions regarding the response of cell bodies to NGF in our lesion paradigm (death or shrinkage of neurons, penetration of NGF in the brain). The second part deals with the functional response of adult cholinergic neurons to NGF. At the presynaptic level the actions of NGF on choline acetyltransferase (ChAT) expression, high affinity choline uptake, acetylcholine synthesis and release will be explored. To assess whether presynaptic changes have consequences at the postsynaptic level, carbachol-stimulated breakdown of phosphatidylinositol will be monitored. The third part addresses the question whether bFGF and insulin (which, similar to NGF, stimulate ChAT activity of cultured cholinergic neurons) produce similar or different actions on cholinergic neurons. Studies will be carried out on cholinergic neurons in culture and on adult rats with partial fimbrial transection. The findings will help to understand the physiological role of NGF in development and adult function of basal forebrain cholinergic neurons. The major goal of the study is to understand the consequences of pharmacological administration of NGF administration. The findings have direct relevance for the potential use of NGF in Alzheimer's disease and will help to develop neuropharmacological applications of neurotrophic factors.
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