Topology of intrastriatal dopaminergic grafts determines functional and emotional outcome in neurotoxin-lesioned rats

Many Parkinson's disease (PD) patients suffer from anxiety disorders, which often precede the onset of classical motor symptoms. So far, there is no evidence from randomized, placebo-controlled trials for successful treatment of anxiety in patients with PD. Grafts of fetal nigral neurons are currently explored as a restorative cell therapy for PD. In PD animal models, intrastriatal transplantations of embryonic dopaminergic neurons have been shown to ameliorate behavioral defects. In our previous study we showed that expanded and differentiated neural progenitors improved drug-induced rotation behavior and posture balance as a more complex motor task. However, it is not clear whether grafting of these cells affected spontaneous locomotor activity and anxiety-like behavior in 6-OHDA lesioned rats. Therefore, we analyzed behavior of control, lesioned, sham-transplanted, and transplanted rats using open field (OF) and elevated plus maze (EPM). After unilateral 6-OHDA lesion of the medial forebrain bundle, we observed reduced locomotor activity in the EPM (wall-rearing, entries in closed arms) in lesioned and sham-transplanted rats, which correlated with the loss of dopaminergic neurons and apomorphine-induced rotation behavior. Furthermore, anxiety-like behavior in the EPM (entries and time in open arms) was increased in lesioned and sham-transplanted rats. Although exogenous cell replacement improved apomorphine-induced rotation behavior, locomotor activity and anxiety-like behavior was not reconstituted in transplanted rats. However, we provided evidence for an interaction of locomotor activity/anxiety-like behavior with graft localization in the host striatum. These results emphasize the crucial role of graft localization for benefit of restorative cell therapy for PD.

Research highlights▶ Locomotor activity measured in the EPM was decreased in 6-OHDA lesioned rats and could not be reversed by transplantation of differentiated progenitor cells. ▶ Anxiety-like behavior analyzed in the OF was increased after 6-OHDA lesions. ▶ Level of anxiety-like behavior and locomotor activity in transplanted animals correlated with the topology of the grafts.