The NeuroD6 subtype of VTA neurons contributes to psychostimulant sensitization and behavioral reinforcement
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Abstract Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. ComparingVmat2lox/lox;NEX-Creconditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neuronsin vivoinduced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.
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Optogenetic stimulation of Neurod6+ neurons induces place preference behavior.
“When optogenetically stimulated, Neurod6+ neurons induce place preference behavior [35].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [35]
Neurod6+ dopamine neurons appear to co-release glutamate.
“Furthermore, these neurons appear to co-release glutamate [35], consistent with a larger body of work showing glutamate co-release in the medial shell [38–45].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [35]
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“In contrast, another study found that photostimulation of Vglut2-Cre neurons in VTA induced modest real time place preference and self-stimulation (Wang et al., 2015).”
BackgroundResultCre-driven optogenetics in the heterogeneous genetic panorama of the VTA
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Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches
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- Authors
- Bimpisidis, Z., König, N., Stagkourakis, S., Zell, V., Vlcek, B., Dumas, S., Giros, B., Broberger, C., Hnasko, T. S., & Wallén-Mackenzie, Å.
- Affiliations
- Uppsala University (SE)
- Karolinska Institutet (SE)
- University of California San Diego (US)
- ORCID
- Venue
- eNeuro
- Publisher
- Society for Neuroscience
- Published
- 2019-05
- Volume
- 6
- Issue
- 3
- Pages
- ENEURO.0066-19.2019
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC6565376
- OpenAlex
- W2945948316
- Cited by
- 36
- References
- 60
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 8 · 2022: 3 · 2021: 6 · 2020: 10 · 2019: 3
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eNeuro (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- hjärnfonden
- vetenskapsrådet
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- NeuroD6, ventral tegmental area, dopaminergic neurons, psychostimulant sensitization, behavioral reinforcement, reward-related behavior, VGLUT2, glutamatergic projections, nucleus accumbens, optogenetic stimulation, calretinin, cocaine, amphetamine, locomotion
- MeSH terms
- Ethanol, Amphetamine, Central Nervous System Stimulants, Animals, Cocaine, Corpus Striatum, Female, Locomotion, Male, Nerve Tissue Proteins, Reward, RNA, Messenger, Ventral Tegmental Area, Mice, Knockout, Vesicular Monoamine Transport Proteins, Basic Helix-Loop-Helix Proteins, Dopaminergic Neurons, Optogenetics
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