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TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation
Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50–60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727490/ https://www.ncbi.nlm.nih.gov/pubmed/27187237 http://dx.doi.org/10.1038/tp.2016.72 |
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author | Aurelian, L Warnock, K T Balan, I Puche, A June, H |
author_facet | Aurelian, L Warnock, K T Balan, I Puche, A June, H |
author_sort | Aurelian, L |
collection | PubMed |
description | Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50–60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We have previously shown that alcohol-preferring P rats have innately elevated levels of a neuronal Toll-like receptor 4 (TLR4) signal in the ventral tegmental area (VTA) that controls the initiation of excessive alcohol drinking. Here we report that TLR4 is localized in dopaminergic (TH+) neurons and it upregulates the expression of tyrosine hydroxylase (TH) through a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal. P rats have higher impulsivity than wild-type (WT) rats and VTA infusion of a non-replicating Herpes simplex virus (HSV) vector for TLR4-specific small interfering RNA (siRNA; pHSVsiTLR4) inhibits both impulsivity and TLR4/TH expression. A scrambled siRNA vector does not affect gene expression or impulsivity. The data suggest that TLR4 signaling in VTA dopaminergic neurons controls impulsivity related to the regulation of TH expression, likely contributing to the initiation of alcohol drinking and its transition to alcohol dependence. |
format | Online Article Text |
id | pubmed-5727490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-57274902017-12-14 TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation Aurelian, L Warnock, K T Balan, I Puche, A June, H Transl Psychiatry Original Article Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50–60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We have previously shown that alcohol-preferring P rats have innately elevated levels of a neuronal Toll-like receptor 4 (TLR4) signal in the ventral tegmental area (VTA) that controls the initiation of excessive alcohol drinking. Here we report that TLR4 is localized in dopaminergic (TH+) neurons and it upregulates the expression of tyrosine hydroxylase (TH) through a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal. P rats have higher impulsivity than wild-type (WT) rats and VTA infusion of a non-replicating Herpes simplex virus (HSV) vector for TLR4-specific small interfering RNA (siRNA; pHSVsiTLR4) inhibits both impulsivity and TLR4/TH expression. A scrambled siRNA vector does not affect gene expression or impulsivity. The data suggest that TLR4 signaling in VTA dopaminergic neurons controls impulsivity related to the regulation of TH expression, likely contributing to the initiation of alcohol drinking and its transition to alcohol dependence. Nature Publishing Group 2016-05 2016-05-17 /pmc/articles/PMC5727490/ /pubmed/27187237 http://dx.doi.org/10.1038/tp.2016.72 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Aurelian, L Warnock, K T Balan, I Puche, A June, H TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title | TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title_full | TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title_fullStr | TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title_full_unstemmed | TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title_short | TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
title_sort | tlr4 signaling in vta dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727490/ https://www.ncbi.nlm.nih.gov/pubmed/27187237 http://dx.doi.org/10.1038/tp.2016.72 |
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