Longitudinal Assessment of Motor Function Following the Unilateral Intrastriatal 6-hydroxydopamine Lesion Model in Mice

Introduction: Despite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound's long-term therapeutic effects.

Materials And Methods: In the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.

Results: Our results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH cells and TH fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.

Conclusion: In summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.