Intracerebral neuronal grafting in experimental animal models of age-related motor dysfunction.
The combined morphological, biochemical, electrophysiological, and behavioral data summarized above show that implanted embryonic nerve cells in some cases can substitute quite well for a lost intrinsic neuronal system in mammals. The intracerebral implants probably exert their effects in several ways. The functional effects seen with grafts placed into one of the cerebral ventricles (such as those described in the studies of Perlow et al., Freed et al., and Gash et al.) are thus probably explained on the basis of a diffuse release of an active amine or peptide into the host CSF and adjacent brain tissue. In other instances, as in animals with DA-rich grafts reinnervating the neostriatum, we believe that the available data provide quite substantial evidence that the behavioral recovery is caused by the ability of the grafted neurons to reinnervate relevant parts of the host brain. This is illustrated by the studies mentioned above that show that the degree of functional recovery in 6-OHDA-lesioned rats with nigral transplants is directly correlated with the extent of striatal DA reinnervation and that the "profile" of functional recovery is dependent on that area of the striatal complex that is reinnervated by the graft. This point is particularly well illustrated in a further study in which rats with electrodes implanted into the center of intracortical nigral grafts were allowed to "self-stimulate" via the graft. The results show that the graft can indeed sustain self-stimulation behavior and that the rate of lever-pressing is related to the proximity between the electrode tip and the DA-containing neurons in the graft. This strongly supports the notion that the implanted DA neurons can transmit behaviorally meaningful and temporally organized information to the host brain via their efferent connections. To what extent the intracerebral implants can be functionally integrated with the host brain is still poorly known, though, and it therefore remains an interesting question for further investigation. The chances for extensive integration may be greatest for neuronal suspension grafts implanted as deposits directly into the depth of the brain, but even solid grafts inserted as whole pieces into the brain have, in several cases, been seen to become reinnervated from the host brain in adult and developing recipients. Nevertheless, a recent HRP study failed to detect any host afferents to intracortical solid nigral grafts, despite the fact that these grafts had themselves formed extensive DA connections in the host striatum and had produced behavioral recovery.(ABSTRACT TRUNCATED AT 400 WORDS)
Gage
F H
FH
Department of Neurosciences, University of California, San Diego, La Jolla 92093.
Brundin
P
P
Strecker
R
R
Dunnett
S B
SB
Isacson
O
O
Bjorklund
A
A
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000502:physiology; D002395:Catecholamines / Q000502:physiology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D006085:Graft Survival; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism / Q000637:transplantation; D009069:Movement Disorders / Q000209:etiology / Q000628:therapy*; D009474:Neurons / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*
D002395:Catecholamines; D004298:Dopamine