Demyelination Plus Transplantation to Study CNS Repair

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Demyelination represents a unique injury to the adult CNS in that it is followed in many instances by repair. Regions of demyelination that are capable of remyelinating are not characterized by an astroglial scar. We have demonstrated that regions of immunological demyelination, produced by the intraspinal injection of anti-galactocerebroside antibodies plus complement proteins, are capable of remyelination by endogenous oligodendrocytes, and that astroglial hypertrophy is absent within and around regions of immunological demyelination. Furthermore, our preliminary studies indicate that astrocytes within regions of immunological demyelination do not become hypertrophic following axonal injury. Thus, immunological demyelination provides us with a means to manipulate the response of reactive cells to axonal injury and investigate the ways in which that response differs from that following the majority of CNS injuries, which result in scarring. We will use integrated optical density measurements to determine whether the astrocyte and/or microglial/macrophage response to injury is eliminated, suppressed or delayed by immunological demyelination. These studies, which constitute the last two AIMS of this proposal, may lead to novel means of manipulating astrocytes such that astroglial activation or scarring is prevented. Likely associated with the absence of astroglial hypertrophy, regions of immunological demyelination promote long distance homogeneous redistribution of transplanted cells throughout the region of immunological demyelination. This provides a unique opportunity to create a PNS-like terrain within the CNS that is not bordered by an astroglial scar. This experimental paradigm allows us to study the ability to injured axons to regenerate from such a PNS-like terrain into the CNS environment without confronting a sclerotic border zone. Our regenerative analysis will be conducted using anterograde tract tracing. These studies constitute the first AIM of this proposal. There are three specific aims; 1) test the hypothesis that regenerating dorsal column axons will extend from a PNS-like terrain into a purely CNS terrain in the absence of scarring at the interface, 2) test the hypothesis that immunological demyelination suppresses astroglial hypertrophy following axonal injury, and 3) test the hypothesis that immunological demyelination alters the magnitude and duration of microglial/macrophage activation following axonal injury.