A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice

An, Sile; Li, Xiangning; Deng, Lei; Zhao, Peilin; Ding, Zhangheng; Han, Yutong; Luo, Yu; Liu, Xin; Li, Anan; Luo, Qi; Feng, Zuren; Gong, Hui

doi:10.3389/fnana.2021.818242

Cited by 16 publications

(15 citation statements)

References 52 publications

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“…These circuits likely contribute to the high sensitivity of VTA VGluT2+VGaT+ neurons toward stressful stimuli that result in social and exploratory deficits in mice 52 . On the whole, brain-wide inputs to VTA VGluT2+VGaT+ neurons were similar to those found examining all VTA VGluT2+ neuron inputs 33,35 . Highly dense inputs arose from lateral habenula, dorsal raphe, locally within the VTA, and subdivisions of the periaqueductal gray.…”

Section: Discussionsupporting

confidence: 70%

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Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Prevost

Phillips

Lauridsen

et al. 2023

Preprint

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A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice. We found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons robustly activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). For both pathways, behaviors induced by stimulation were uncorrelated with VTA VGluT2+VGaT+ neuron activity, suggesting that VGluT2+VGaT+ neurons are integrators of signals related to aversive outcomes but not of aversion-induced behavioral kinematics. We interpret these results such that VTA VGluT2+VGaT+ neurons may integrate diverse inputs related to the detection and processing of motivationally-salient outcomes.

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Section: Discussionsupporting

confidence: 70%

“…Another major input to VTA VGluT2+ neurons is from the superior colliculus (An et al, 2021) (SC), which accounted for the largest proportion of inputs to VGluT2+VGaT+ neurons (Figure 2A; Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Prevost

Phillips

Lauridsen

et al. 2023

Preprint

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“…GABAergic neurons in the VTA also may comprise a heterogeneous population, and some of these neurons act locally to inhibit dopamine neurons while others project out of the VTA ( Tan et al, 2012 ; van Zessen et al, 2012 ; Paul et al, 2018 , 2019 ; Polter et al, 2018 ; An et al, 2021 ). Some of our data appear to cluster ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Function of Excitatory Periaqueductal Gray Synapses in the Ventral Tegmental Area following Inflammatory Injury

Manning

Fritz

Kauer

2022

eNeuro

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Manipulating the activity of ventral tegmental area (VTA) dopamine (DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal gray (PAG), a nexus of ascending pain information. We tested whether PAG–VTA synapses undergo functional plasticity in response to a pain model using optical stimulation in conjunction with slice electrophysiology. We found that acute carrageenan inflammation does not significantly affect the strength of excitatory PAG synapses onto VTA DA neurons. However, at the PAG synapses on VTA GABA neurons, the subunit composition of NMDA receptors is altered; the complement of NR2D subunits at synaptic sites appears to be lost. Thus, our data support a model in which injury initially alters synapses on VTA GABA neurons. Over time, these alterations may increase tonic inhibition of VTA DA neurons leading to their reduced firing.

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“…Dopamine transmission in the striatum plays critical roles in complex cognitive and behavioral processes including reward, motivation, reinforcement learning, effort, and responses to salience (Berke, 2018;Kutlu et al, 2021;Walton & Bouret, 2019). Dopamine neurons that project to striatal regions originate in the substantia nigra pars compacta (SNc), which densely innervates the dorsal striatum, and the ventral tegmental area (VTA), which projects to the ventral aspect of the striatum (the nucleus accumbens or NAc) and cortical areas that are important for executive functions (An et al, 2021;de Jong et al, 2022). Dopamine exerts several types of modulatory influence on striatal physiology (Yamada et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Examples of GPCR modulation of dopamine neuron activity in the midbrain.A) SNc and VTA neurons modulate striatal activity via projections to the dorsal striatum and NAc. Midbrain dopamine neurons receive both local and long-range GABA inputs, including GABAergic projections from the striatum, and glutamatergic inputs from a variety of brain regions(An et al, 2021). B) D2 autoreceptors expressed in somatodendritic compartments of dopamine neurons activate GIRK, causing hyperpolarization.…”

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confidence: 99%

G protein-coupled receptor modulation of striatal dopamine transmission: Implications for substance use disorders

Littlepage-Saunders

Hochstein

Chang

et al. 2023

Preprint

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Dopamine transmission in the striatum is a critical mediator of the rewarding and reinforcing effects of commonly misused psychoactive drugs. G protein-coupled receptors (GPCRs) that bind a variety of neuromodulators including dopamine, endocannabinoids, acetylcholine, and endogenous opioid peptides regulate dopamine release by acting on several components of dopaminergic circuitry. Striatal dopamine release can be driven by both somatic action potential firing and local mechanisms that depend on acetylcholine released from striatal cholinergic interneurons. GPCRs that primarily regulate somatic firing of dopamine neurons via direct effects or modulation of synaptic inputs are likely to impact distinct aspects of behavior and psychoactive drug actions compared with GPCRs that primarily regulate local acetylcholine-dependent dopamine release in striatal regions. This review will highlight mechanisms by which GPCRs modulate dopaminergic transmission and the relevance of these findings to psychoactive drugs involved in substance use disorders.

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A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice

Cited by 16 publications

References 52 publications

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Function of Excitatory Periaqueductal Gray Synapses in the Ventral Tegmental Area following Inflammatory Injury

G protein-coupled receptor modulation of striatal dopamine transmission: Implications for substance use disorders

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