An atlas of transcriptionally defined cell populations in the rat ventral tegmental area

Phillips, Robert A.; Tuscher, Jennifer J.; Black, Samantha L; Andraka, Emma; Fitzgerald, N. Dalton; Ianov, Lara; Day, Jeremy J.

doi:10.1016/j.celrep.2022.110616

Cited by 77 publications

(59 citation statements)

References 99 publications

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“…Growing evidence demonstrate that midbrain DAergic systems are integrated by a spectrum of molecularly, anatomically, and functionally distinct neuron subtypes. In addition, single-cell gene expression profiling ( Tiklová et al, 2019 ; Poulin et al, 2020 ; Phillips et al, 2022 ), together with projection-specific functional mapping, support the hypothesis that heterogeneous DA neuronal clusters can influence individual behavioral readouts ( Lammel et al, 2014 ; Morales and Margolis, 2017 ; Poulin et al, 2018 ).…”

Section: Introductionmentioning

confidence: 65%

Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated Exploration

Molas

Zhao-Shea

Freels

et al. 2023

eNeuro

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Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomical location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter (DAT)-Cre mouse line. Consistent with previous reports, synaptic tracing revealed axon terminals from the VTA innervate the caudal IPN; whereas, retrograde tracing revealed DAergic VTA neurons, predominantly in the paranigral region, project to the nucleus accumbens shell, as well as the IPN. To test if functional DAergic neurotransmission exist in the IPN we expressed the genetically encoded DA sensor, dLight 1.2, in the IPN of C57Bl/6J mice and measured IPN DA signals in vivo during social and anxiety-like behavior using fiber photometry. We observed an increase in IPN DA signal during social investigation of a novel but not familiar conspecific and during exploration of the anxiogenic open arm of the elevated plus maze. Together, these data confirm VTA DAergic neuron projections to the IPN and implicate this circuit in encoding perceived motivated exploration.Significance StatementVentral tegmental area (VTA) dopamine (DA) neurons respond to reward but can also be engaged by aversive stimuli highlighting the need to functionally characterize VTA projections to understand how DA signaling underlies motivated behavior. Previous studies identified VTA DA neurons that project to the interpeduncular nucleus (IPN) where they modulate anxiety and novelty preference. In mice, the existence of IPN-projecting VTA DA neurons was confirmed using viral tracing. Expressing a genetically encoded DA sensor in the IPN and monitoring DA revealed that IPN DA is increased in response to novel and anxiogenic stimuli. These data verify that a small population of DA neurons in the VTA project to the IPN where they are engaged during motivated exploration.

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Section: Introductionmentioning

confidence: 65%

Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated Exploration

Molas

Zhao-Shea

Freels

et al. 2023

eNeuro

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“…Several anatomically-defined regions in the brain, especially the ventral tegmental area, nucleus accumbens (NAc), and PFC, are associated with motivational states and addiction [ 75 , 76 ]. Recently, cellular profiling of these regions was performed in human and rodent samples [ 77 , 78 , 79 ], highlighting specific cell types involved in increased motivation [ 14 , 79 ].…”

Section: Alcohol Use Disordermentioning

confidence: 99%

Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches

Chehimi

Crist

Reiner

2023

Genes

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The development of single-cell and single-nucleus transcriptome technologies is enabling the unraveling of the molecular and cellular heterogeneity of psychiatric disorders. The complexity of the brain and the relationships between different brain regions can be better understood through the classification of individual cell populations based on their molecular markers and transcriptomic features. Analysis of these unique cell types can explain their involvement in the pathology of psychiatric disorders. Recent studies in both human and animal models have emphasized the importance of transcriptome analysis of neuronal cells in psychiatric disorders but also revealed critical roles for non-neuronal cells, such as oligodendrocytes and microglia. In this review, we update current findings on the brain transcriptome and explore molecular studies addressing transcriptomic alterations identified in human and animal models in depression and stress, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), schizophrenia, opioid use disorder, and alcohol and psychostimulant abuse. We also comment on potential future directions in single-cell and single-nucleus studies.

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“…The VTA is an aggregate of dopamine-, GABA-, and glutamate-releasing neurons (Morales and Margolis, 2017 ), some of which co-release a combination of these neurotransmitters (Trudeau et al, 2014 ). There is also cellular diversity within these populations as defined by differential gene expression, projection patterns, and function at the level of behavioral regulation (Poulin et al, 2018 , 2020 ; Heymann et al, 2020 ; Phillips et al, 2022 ). Although there are clear differences in the functionality of dopamine-, glutamate-, and GABA-releasing neurons of the VTA, these neurons receive inputs from many common sources (Faget et al, 2016 ), though the strength of connections of these inputs onto specific cell types, as measured by the amplitude of evoked responses using optogenetic circuit mapping, is variable (Bocklisch et al, 2013 ; Hjelmstad et al, 2013 ; Jennings et al, 2013 ; Nieh et al, 2016 ; McHenry et al, 2017 ; Yang et al, 2018 ; Soden et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA

Soden

Yee

Cuevas

et al. 2022

Front. Neural Circuits

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Neuropeptides play an important role in modulating mesolimbic system function. However, while synaptic inputs to the ventral tegmental area (VTA) have been extensively mapped, the sources of many neuropeptides are not well resolved. Here, we mapped the anatomical locations of three neuropeptide inputs to the VTA: neurotensin (NTS), corticotrophin releasing factor (CRF), and neurokinin B (NkB). Among numerous labeled inputs we identified the bed nucleus of the stria terminalis (BNST) as a major source of all three peptides, containing similar numbers of NTS, CRF, and NkB VTA projection neurons. Approximately 50% of BNST to VTA inputs co-expressed two or more of the peptides examined. Consistent with this expression pattern, analysis of calcium dynamics in the terminals of these inputs in the VTA revealed both common and distinct patterns of activation during appetitive and aversive conditioning. These data demonstrate additional diversification of the mesolimbic dopamine system through partially overlapping neuropeptidergic inputs.

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An atlas of transcriptionally defined cell populations in the rat ventral tegmental area

Cited by 77 publications

References 99 publications

Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated Exploration

Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated Exploration

Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA

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