Rewiring dopaminergic nigral connections in the human brain: a multi-scale and integrated study

Background: the subcortical network of the substantia nigra pars compacta (SNc), one of the main dopaminergic nuclei of the brain, is well known and mainly represented by the nigro-striatal pathway. However, dopaminergic modulation of other brain centers, such as the thalamus, has been only investigated in non-human primates and never characterized in the humans.

Methods: we aim to dissect the dopaminergic innervation of the human thalamus using multi-scale and integrated analyses.

First, immunohistochemical analysis will be performed on human thalamic sections, stained for the main dopaminergic markers (TH, VMAT, DAT, AADC).

Second, starting from high-resolution MRI segmentation of the SN (that allows the identification of the postero-medial SNc from the gabaergic anterolateral SN pars reticulata – SNr) and multi-shell high-angular resolution diffusion MRI (MS-HARDI) (that allows the tractographic reconstruction of the SNc) will be performed in a group of 10 healthy subjects.

Finally, PET-FDOPA data coming from healthy subjects (n=20) will be evaluated for both qualitative and quantitative analysis of the thalamic region.

Results: our preliminary MS-HARDI results performed with two previously validated diffusion MRI schemes demonstrate a reproducible structural connectivity between the SNc and the thalamus, with up to an average of ~19% of the total number of streamlines encompassing the SNc and the thalamus depending on the algorithmic constrains but with no other major subcortical structures involved (and without necessarily reaching the cortex).

Conclusions: to our best knowledge, this is the first pilot report of a direct nigro-thalamic dopaminergic projection, with a multi-scale and integrated approach. The significance and the characterization of these connections, however, is still under investigation.