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

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.

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

“…More than 90% of both SNc and VTA DA neurons labeled with zsGreen ( Figure 5D). However, in the adult mouse and other mammals, only a subset of midbrain DA neurons express VGLUT2 (or VGLUT2 Cre ), and these are more abundant in the medial VTA (5,7,8,35,36). Together, these results indicate that most SNc and VTA DA neurons transiently express VGLUT2 during development, but only a small subset continue to express VGLUT2 in the adult.…”

“…But what might this teach us of the underlying neurobiology, or about selective DA neuron vulnerability? In the mouse, rat, marmoset, and human, endogenous VGLUT2 expression has been colocalized to a subset of midbrain DA neurons (5,7,8,45). The fraction varies by subregion and projection target, and estimates range across species, study, and approach, but generally only a minority (<20%) of midbrain DA neurons express detectable levels of VGLUT2 in the adult.…”

“…A subset of midbrain DA neurons corelease glutamate and express vesicular glutamate transporter 2 (VGLUT2) in the adult mouse, rat, primate, and human (5)(6)(7)(8)(9). Evidence indicates that VGLUT2 is expressed more broadly in midbrain DA neurons during development (10)(11)(12); but VGLUT2 expression is restricted to smaller subsets in the adult mouse, when colocalization with DA markers is most pronounced in medial regions of the VTA (7,10,13).…”

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

“…Such cellular events provide a mechanism through which glutamate contribute to the regulation of ERK activation induced by d‐amphetamine and D1R agonists (Choe et al ; Valjent et al ; Pascoli et al ). Because TS‐projecting DA neurons express VGLUT2 (Poulin et al ; Root et al ; Poulin et al ), future studies will be necessary to determine whether glutamate co‐released by these DA neurons is essential for D1R‐dependent stimulation of ERK in the TS.…”

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

“…There is renewed interest in exploring DA neuron diversity in primate studies in order to achieve insights into primate-specific behaviors that are influenced by the DA system (Root et al , 2016). For the specifics of the CEA-DA-striatal path, many questions exist.…”