Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward
| Autor: | Sunanda Marella, Gregory L. Engel, Julia Wu, Karla R. Kaun, Fred W. Wolf, Pratik Adhikari, Eric C. Kong |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Nervous system Presynaptic Terminals Medical and Health Sciences Histone Deacetylases Histones 03 medical and health sciences 0302 clinical medicine Reward Transcriptional regulation medicine Animals Drosophila Proteins Sirtuins transcriptional regulation Epigenetics Alcohol tolerance Histone H3 acetylation Mushroom Bodies Neurology & Neurosurgery biology behavior General Neuroscience Psychology and Cognitive Sciences Synapsin Articles Synapsins enzymes and coenzymes (carbohydrates) Alcoholism 030104 developmental biology medicine.anatomical_structure Mushroom bodies Sirtuin biology.protein Drosophila addiction ethanol Transcriptome Neuroscience Alcoholic Intoxication 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience, vol 36, iss 19 Engel, GL; Marella, S; Kaun, KR; Wu, J; Adhikari, P; Kong, EC; et al.(2016). Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward. JOURNAL OF NEUROSCIENCE, 36(19), 5241-5251. doi: 10.1523/JNEUROSCI.0499-16.2016. UC Merced: Retrieved from: http://www.escholarship.org/uc/item/6kv5z0kx |
| ISSN: | 1529-2401 |
| Popis: | Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit flyDrosophilapromotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body α/β-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward.SIGNIFICANCE STATEMENTWe identify a mechanism by which acute ethanol inebriation leads to changes in nervous system function that may be an important basis for increasing ethanol intake and addiction liability. The findings are significant because they identify ethanol-driven transcriptional events that target presynaptic properties and direct behavioral plasticity. They also demonstrate that multiple forms of ethanol behavioral plasticity that are relevant to alcoholism are initiated by a shared mechanism. Finally, they link these events to theDrosophilabrain region that associates context with innate approach and avoidance responses to code for reward and other higher-order behavior, similar in aspects to the role of the vertebrate mesolimbic system. |
| Databáze: | OpenAIRE |
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