There is extensive evidence demonstrating the long-term interdependence of neurons and their peripheral target organs. Motoneurons and skeletal muscles depend on each other for their normal development, function, and, ultimately, for their survival. Interrupting the communication link between them produces severe metabolic and physiological alterations in both; neural regeneration is primarily aimed at restoring this link. Yet, the nature of the communication system, and the "signals" involved are not known. This project is aimed at identifying the temporal progression of, and possible causal relationships between, the various neuronal metabolic and physiological responses to motoneuron axotomy. Once we have described the earliest response in the sequence it should be possible to determine mechanisms. The project uses the frog spinal cord as the experimental preparation. The preparation offers an opportunity to conduct carefully controlled biochemical measurements in an in vitro system, and long-term electrophysiological studies in an in vivo system. By combining both systems I will be able to provide a complete temporal description of the neuronal changes which follow axotomy. I plan to focus on postaxotomy changes in the cyclic nucleotides as a potential link in the nerve-muscle communication system. Muscle cyclic AMP is known to be trophically-regulated; it is also possible that neuronal cyclic nucleotides serve as modulators for the "signals" providing trophic regulation to motoneurons.