Abstract
Neuromodulatory subcortical systems (NSSs) are monoaminergic and cholinergic neuronal groups that are markedly and precociously involved in the pathogenesis of many neurodegenerative disorders (NDDs), including Parkinson's and Alzheimer's diseases. In humans, although many tools have been developed to infer information on these nuclei, encompassing neuroimaging and neurophysiological methods, a detailed and specific direct evaluation of their cellular features in vivo has been difficult to obtain until recent years. The development of induced pluripotent stem cell (iPSC) models has allowed research to deeply delve into the cellular and molecular biology of NSS neurons. In fact, iPSCs can be produced easily and non-invasively from patients' fibroblasts or circulating blood monocytes, by de-differentiating those cells using specific protocols, and then be re-differentiated towards neural phenotypes, which may reproduce the specific features of the correspondent brain neurons (including NSS ones) from the same patient. In this review, we summarized findings obtained in the field of NDDs using iPSCs, with the aim to understand how reliably these might represent in vitro models of NSS. We found that most of the current literature in the field of iPSCs and NSSs in NDDs has focused on midbrain dopaminergic neurons in Parkinson's disease, providing interesting results on cellular pathophysiology and even leading to the first human autologous transplantation. Differentiation protocols for noradrenergic, cholinergic, and serotoninergic neurons have also been recently defined and published. Thus, it might be expected that in the near future, this approach could extend to other NSSs and other NDDs.