RESUMEN
UNLABELLED: 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 fly Drosophila promotes 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/ß-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 STATEMENT: We 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 the Drosophila brain 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.
Asunto(s)
Intoxicación Alcohólica/metabolismo , Alcoholismo/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Histona Desacetilasas/metabolismo , Terminales Presinápticos/metabolismo , Recompensa , Sirtuinas/metabolismo , Intoxicación Alcohólica/genética , Alcoholismo/genética , Animales , Drosophila/genética , Drosophila/fisiología , Proteínas de Drosophila/genética , Histona Desacetilasas/genética , Histonas/metabolismo , Cuerpos Pedunculados/metabolismo , Terminales Presinápticos/fisiología , Sirtuinas/genética , Sinapsinas/genética , Sinapsinas/metabolismo , TranscriptomaRESUMEN
There are five known taste modalities in humans: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate). Although the fruitfly Drosophila melanogaster tastes sugars, salts and noxious chemicals, the nature and number of taste modalities in this organism is not clear. Previous studies have identified one taste cell population marked by the gustatory receptor gene Gr5a that detects sugars, and a second population marked by Gr66a that detects bitter compounds. Here we identify a novel taste modality in this insect: the taste of carbonated water. We use a combination of anatomical, calcium imaging and behavioural approaches to identify a population of taste neurons that detects CO2 and mediates taste acceptance behaviour. The taste of carbonation may allow Drosophila to detect and obtain nutrients from growing microorganisms. Whereas CO2 detection by the olfactory system mediates avoidance, CO2 detection by the gustatory system mediates acceptance behaviour, demonstrating that the context of CO2 determines appropriate behaviour. This work opens up the possibility that the taste of carbonation may also exist in other organisms.
Asunto(s)
Dióxido de Carbono/análisis , Drosophila melanogaster/fisiología , Gusto/fisiología , Animales , Conducta Animal , Encéfalo/citología , Encéfalo/metabolismo , Dióxido de Carbono/química , Hielo Seco , Preferencias Alimentarias , Gases/química , Concentración de Iones de Hidrógeno , Ligandos , Neuronas/metabolismo , Olfato/fisiología , Bicarbonato de Sodio/análisis , Soluciones/química , Agua/químicaRESUMEN
The sense of taste allows animals to distinguish nutritious and toxic substances and elicits food acceptance or avoidance behaviors. In Drosophila, taste cells that contain the Gr5a receptor are necessary for acceptance behavior, and cells with the Gr66a receptor are necessary for avoidance. To determine the cellular substrates of taste behaviors, we monitored taste cell activity in vivo with the genetically encoded calcium indicator G-CaMP. These studies reveal that Gr5a cells selectively respond to sugars and Gr66a cells to bitter compounds. Flies are attracted to sugars and avoid bitter substances, suggesting that Gr5a cell activity is sufficient to mediate acceptance behavior and that Gr66a cell activation mediates avoidance. As a direct test of this hypothesis, we inducibly activated different taste neurons by expression of an exogenous ligand-gated ion channel and found that cellular activity is sufficient to drive taste behaviors. These studies demonstrate that taste cells are tuned by taste category and are hardwired to taste behaviors.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/fisiología , Gusto/fisiología , Animales , Animales Modificados Genéticamente , Encéfalo/citología , Mapeo Encefálico , Drosophila , Femenino , Colorantes Fluorescentes , Procesamiento de Imagen Asistido por Computador , Ligandos , Microscopía Confocal , Neuronas/fisiología , Órganos de los Sentidos/fisiologíaRESUMEN
For an animal to survive in a constantly changing environment, its behavior must be shaped by the complex milieu of sensory stimuli it detects, its previous experience, and its internal state. Although taste behaviors in the fly are relatively simple, with sugars eliciting acceptance behavior and bitter compounds avoidance, these behaviors are also plastic and are modified by intrinsic and extrinsic cues, such as hunger and sensory stimuli. Here, we show that dopamine modulates a simple taste behavior, proboscis extension to sucrose. Conditional silencing of dopaminergic neurons reduces proboscis extension probability, and increased activation of dopaminergic neurons increases extension to sucrose, but not to bitter compounds or water. One dopaminergic neuron with extensive branching in the primary taste relay, the subesophageal ganglion, triggers proboscis extension, and its activity is altered by satiety state. These studies demonstrate the marked specificity of dopamine signaling and provide a foundation to examine neural mechanisms of feeding modulation in the fly.