Showing papers by "Anders Björklund published in 1982"

Function recovery following neural transplantation of embryonic septal nuclei in adult rats with septohippocampal lesions

Abstract: The remarkable capacity of transplanted embryonic neurones to innervate the hippocampal formation of mature recipients has been well documented, with the pattern of innervation being shown to be anatomically specific and to resemble normal connectivity1–3. Although transplants are known to have functional consequences in other systems4–9, information has yet to be obtained regarding the functional nature of embryonic septal transplants and the behavioural consequences of transplant innervation of the host hippocampal formation. We provide here evidence that a reinnervation of the hippocampal formation from cholinergic-rich septal transplants is functional in terms of the physiology of neural connectivity and that the newly formed connections can interact with an intrinsic afferent system, the perforant path. Moreover, we demonstrate that the reinnervation can aid in the partial recovery of the performance of a radial maze task that is thought to depend on the integrity of septohippocampal connections10. The behavioural performance of animals with transplants improved significantly compared with those without transplants when both groups were systemically injected with the acetylcholinesterase (AChE) inhibitor, physostigmine. These results suggest that neural transplants from embryonic tissue that reinnervate the hippocampal formation can form functional synaptic connections that can lead to the partial restoration of maze performance.

Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [14C]2-deoxy-D-glucose autoradiography.

Abstract: Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudate-putamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudate-putamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplant-reinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral transplants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.

Cross-species neural grafting in a rat model of Parkinson's disease

Abstract: Previous studies1–7 have shown that intracerebral implants of embryonic mesencephalic dopamine (DA) neurones, grafted between individuals of the same inbred rat strain, can reverse some of the functional deficits caused by damage to the nigrostriatal DA pathway These observations have raised the possibility that the intracerebral neural grafting technique may eventually find a clinical application in the treatment of neurodegenerative disorders, particularly Parkinson's disease One obvious obstacle to any such attempts is the immunological rejection mechanisms associated with allogeneic or xenogeneic grafting Thus, neural tissue (sensory and sympathetic ganglia), transplanted across immunological barriers to sites outside the central nervous system (CNS), are known to be rejected8,9 The brain has, however, been described as an immunologically ‘privileged’ site, partly perhaps because of its protective blood–brain barrier10–12 This may be the case for grafts of embryonic tissue, in particular Thus, Zalewski et al13 have reported rejection of allografts of adult ganglionic neurones transplanted o the spinal cord, while Low et al14 found prolonged survival of embryonic brain tissue in the hippocampal region, grafted between rats of different strains We report here long-lasting functional cross-species transplantation of mesencephalic DA neurones, taken from mouse embryos, to the dopaminergically denervated neostriatum of adult recipient rats

Hippocampal deafferentation: transplantderived reinnervation and functional recovery

Abstract: A brief review is provided of the capacity of neural tissue transplants to reinnervate the deafferented hippocampus and repair functional deficits induced by the lesion. The techniques for transplantation of solid pieces of embryonic septum, locus coeruleus or raphe nuclei, or tissue suspensions of embryonic septum, to the adult rat hippocampus are described. Such grafts manifest good long-term survival, provide a good reinnervation of the hippocampus that is histochemically and biochemically appropriate and specific, can establish ultrastructural synaptic contacts with the host, and are electrophysiologically active. Rats with septal grafts manifest recovery of the capacity to learn certain aspects of radial 8-arm maze, T-maze alternation and Morris water-maze tasks. Rats with locus coeruleus grafts manifest an amelioration of lesion-induced hyperactivity. It is concluded that neural tissue transplantation provides a powerful new tool in the study of the functional organization of the hippocampus and its various neurotransmitter-specific afferent systems.

CNS transplantation: structural and functional recovery from brain damage.

Abstract: Publisher Summary The transplantation of neural tissue has been possible since the early years of the present century. However, whereas a high level of success has been obtained placing grafts into the anterior chamber of the eye, early attempts to transplant neural tissue to the brain of both adult and young mammals were hampered by low survival rates, which can be attributed to a failure to provide a milieu for the transplanted tissue in the brain as suitable as the anterior eye chamber. Only over the past decade have the conditions for successful transplantation of neural tissue to mammalian brain been achieved with a relatively high level of success. Although the use of both the anterior eye chamber and the neonatal brain as transplantation sites continues to provide powerful models for the study of factors controlling neuronal maturation and growth. This chapter concentrates on studies of CNS tissue transplantation to the brains of adult rats, in particular within the context of the restitution of structural and functional impairments induced by brain lesions.

Functional recovery following brain damage: conceptual frameworks and biological mechanisms.

Abstract: Mammals are well known to manifest recovery over time of many functional impairments induced by brain lesions. A brief reveiw is provided of the different conceptual frameworks within which functional recovery has been examined in the literature, and of different neurobiological mechanisms that have been proposed to account for the phenomenon. We observe that these two levels of analysis have frequently been only loosely related. Finally, a newly identified biological mechanism—compensatory collateral sprouting—is described which appears to be closely related to functional recovery in animals with hippocampal lesions, and this is proposed as a powerful new model within which to investigate further the relationship between the phenomenon of functional recovery and its underlying mechanisms.