Afferent Inputs to Neurotransmitter-Defined Cell Types in the Ventral Tegmental Area

Abstract

The ventral tegmental area (VTA) plays a central role in the neural circuit control of behavioral reinforcement. Though considered a dopaminergic nucleus, the VTA contains substantial heterogeneity in neurotransmitter type, containing also GABA and glutamate neurons. Here we used a combinatorial viral approach to transsynaptically label afferents to defined VTA dopamine, GABA, or glutamate neurons. Surprisingly, we find that these populations received qualitatively similar inputs, with dominant and comparable projections from the lateral hypothalamus, raphe, and ventral pallidum. However, notable differences were observed with striatal regions and globus pallidus providing a greater share of input to VTA dopamine neurons, cortical input preferentially on to glutamate neurons, and GABA neurons receiving proportionally more input from the lateral habenula and laterodorsal tegmental nucleus. By comparing inputs to each of the transmitter-defined VTA cell types this study sheds important light on the systems-level organization of diverse inputs to VTA.

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.…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…We therefore only included mice for this study that met all of the following criteria: 1) the FG injection and apparent spread was within the vicinity of the VTA (Fig. 2B–F, magenta shading), 2) numerous FG-labeled cell bodies were observed within the LHA and NA, consistent with the established LHA → VTA and NA → VTA projections and 3) absence of FG-labeled cell bodies within the DS that would suggest FG spread to the SN, consistent with the established DS → SN projection (Watabe-Uchida et al, 2012, Faget et al, 2016). Out of 10 FG-injected Nts Cre ;GFP mice, 5 were excluded from analysis because the injection was targeted lateral or dorsal to the VTA and/or the pattern of FG-labeled neurons was more consistent with SN rather than VTA afferents.…”

“…In general, mice were included in the study if the FG injection was targeted to and confined within the VTA, and if FG-labeled neurons were observed in a pattern consistent with mouse VTA afferents based on prior studies that separately labeled afferents to VTA DA, GABA and glutamate neurons (Faget et al, 2016; Watabe-Uchida et al, 2012). As a first step to recognizing such mice, we identified the injection site via the scarring and/or autofluoresence that accompanies tissue disruption along the injection tract, then we examined potential FG spread around these sites.…”

The Input-Output Relationship of the Cholinergic Basal Forebrain

“…In addition, these transmitter-specific neurons contain in various degrees dopamine (DAT) and vesicular monoamine (VMAT2) transporters and D2 receptors, thus individual subpopulations of neurons are likely to be differentially involved in drug addiction and various motivational and cognitive functions (Faget et al, 2016; Hur and Zaborszky, 2005; Morales and Root, 2014; Nair-Roberts et al, 2008; Tritsch et al, 2012). Cholinergic neurons in the BF receive synapses from the VTA and substantia nigra (Gaykema and Zaborszky, 1997; Zaborszky and Cullinan, 1996).…”

“…Monosynaptic viral tracing of neuromodulatory systems has been used in the noradrenergic, dopaminergic and serotonergic systems (Beier et al, 2015; Faget et al, 2016; Lerner et al, 2015; Ogawa et al, 2014; Pollak Dorocic et al, 2014; Schwarz et al, 2015; Watabe-Uchida et al, 2012; Weissbourd et al, 2014). BFc monosynaptic tracing was also reported (Do et al, 2016; Hu et al, 2016) though without reference to target specificity.…”