Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans.

David H Root,Péter Szocsics,Zsófia Maglóczky,Bing Liu,David J Barker,Marisela Morales,Afonso C Silva,László Mód,Hui-Ling Wang

doi:10.1038/srep30615

Abstract

The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease.

Highlights

To determine whether glutamate neurons are present within the ventral tegmental area (VTA) or substantia nigra pars compacta (SNC) of nonhuman primates and humans, we combined immunodetection of TH, with radioactive in situ hybridization to identify the neuronal expression of transcripts encoding VGluT2 mRNA11
We found neurons expressing VGluT2-mRNA intermingled with TH-neurons in the VTA and SNC of both marmoset (Callithrix jacchus) and squirrel (Saimiri sciureus) monkeys
The abundance of VGluT2-neurons within the VTAR differed from the neighboring SNC, which was dominated by TH-only neurons (Fig. 1C,E)

Summary

Introduction

Applies to B-B” and C-C”. (D,E). Distribution of VGluT2-only neurons (green circles), TH-only neurons (blue triangles), or VGluT2-TH neurons (red circles) within different aspects of the VTA (D) or the SNC (E). (D) Within the VTA, the VTAR contains mainly VGluT2-only neurons whereas the RLi (rostral linear nucleus) and VTAC (caudal ventral tegmental area subdivision) contain almost equivalent proportions of VGluT2-only and TH-only neurons. In contrast to the advances made in identifying unique neuronal phenotypes and their functions in the mouse and rat midbrain, the cellular composition of the dopaminergic midbrain in higher mammals, such as the nonhuman primate and human, is unknown. The lack of information on the cellular composition of the human midbrain contributes to a translational gap in our understanding of the neurobiology of addiction, depression, and other midbrain-associated disorders. To start addressing this gap, here we combined in situ hybridization and immunohistochemistry to determine the possible presence of glutamate or glutamate-dopamine neurons within the VTA and SNC in nonhuman primates and humans

Methods

Results

Conclusion