Neurotrophic agents (peptide growth factors) are essential for the development and maintenance of the nervous system. Evidence for this notion is largely derived from experiments in the peripheral nervous system. Little is known about the effects and functions of neurotrophic peptides in the development and maintenance of circuits within the normal central nervous system. This lack of information is vexing, because neurotrophic factors appear to be involved in pathologic circumstances, e.g. regenerative processes after neuronal injury and neurodegenerative diseases like Alzheimer's. The application's central aim is to develop and apply an in vivo model to test specific functions of trophic factors for neural circuits in the developing and mature brain. The chick embryo's visual system is a particularly useful model for this undertaking because it permits experimental manipulations during embryonic development in vivo. The proposed experiments will focus on two neuronal populations, the isthmo-optic nucleus, a nucleus with transient expression of NGF receptors during target innervation; and the ceruleus complex, a heterogeneous complex of neuronal populations with continued expression of NGF receptors and FGF receptors in the mature brain. The proposed research will determine how changes in the supply of trophic factors (by directly increasing or decreasing their levels in the target, or by pharmacological manipulations of target populations) will affect the formation, stabilization and rewiring of neural projections in the normal brain and following perturbation of neural circuits. Specifically, the proposed experiments will determine which of the neurotrophins supports isthmo-optic neurons, whether this neurotrophin and other target manipulations can stabilize normally transient collateral projections, whether neural activity is necessary for trophic regulations, and whether expression of neurotrophic receptors can be induced in the mature isthmo-optic nucleus. Studies on the ceruleus complex will determine how target specificity develops, how trophic factors influence the development and maintenance of target specificity, transmitter phenotypes and trophic phenotypes, and whether trophic factors have ongoing functions in the regulation of trophic receptors, transmitter phenotypes and target innervation in the mature brain. The proposed experiments will provide new insights into the trophic regulation of neural circuits in the developing brain in vivo, and they will determine how trophic factors may improve the survival, regeneration, and rewiring of lesioned mature neurons in the CNS, properties that are usually restricted to the peripheral nervous system and to the embryonic period of CNS circuits. These studies will help to explore how pathologic neural conditions may be improved by the manipulation of trophic systems.
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