Neuronal survival, differentiation,and maturation are influenced by soluble trophic agents. The importance of trophic factors has been best demonstrated in the case of nerve growth factor (NGF) and its responsive peripheral neurons. Sequestration of endogenous NGF by appropriately timed injections of NGF antibodies destroys sympathetic and sensory neurons. Identification and characterization of central nervous system (CNS) trophic agents has been hampered by the tiny amounts present in nervous and other tissues. It appears that this problem may be circumvented in the case of basal forebrain cholinergic neurons. NGF injected into the cerebral ventricle of neonatal rats produces dramatic and selective increases in the activity of choline acetyltransferase (ChAT), the neurotransmitter synthetic enzyme for cholinergic neurons. It has been hypothesized that NGF is the endogenous trophic factor for these cells, and a number of observations suggest that this is the case. In this application we propose to determine whether NGF supports the viability and differentiation of developing basal forebrain cholinergic neurons. NGF will be purified by high-performance, reverse-phase liquid chromatography. To determine the nature and pattern of NGF activities in the CNS we will examine several neurochemical markers. These studies will record the response of septohippocampal cholinergic neurons before, during and after the period of synapse formation. An immunoadsorption protocol for ChAT will allow us to examine the mechanism of the NGF effect on ChAT activity. The physiological role of endogenous NGF will be examined during the same developmental stages by intracerebroventricular injections of affinity-purified NGF antibodies. These studies will indicate whether cholinergic neurochemical markers are selectively depressed. If so, we will conduct morphological studies to determine whether NGF antibody effects are associated with loss of basal forebrain cholinergic neurons. Our studies may provide evidence that NGF is an endogenous trophic factor these cells. It is expected that the proposed studies will lead to an improved understanding of the growth and development of CNS cholinergic neurons. It is hoped that they will provide insights regarding the role of trophic factors in the developing CNS. Furthermore, they may indicate the potential physiological consequences of altered synthesis or release of trophic factors and suggest means for evaluating the contribution of such disturbances to neurological disease.
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