FUNCTIONAL BRAIN-TISSUE TRANSPLANTATION - REVERSAL OF LESION-INDUCED ROTATION BY INTRAVENTRICULAR SUBSTANTIA NIGRA AND ADRENAL-MEDULLA GRAFTS, WITH A NOTE ON INTRACRANIAL RETINAL GRAFTS

Abstract

Using a rotational behavior animal model, embryonic substantia nigra (SN) can be homologously transplanted to the brain lateral ventricles to reverse the effects of SN lesions. These grafts decrease the lesion-induced rotational behavior that was provoked either by apomorphine or amphetamine. This effect was not duplicated by grafts of other embryonic brain regions. The SN grafts produced a dopaminergic reinnervation of the dorsomedial striatum that appeared to be responsible for the behavioral amelioration. Behavioral efficacy and survival continued for at least 6 mo. to 1.5 yr. The catecholaminergic chromaffin cells of the adrenal medulla possess a remarkable ability to change morphologically and biochemically in response to their environmental hormonal milieu. This plasticity was exploited by transplanting adrenal medulla to the rat brain to reverse the effects of SN lesions. This tissue changed biochemically by producing large amounts of dopamine, and morphologically, by extending coarse fiber processes. Although these grafts appeared to secrete catecholamines, they did not reinnervate the striatum. Rotational behavior was reduced by these grafts, apparently as a consequence of the catecholamine secretion. When adrenal chromaffin tissue was obtained from 1- or 2-yr-old donors, however, lesion-induced rotational behavior was not reduced. Evidently, adrenal chromaffin cell grafts from young donors possess a biochemical plasticity that is the basis for the behavioral effect, but that this plasticity is lost with maturity of the tissue. Both embryonic brain tissue and adult adrenal medulla allografts from Brown Norway rat donors consistently survived for at least 6 mo. in the ventricles of Fisher 344-strain rat hosts. These strains differ in major histocompatibility antigens and, as expected, Fisher 344 rats rapidly rejected Brown Norway skin grafts. Skin graft survival times were not influenced by the presence of established brain grafts, nor did brain grafts elicit systemic humoral immunity. Independent elicitation of systemic immunity by skin grafting resulted in the rejection of long-established brain grafts concomitant with rejection of the skin grafts. Rotational behavior in Fisher 344 hosts was reduced by brain grafts from Brown Norway donors; yet, after rotation had been reduced it could be brought back to baseline levels through systemic immunization and associated brain graft rejection. The rat brain ventricles possess essentially complete immunological privilege for brain tissue and adrenal medulla grafts. This privilege can be abrogated by extracerebral antigenic stimulation, resulting in immunological removal of established brain grafts. A set of scientific criteria is proposed as a goal to precede application to humans with Parkinson''s disease. The criteria involved optimization of the grafting procedure, maximization of the effect of the grafts, understanding species scaling factors, understanding the relevant immunological factors and gaining consistent success in primates. Fetal eyes and retina were found to survive transplantation to the brain, and developed variable but sometimes extensive morphological organization. Light-evoked potentials were consistently generated by the grafted eyes. A method for determining whether visual function, as measured by a primitive light-avoidance response, was conferred to blind rats by these grafts is described. A degree of visual responsivity may occur in a small percentage of blinded recipients. Perhaps, in the future the functional effects of brain grafts may be increased so that major functional effects can be produced not only by catecholaminergic grafts but by other types of brain grafts as well.