Evidence suggests that parallel biochemical and regulatory processes occur during normal development and following various forms of CNS injury. Among the areas of particular interest are (1) the identification of CNS neurotrophic factors, and (2) the analysis of the regulation of neuropeptide gene expression during development and in response to injury. Studies are underway to identify tropic factors produced in two specific model systems, since recent evidence suggests that a family of nerve growth factors exists, each specific for certain populations of neurons. Mouse cerebellum contains a factor which is NGF-like by immunological criteria but has no biological activity on chick sensory neurons. This factor increases in the cerebellum of the pcd mutant mouse as the Purkinje cells die out and astrocytes proliferate. The mRNA for this factor appears to hybridize with mouse beta-NGF cDNA and is increased in pcd cerebellum. Screening of cDNA libraries is currently in progress, in order to clone the factor. In another injury paradigm, multiple cortical lesions are made in rat brain: one week later, RNA is prepared from various brain regions to be analyzed for any change in NGF- like mRNA's relative to unlesioned brain. At the same time, these injury models can be evaluated for changes in neuropeptide and/or neurotransmitter synthesis occurring in response to the lesions. One can derive as estimate of peptide turnover by combining measurements of the precursor mRNA, the precursor, and the peptide. Our studies have demonstrated that peptides are differentially regulated by such chronic drug treatments as reserpine, haloperidol, 6- hydroxydopamine or 5, 7-dihydroxytrptamine. Work is in progress to determine the effects of CNS injury and recovery on various neuropeptides as well as such neurotransmitter synthetic enzymes as tyrosine hydroxylase and GAD.
