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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement

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...

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Autores principales: Bimpisidis, Zisis, König, Niclas, Stagkourakis, Stefanos, Zell, Vivien, Vlcek, Bianca, Dumas, Sylvie, Giros, Bruno, Broberger, Christian, Hnasko, Thomas S., Wallén-Mackenzie, Åsa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565376/
https://www.ncbi.nlm.nih.gov/pubmed/31097625
http://dx.doi.org/10.1523/ENEURO.0066-19.2019
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author Bimpisidis, Zisis
König, Niclas
Stagkourakis, Stefanos
Zell, Vivien
Vlcek, Bianca
Dumas, Sylvie
Giros, Bruno
Broberger, Christian
Hnasko, Thomas S.
Wallén-Mackenzie, Åsa
author_facet Bimpisidis, Zisis
König, Niclas
Stagkourakis, Stefanos
Zell, Vivien
Vlcek, Bianca
Dumas, Sylvie
Giros, Bruno
Broberger, Christian
Hnasko, Thomas S.
Wallén-Mackenzie, Åsa
author_sort Bimpisidis, Zisis
collection PubMed
description 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. Comparing Vmat2(lox/lox;NEX-Cre) conditional 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 neurons in vivo induced 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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spelling pubmed-65653762019-06-18 The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement Bimpisidis, Zisis König, Niclas Stagkourakis, Stefanos Zell, Vivien Vlcek, Bianca Dumas, Sylvie Giros, Bruno Broberger, Christian Hnasko, Thomas S. Wallén-Mackenzie, Åsa eNeuro New Research 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. Comparing Vmat2(lox/lox;NEX-Cre) conditional 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 neurons in vivo induced 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. Society for Neuroscience 2019-06-07 /pmc/articles/PMC6565376/ /pubmed/31097625 http://dx.doi.org/10.1523/ENEURO.0066-19.2019 Text en Copyright © 2019 Bimpisidis et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Bimpisidis, Zisis
König, Niclas
Stagkourakis, Stefanos
Zell, Vivien
Vlcek, Bianca
Dumas, Sylvie
Giros, Bruno
Broberger, Christian
Hnasko, Thomas S.
Wallén-Mackenzie, Åsa
The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title_full The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title_fullStr The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title_full_unstemmed The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title_short The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
title_sort neurod6 subtype of vta neurons contributes to psychostimulant sensitization and behavioral reinforcement
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565376/
https://www.ncbi.nlm.nih.gov/pubmed/31097625
http://dx.doi.org/10.1523/ENEURO.0066-19.2019
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