Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery

Abstract

Transplants of fetal ventral mesencephalic (VM) dopamine neurons implanted into the substantia nigra in 6-hydroxy-dopamine (6-OHDA)- lesioned neonatal pups establish axonal connections with the denervated caudate putamen (Nikkhah et al., 1995). In the present study, we have explored the functional capabilities of these animals after they reached adulthood on a battery of spontaneous and drug-induced behavioral tasks. The results demonstrate that unilateral intranigral VM grafts in bilaterally lesioned neonates induce a marked bias in spontaneous- and stress-induced rotation contralateral to the implant not present in the lesion-only controls. Amphetamine and apomorphine induced vigorous contra- and ipsilateral rotation, respectively. Moreover, grafted animals achieved 75% of the performance level in contralateral skilled forelimb use when compared to normal controls, which was significantly above lesion-only animals (50% of normal). Spontaneous nocturnal locomotor activity was elevated 2.2-fold in the grafted animals. Sensorimotor orientation and disengage behavior was spared by the neonatal dopamine lesion and unaffected by the grafts. The level of functional restoration seen in the present study was more extensive than reported previously in neonatally 6-OHDA-lesioned rats where the VM grafts were implanted ectopically into the striatum. However, functional recovery remained incomplete also after intranigral graft placement compared to normal intact animals. The present approach should provide a new promising avenue for the continued exploration of the mechanisms involved in functional recovery and structural repair in the damaged nigrostriatal system.

Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. I. Evidence for anatomical reconstruction of the nigrostriatal pathway

“…The behavioral analysis of the present animals, reported in the following companion article (Nikkhah et al, 1995) provides evidence that the reformation of the nigrostriatal pathway is associated with recovery of certain lesion-induced deficits, such as spontaneous and stress-induced turning and skilled forelimb use, which are resistant to transplant-induced behavioral recovery after ectopic intrastriatal VM grafts in neonatal pups (Herman et al, 1991;Abrous et al, 1993a,b). The microtransplantation strategy, therefore, may provide new insights into the mechanisms controlling long-distance axon growth in the nigrostriatal system and contribute to the ongoing efforts to achieve more complete functional recovery with fetal VM transplants in experimental and clinical neurotransplantation in Parkinson's disease.…”

“…The purpose of the present study was to investigate whether intranigral VM grafts, implanted homotopically into the 6-OHDA-lesioned SN of neonatal pups, could demonstrate long-distance axon growth towards their normal major target, the caudate-putamen, and to analyze the functional effects such grafts may have when testing the animals in adulthood. The grafted animals were tested on a range of spontaneous and drug-induced behaviors, which is described in detail in the following companion report (Nikkhah et al, 1995). Here we report that grafts implanted into the SN of P3 hosts can successfully reinnervate the caudate-putamen and form functional connections as assessed by dopamine-related Fos expression in the reinnervated target.…”

“…Grafting was performed 2 d later (P3). Following lesion and transplantation surgery a battery of tests for spontaneous and druginduced behavior was performed, as described in detail in the following companion article (Nikkhah et al, 1995). During this period seven lesioned and nine grafted animals died, most likely due to cardiovascular decompensation, after the amphetamine rotation test at P21.…”

Microtransplantation of Dopaminergic Cell Suspensions: Further Characterization and Optimization of Grafting Parameters

“…This has led to a signifionly to the close vicinity around the transplants (i.e., the dorsal striatum). Björklund and colleagues (5,6) introcant improvement of DA graft survival, reproducibility, and accuracy of graft implantations (21,22) and a more duced the cell suspension approach that significantly improved the placement of DA grafts into deeper brain extensive behavioral recovery in neonatal and adult animal models of Parkinson's disease (PD) (23)(24)(25). Howstructures by using stereotactic techniques and a partial ever, following the original description (26) a number 1 µl/min and the cannula was left at the injection place for additional 4 min before slowly being retracted.…”

Global gene and cell replacement strategies via stem cells

“…These are best exemplified by Parkinson's disease, [1][2][3][4] where the goal has been the engraftment and enhanced survival of dopamine-producing cells within the striatum, or by forestalling degeneration of dopaminergic neurons within the substantia nigra (SN). However, the pathologic lesions of most neurogenetic diseases -indeed, most neurologic disordersare usually widely disseminated in the brain and spinal cord and have not typically been regarded as within the purview of neural transplantation.…”