Gerald E. Schneider - US grants

A major goal of this project is to explain the development of mammalian visual system axons and their connections in terms of basic principles that can be used to understand how this sequence of development is altered by early brain damage. In addition, we aim to specify how the altered development affects behavior, and to use the early-damaged brain as a means for elucidating the nature of subcortical vision. New, related studies of plastic changes induced in the adult visual system are particularly promising for future application to the major health problem of functional restoration after brain injury. Using the hamster optic tract as a model, experiments are designed to relate damage-induced neuronal plasticity during development to two distinct modes of axon growth. Regeneration of long tracts appears to be possible only for axons in the earlier mode of rapid, fasciculated elongation; experiments are designed to find out whether this mode can be extended or reinstated by early axon transection, or by inducing transected axons in the adult retina to regenerate within a peripheral nerve implant. Sensitive behavioral methods will be used to assess recovery of vision which may be subserved by induced regeneration in adult animals. Even after the age at which regeneration (without implants) fails, sprouting into denervated tissue can still occur, seemingly by axons which are in the second mode of growth, characterized by reduced rate and by progressive arborization and terminal formation. Mean for altering this growth mode will also be explored. Intrinsic differences in axons in different growth states will be examined in a study of proteins rapidly transported by the axons to the terminals; specific proteins may differ in the two modes of growth. Detailed descriptions of morphological transformations are being undertaken with the aid of techniques for filling single axons with tracer substances (HRP, PHA-L). In other experiments, new techniques will be employed to distinguish subpopulations of retinal ganglion cells and their axons which may follow different rules during development or during regeneration or sprouting. The model systems created by neonatal lesions will also be exploited to extend basic knowledge of subcortical vision, its sparing or alteration after neonatal lesions, and its recovery following neocortical lesions in adults.

A long-term goal of this project is to explain the anatomical and behavioral effects of brain damage suffered in fetal or perinatal life. This requires an understanding of how nerve fibers (axons) develop, and how they respond to brain damage. Thus, the project's focus is on the growth of axons in both normal and abnormal situations, and on the consequences of abnormal axonal development. The claim that the optic tract can regenerate in a mammal if it is transected very early in life, but not once a critical age is reached, will be investigated. If true regeneration is found, it will be compared with normal development, for major fiber groups in the visual system. No regrowth is found after a critical age, but it has been discovered that axon regeneration can be induced by surgical implants containing a growth factor (FGF). Just how late in development this regeneration can be obtained, and whether it can be influenced to produce a restoration of lost connections, will be examined using implants of embryonic tissue or cultured cell lines, or of agents of block recently discovered growth inhibitors. The role of a cell type found in large numbers only in the developing brain, the radial cell (radial glia), in axon growth and in regeneration, will be explored. The possibility that different neuronal cell types in the retina give rise to axons with different potentials for regeneration or for abnormal termination (by collateral sprouting) will be examined, with the possibility in mind that a selective growth after brain damage could have important behavioral consequences. The finding that early brain lesions damaging the optic tract, and subsequent regrowth of this tract to the midbrain, cause hamsters to show supersensitivity to potential predators, will be further investigated. In pursuing these aims, new techniques that could yield very novel information about axonal growth and regeneration will be explored: methods of imaging growth axons in the living brain, brain implants of cells grown in culture with special properties, and a new way to block activity of growing axons in an attempt to increase their regrowth.