Injury can induce a demonstratable neurotrophic activity for specific chemical neuronal systems in the brain. Specific lesion of 5-H T fibers using 5, 7-dihydroxytryptamine (5, 7-DHT) in the hippocampal afferent path is able to trigger a homotypic sprouting in the hippocampus. The norepinephrine (NE) and acetylcholine containing fibers which travel in the same pathways and terminate in an overlapping area in the hippocampus do not respond to the denervation of 5-HT. This proposal is based on the following two working hypotheses. 1. A neurochemical lesion of single-type fiber-system will induce the production of neurotrophic factor(s). 2. The induced neurotrophic factor will be specific for the lesioned-type fiber-system. We have obtained preliminary evidence to support these two hypotheses. Specific and localized lesions of the serotonergic afferents to the hippocampus provided an enriched trophic environment for transplanted and cultured fetal 5-HT neurons. The transplanted 5-HT neurons had more synaptosomal high- affinity uptake (SHAU) of 5-HT, a higher content of serotonin, and an increased soma area in the denervated hippocampus than in the normal hippocampus. In addition we have shown that a high speed supernatant extract from the lesioned hippocampus increased SHAU in the cultured fetal 5-HT neurons. In contrast, transplanted and cultured locus ceruleus (LC) NE neurons did not respond differently to the 5, 7-DHT lesioned hippocampus. We propose to confirm these observations and extend our findings by using 5, 7-DHT to partially deplete 5-HT fibers in hippocampus and carefully monitoring and characterizing the growth of implanted fetal 5-HT raphe or NE-LC neurons. Further testing of neurotrophic activity will be done by in vivo assaying the extracts obtained from lesioned hippocampus on the two neuronal types in an appropriate target area (hippocampus) and an inappropriate area (cerebellum). Neurotrophic activity will be assessed morphometrically after immunocytochemical staining with antibodies raised against 5-HT and tyrosine hydroxylase by recording neuronal number, neurite branching and extension, and soma area. Biochemically, transmitter development will be assessed by high-affinity uptake and HPLC level measurement of 5-HT and NE. The importance of our studies will be in the area of recovery of function after injury. In addition, the availability of specific growth factor and an understanding of their regulation in the adult brain may help explain the etiology of neuronal degenerative diseases and aging of specific fiber systems and provide insights into their treatment.
