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

Abstract

Parkinson 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.

Restoration of locomotor function following stimulation of the A13 region in Parkinson’s mouse models

“…To minimize the influence of experimental variation on the total labeling of neurons and fibers, the afferent cell counts or efferent fiber areas in each brain region were column divided by the total number found in a brain to obtain the proportion of total inputs and outputs. Connectome analyses were performed using custom R scripts (L. H. Kim et al, 2021 ). For interregional correlation analyses, the data were normalized to a log 10 value to reduce variability and bring brain regions with high and low proportions of cells and fibers to a similar scale.…”

“…Moreover, PD-related bradykinesia is ameliorated with A13 region photoactivation in the presence of remodelling of the A13 region connectome. Some of these data have been published in abstract form (L. Kim et al, 2021 ).…”