Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: motor impairments identify extent of dopamine depletion at three different lesion sites

Abstract

The unilateral 6-hydroxydopamine mouse lesion models of Parkinson's disease have received increasing attention in recent years, but comparison of the different lesion models was largely focused at a histological level. An extensive behavioural comparison between different mouse models on tests of motor function has yet to be carried out, to pin point tests that accurately discriminate between different extents of dopaminergic depletion. In the present study we examine the consequences of injection of the toxin at three sites along the nigrostriatal tract (substantia nigra, medial forebrain bundle, and striatum) on a broad range of simple motor tasks, and on the dopaminergic pathology. All lesion groups demonstrated marked behavioural deficits and displayed distinct profiles of degeneration along the nigrostriatal dopamine pathway. Tests that correlated closely with the level of substantia nigra cell loss included the corridor, cylinder and balance beam tests, the rotarod, inverted cage lid and three types of rotational assessment (spontaneous, amphetamine-induced and apomorphine-induced). Specific tasks are identified which are capable of distinguishing a near-complete lesion, with amphetamine rotation, corridor and cylinder tests showing the highest correlations with levels of nigral cell loss. Performance in the different behavioural tests was associated with distinct profiles of cell loss in the SN and VTA. We provide a comprehensive behavioural assessment of lesion-induced deficits in mouse models of PD, which should facilitate selection of the most appropriate lesion model and most sensitive behavioural tests for use in future studies investigating therapeutic interventions.