Despite some clinical promise, using fetal transplants for degenerative and traumatic brain injury remains controversial and a number of issues need further attention. This response reexamines a number of questions. Issues addressed include: temporal factors relating to neural grafting, the role of behavioral experience in graft outcome, and the relationship of rebuilding of neural circuitry to functional recovery. Also discussed are organization and type of transplanted tissue, the of transplant viability, and whether transplants are really needed to obtain functional recovery (...) after brain damage. (shrink)

The responses displayed by an injured or diseased nervous system are complex. Some of the responses may effect a functional reorganization of the affected neural circuitry. Strategies aimed at the restoration of function, whether or not these involve transplantation, need to recognize the innate reactive capacity of the nervous system to damage. More successful strategies will probably incorporate, rather than ignore, the adaptive responses of the compromised neural systems.

Each of us is uniquely subject to certain kinds of stimulation from a small part of the universe within our skins. Mentalistic psychologies insist that other kinds of events, lacking the physical dimensions of stimuli, are accessible to the owner of the skin within which they occur. One solution often regarded as behavioristic, granting the distinction between public and private events and ruling the latter out of consideration, has not been successful. A science of behavior must face the problem of (...) privacy by dealing with events within the skin in their relation to behavior, without assuming they have a special nature or must be known in a special way. (shrink)

The use of neural transplantation to alleviate cognitive deficits is still in its infancy. We have an inadequate understanding of the deficits induced by different types of brain damage and their homologies in animal models against which to assess graft-induced recovery, and of the ways in which graft growth and function are influenced by factors within the host brain and the environment in which the host is operating. Further, use of fetal tissue may only be a transitory phase in the (...) search for appropriate donor sources. Nevertheless, findings from our laboratory and elsewhere have made a prima facie case for successful cognitive reconstruction by graft methods. (shrink)

We concur that basic research on the use of CNS grafts is needed. Two important model systems for functional studies of grafts are ignored by Stein & Glasier. In the first, reproductive function is restored in hypogonadal mice by transplantation of GnRH-synthesizing neurons. In the second, circadian rhythmicity is restored by transplantation of the suprachiasmatic nucleus.

Gene replacement therapy holds great promise in the treatment of many genetic CNS disorders. This commentary discusses the feasibility of gene replacement therapy in the unique context of the retina, with regard to: (1) the genetics of retinal neoplasia and degeneration, (2) available gene transfer technology, and (3) potential gene delivery vehicles.

The transition from research to patient following advances in transplantation research is likely to be disappointing unless it includes a better understanding of critically relevant characteristics of the neurological disorder and improvements in the animal models, particularly the behavioral features. The appropriateness of the model has less to do with the species than with how the species is used.

Neuwelt et al. have proposed gene-transfer experiments utilizing an animal model that offers many important advantages for investigating the feasibility of gene therapy in the human brain. A variety of tissues concerning the viral vector and mode of delivery of the corrective genes need to be resolved, however, before such therapy is scientifically supportable.

The work of Sinden et al. suggests that it may be possible to produce improvement in the areas of brain function by transplanting brain tissue. What appears to be the limiting factor is not the complexity of the mental process under consideration but the discreteness of the lesion which causes the impairment and the appropriateness and accuracy of placement of the grafted tissue.

All recent memory theories of hippocampal function have incorporated the idea that the hippocampus is required to process items only of some qualitatively specifiahle kind, and is not required to process items of some complementary set. In contrast, it is now proposed that the hippocampus is needed to process stimuli of all kinds, but only when there is a need to associate those stimuli with other events that are temporally discontiguous. In order to form or use temporally discontiguous associations, it (...) is essential to maintain some memory of the first component until the second component has occurred. When the temporal gap to he spanned is small, and the number of items to be temporarily retained is low, a limited-capacity, short-term store is sufficient to allow associations to be formed. Such a store is presumed to operate in parallel with the hippocampus in normal animals. Hippocampal damage disrupts a much higher-capacity store that has a slower decay rate, and so leaves animals with only a very limited ability to form temporally discontiguous associations. Hippocampal damage, however, is not held to affect the long-term storage of associations of any kind, if they can be formed. Analyses of both new and existing data are presented to show that by classifying tasks in terms of the need to use a temporary memory store to retain temporally discontiguous information one can cut right across existing classifications as well as achieve a better fit to the data. The hippocampus thus seems best described as a high-capacity, intermediate-term memory store. (shrink)

The spinal cord provides an alternative model for nerve tissue grafting experiments. Anatomo-functional correlations are easier to make here than in any other region of the CNS because of a direct implication of spinal cord neurons in sensorimotor activities. Lesions can be easily performed to isolate spinal cord neurons from descending inputs. The anatomy of descending monoaminergic systems is well defined and these systems offer a favourable paradigm for lesion-graft experiments.