Structural and functional repair of nerve circuits in the brain by neural transplants

ABSTRACT

The field of neural transplantation has developed dramatically over the last three decades both as an experimental tool for studying functional organization, development and plasticity in the nervous system, and as a powerful clinical technique for delivering novel cell therapies to the brain. The surgical techniques themselves have turned out to be relatively straightforward, whereas the big challenges have been [a] to understand the mechanisms of graft function so that targets for graft-derived repair can be selected on a rational basis, and [b] to generate suitable cells of the quality and specificity required to achieve functional repair in each disease context. In some circumstances it has turned out that relatively simple recovery processes [such as replacement of a deficient neurochemical] are sufficient to have a big impact on the host - whether a patient or experimental animal - whereas in other cases a true reconstruction of damaged brain pathways turns out to be necessary to achieve significant recovery. Although such a level of repair was once considered to be beyond the limits of the surgical technique - and may be of brain plasticity itself - it has become apparent over the last decade that in one or two model systems a quite remarkable degree of reconstruction is achievable, of which striatal degeneration and repair has provided the clearest example. In animals with experimental striatal degeneration, embryonic striatal grafts can survive, differentiate, connect, and function so as to sustain a remarkable degree of recovery, even in the highest aspects of thought and cognition. Moreover, detailed studies in grafted animals indicates that the graft neurons must - and do - become integrated within the neural circuitry of the host brain for successful recovery to be achieved, and that they then participate in the neuronal processing of the host brain in such processes as habit learning and synaptic plasticity. The principles identified in experimental animals are now leading to the development of new therapies for diseases of higher nervous system activity, such as Huntington's, in which cognitive and psychiatric as well as motor symptoms predominate, and may provide the foundation for the next generation of truly reparative therapies for a wide range of currently unbeatable neurodegenerative conditions