Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

Abstract

Dopaminergic neurons in the ventral mesencephalon (the ventral mesencephalic dopaminergic complex) are known for their role in a multitude of behaviors, including cognition, reward, addiction and voluntary movement. Dysfunctions of these neurons are the underlying cause of various neuropsychiatric disorders, such as depression, addiction and schizophrenia. In addition, Parkinson's disease (PD), which is the second most common degenerative disease in developed countries, is characterized by the degeneration of dopaminergic neurons, leading to the core motor symptoms of the disease. However, only a subset of dopaminergic neurons in the ventral mesencephalon is highly vulnerable to the disease process. Indeed, research over several decades revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group with respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in different diseases. Here, we review how the concept of dopaminergic neuron diversity, assisted by the advent and application of new technologies, evolved and was refined over time and how it shaped our understanding of PD pathogenesis. Understanding this diversity of neurons in the ventral mesencephalic dopaminergic complex at all levels is imperative for the development of new and more selective drugs for both PD and various other neuropsychiatric diseases.

Mest/Peg1 Is Essential for the Development and Maintenance of a SNc Neuronal Subset

“…Taken together, these data suggest that Mest has a crucial role in the maintenance of SNc neurons. During the progression of PD, neurons in the ventral tier and medial tier of the SNc are lost before the disease affects the entire SNc (Braak et al, 2003, 2004; Vogt Weisenhorn et al, 2016). Interestingly, the progressive loss of mdDA neurons detected in the SNc of Mest neurons partly resembles this loss as seen in PD, indicating that the Mest ablated mouse model may serve to study degeneration events as observed in PD.…”

Analysis of Neuropsychiatric Disease‐Related Functional Neuroanatomical Markers in Mice

“…The choice of brain region will depend on the initial hypothesis. For example, TH+ cells may be quantified in the ventral tegmental area; part of the mesolimbic pathway where dopaminergic neurons project to the striatum, known to be abnormal in schizophrenia (Brisch et al., ; Vogt Weisenhorn, Giesert, & Wurst, ; for an example analysis of TH+ cells see Salminen et al., ). An additional endophenotype of schizophrenia is a reduction in PV+ interneurons or expression in the prefrontal cortex (Volk & Lewis, ).…”

199 years of Parkinson disease – what have we learned and what is the path to the future?

“…Vogt Weisenhorn and colleagues describe the inhomogeneity of dopaminergic neurons (Vogt Weisenhorn et al . ). The diversity of mesencephalic dopaminergic neurons not only comprises diverse functions, afferent, and efferent connections but also diverse gene expression with a dynamic molecular variability.…”

“…To date, the question of selective vulnerability of dopaminergic neurons of the substantia nigra remains unansweredin fact only a subset of dopaminergic neurons in the mesencephalon is selectively vulnerable. Vogt Weisenhorn and colleagues describe the inhomogeneity of dopaminergic neurons (Vogt Weisenhorn et al 2016). The diversity of mesencephalic dopaminergic neurons not only comprises diverse functions, afferent, and efferent connections but also diverse gene expression with a dynamic molecular variability.…”