ACIDIC FIBROBLAST GROWTH FACTOR AND BASAL FOREBRAIN

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The basal forebrain cholinergic system plays an important role in cognitive functions such as memory and attention [8-13, 48-49], and it is therefore of great concern that cholinergic cells are particularly vulnerable to injury-and age-related degeneration. Previous research describes nerve growth factor (NGF), obtained by cholinergic cells via retrograde transport from cortical targets, as the critical substance in maintaining the viability of cholinergic neurons. Recent findings in this laboratory and others, however, indicate a much more complex interaction between endogenous trophic factors and the survival of the cholinergic forebrain system. This laboratory has demonstrated the existence of high levels of mRNA for acidic fibroblast growth factor (aFGF) localized within the cholinergic cells of basal forebrain. This finding along with reports that aFGF has a potent ability to protect and restore the integrity of cholinergic cells [8] suggests that aFGF may act as an autocrine neurotrophic for cholinergic neurons. The proposed research will further characterize the distribution of aFGF and its potential role in the preservation of the cholinergic forebrain system. Specifically, the aims of this study are to determine: (1) whether cholinergic neurons which synthesize aFGF are also expressing the FGF receptor and would therefore be capable of responding to this protective factor, (2) the anatomical relationship between cholinergic neurons which express aFGF and those which are responsive to NGF; (3) if the expression of local trophic factors identified in the forebrain may help sustain the cholinergic cells following ablation of all distant trophic support via excitotoxic lesion; and (4) to test the hypothesis that loss of aFGF expression contributes to age-related degeneration of the basal forebrain cholinergic neurons. The proposed research should further our understanding of the endogenous trophic support available to the cholinergic cells of the forebrain and therefore enhance our ability to develop therapeutic strategies for combating the age-related degeneration of this important brain system.