Recent studies carried out by the applicants and other investigators established that nerve growth factor (NGF) acts as a neurotrophic factor for cholinergic neurons of the basal forebrain. We found that NGF elevates choline acetyltransferase (ChAT) activity and growth of cholinergic fibers in cultures of dissociated forebrain neurons. We now propose to study the regulation of NGF receptor expression by cultured cholinergic neurons and the influence of NGF receptor protein and NGF receptor mRNA will be measured. We furthermore plan to investigate whether the NGF-mediated increase in ChAT activity reflects elevated levels of ChAT protein and mRNA and whether thyroid hormones, which elevate ChAT activity of cultured cholinergic neurons in a similar way as NGF, act by affecting NGF-reflected mechanism. In studies on adult rats, we earlier found that NGF prevents the retrograde degeneration of cholinergic septohippocampal neurons after axonal transection. It is now proposed to investigate the temporal requirements for cholinergic neurons, to study whether NGF treatment stimulates fiber growth from remaining cholinergic neurons into the partly denervated hippocampus, and to test whether NGF treatment is effective in lesioned, aged animals. The studies will further elucidate the role of NGF in development and aging of forebrain cholinergic neurons and in their response to injury and might help to understand the decline of cholinergic functions in aging and neurological diseases.
