Temporal changes in the neurotrophic environment of the denervated striatum as determined by the survival and outgrowth of grafted fetal dopamine neurons.

There is growing evidence that the neurotrophic environment of the denervated striatum may change with time following a lesion of the nigrostriatal pathway in young adult rats. To test this hypothesis, we implanted fetal dopamine grafts into the striatum at several different time points relative to the nigrostriatal pathway lesion and allowed the grafts to integrate with the host for a period of 1 month; subsequently, we observed the function and morphology of the dopamine grafts. Fetal grafts were implanted at the following time points relative to the lesion: 1 week before (-1 Week), at the same time (Week 0), 1 week after (1 Week), 4 weeks after (4 Weeks), or 12 weeks after (12 Weeks). Amphetamine-induced rotational behavior was assessed 4 weeks after grafting for all groups. Rotational scores indicate that grafts for the 1 Week group showed the greatest reversal of amphetamine-induced rotational behavior that was also significantly greater than the scores for the -1 Week group. Morphological analysis revealed that grafts in the Week 0, 1 Week and 4 Weeks groups showed a significantly larger area of tyrosine hydroxylase-positive (TH+) fiber outgrowth than in the -1 Week group, while fiber outgrowth for the 12 Weeks group was significantly lower than for the 1 Week group. Cell count analysis for TH+ neurons within the graft indicate a significantly greater number of TH+ neurons in grafts for the 1 Week group than in grafts for the -1 Week. The results of this study suggest that neurotoxic lesions may induce a compensatory increase in neurotrophic activity within the denervated striatum of young rats that is conducive to the survival and outgrowth of fetal dopamine grafts. These data also correlate well with reports that the expression of several specific dopaminergic neurotrophic factors within the striatum increase following a neurotoxic lesion of the nigrostriatal pathway in young adult rats.