This proposal addresses the role of estrogen/NGF interactions in the differentiation and survival of the cholinergic and non- cholinergic neurons of the basal forebrain an estrogen and NGF target. The proposed experiments are designed to study whether estrogen acts directly on the receptor-containing cell or through intermediate steps with involving interactions with an endogenous growth factor, nerve growth factor (NGF), or with NGF receptors. The experiments are designed to investigate in the murine basal forebrain of both sexes in vivo and in vitro: The ontogeny, distribution natural history and sex differences in estrogen and NGF receptor expression; The cellular phenotype(s) of estrogen and NGF receptor-containing cells; Interactions of estrogen with NGF in neuronal differentiation, survival and regeneration; on cholinergic neurotransmitter activity, and on estrogen and NGF receptor expression. Organotypic cultures of the septum and diagonal band will be cultured singly or co-cultured with their hippocampal target. Representative cultures, exposed to the presence or absence of estrogen and/or NGF will be studied morphologically in living and stained preparations using neurohistological stains, 125-I-estrogen and 3H-thymidine autoradiography, immunocytochemistry and histochemistry. Morphological findings will be correlated with biochemical assays of estrogen receptor content and cholinergic enzyme activity. Correlative morphological analyses will be made of comparable forebrain regions of developing and aging animals of both sexes, including anestrus females. This series of interrelated, multidisciplinary experiments represents a novel and unique approach to gaining an improved understanding into the mechanisms by which estrogen and NGF may influence the basal forebrain cholinergic neurons during their entire life cycle. This has significance for understanding the decline in cognitive functions associated with aging and for the selective degeneration of these neurons in Alzheimer's disease. These studies offer a biological rationale for treatment with estrogen by which cholinergic function in surviving neurons might be increased or even preserved during early Alzheimer's disease and in post-menopausal women who may be at risk due to reproductive senescence with its accompanying loss of estrogen.
