Cell cultures prepared from fetal mammalian central nervous system were used to study the regulation of neuron development. The mechanisms which mediate the regulatory role of electrical activity were investigated. The onset of a critical period for neuron death after electrical blockage was found to correspond to the following developmental events: 1) the onset of spontaneous action potentials in spinal cord neurons, 2) a major increase in basal choline acetyltransferase activity, 3) a significant increase in sodium channel density, as measured by 3H-saxitoxin binding, 4) an increase in the organization of neuronal aggregates and an increase in the size of neuritic cables, 5) the beginning of the period of naturally occurring neuron death, as determined by cell counts. A trophic substance, obtained from spinal cord cultures before or after the critical period, was shown to increase neuronal survival during electrical blockage. The release of this substance was shown to be inhibited during impulse blockage. Addition of cyclic AMP-stimulating agents was also found to increase neuron survival during electrical blockage. Vasoactive intestinal peptide (VIP) was shown to exhibit many of the properties of a activity-dependent neuron survival factor: 1) VIP-like immunoreactivity was demonstrated to be present in 3-5% of the spinal cord neurons in culture, 2) the survival-promoting action of VIP was evident at physiologically relevant concentrations, 3) the spontaneous release of VIP was shown to be inhibited by electrical blockade. We have investigated the possibility that the peptide neurohormones and neurotransmitters play a role in the development of their target organs. The experiments demonstrate that early exposure to the neuropeptides permanently affects the expression of neuropeptide receptors, and that this alteration in receptors is of physiological importance to the mature animal.