Substantia nigra degradation results in widespread changes in medial zona incerta afferent and efferent connectomics

Abstract

Parkinsons disease (PD) is a complex disease affecting many facets of movement, especially gait abnormalities such as shuffling and freezing of gait. The nigrostriatal pathways of the basal ganglia are traditionally targeted by existing therapies; however, other pathways may be more relevant to gait, such as the pedunculopontine nucleus and the zona incerta (ZI). The A13 nucleus may be such a target as it has emerged as an area of interest in dopamine motor function. Yet, this area remains understudied compared to other dopamine nuclei, especially in animal models of PD. In 6-OHDA mice, we found a reduction in locomotion in the open field and gait dysfunction during treadmill tests. Medial ZI dopamine cells, containing the A13 nucleus, were preserved following 6-OHDA, in contrast to a marked reduction in substantia nigra pars compacta (SNc) neurons. There was extensive remodelling of the A13 afferent and efferent connectome following nigrostriatal lesions. Afferent input patterns displayed a marked reduction in cross-correlation across brain regions in 6-OHDA mice, while efferent projections showed an increase. In a human PD patient with advanced gait dysfunction we found that the A13 nucleus was preserved, suggesting that remodelling could also occur in humans. This work points to the A13 region as a potential therapeutic target in PD. Significance StatementRecently it was found that the medial zona incerta projects to the cuneiform nucleus suggesting a parallel dopaminergic projection onto motor regions. Here we investigated the connectome of the A13 region and examined the afferent and efferent projections in normal mice and mice with a unilateral Parkinsonian mouse model. We found that the connectome was reconfigured following nigrostriatal degeneration. This work provides a comprehensive insight into the plasticity in a dopaminergic-rich area of the zona incerta in PD injury models.