Browsing by Subject "Ethanol"
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Item Acute alcoholic fatty liver syndromes(1965-09-16) UnknownItem Alcohol and the heart(1981-05-14) Atkins, James M.Item Alcohol-induced hypoglycemia and alcoholic ketoacidosis: a review(1977-04-21) Madison, Leonard L.Item Alcohol-induced hypoglycemic coma(1967-11-30) Madison, Leonard L.Item Brain Molecules under the Influence: Intracellular Regulation of Behavioral Responses Induced by Ethanol(2013-01-17) Peru Y Colón de Portugal, Raniero Leonette; Rothenfluh, AdrianAlcohol abuse is a devastating condition affecting millions of individuals. Regulation of insulin receptor (InR) signaling is critical for ethanol-induced responses and consumatory ethanol behavior. However, the precise intracellular mechanisms regulating InR signaling, which in turn, affect ethanol-induced behaviors remain unknown. I describe an InR/Arf6/S6K pathway that controls acute ethanol responses in Drosophila. I show that Arf6 mutants are hypersensitive to ethanol's intoxicating effects, and that Arf6 is specifically required in the adult nervous system to regulate na•ve ethanol sensitivity. While Arf6 functionally integrates activated Rac1 to the InR signaling, neuronal S6K, an InR effector, is a key mediator of Arf6-dependent regulation of ethanol-induced behaviors. Ethanol vapor concentrations that produce moderate sedation increase S6K-P, while doses that confer total sedation completely abate S6K-P. Arf6 mutants are completely devoid of neuronal S6K-P at baseline, suggesting that lack of S6K-P pre-sensitizes Arf6 mutants to the intoxicating effects of ethanol, and thus sedate at low physiologic ethanol concentrations. Because Arf6 has been implicated in receptor-mediated endocytosis, and signal transduction pathways are largely regulated by receptor trafficking, I propose a model in which Arf6 regulates InR signaling via endocytosis to control behavioral ethanol responses. My doctoral work on the intracellular mechanisms that govern ethanol's intoxicating effects on behavior will be described. The present dissertation is divided in four main sections: 1) Introduction, 2) results and methods, which include figures and figure legends and 3) a discussion of the results. In the introduction, I will review the scientific literature on the regulatory mechanisms of ethanol-driven behaviors performed in humans and other vertebrate species, while the central focus of this thesis is on Drosophila research. In doing so, I will also highlight current issues and problems concerning the study of ethanol's direct and candidate targets, which affect behavioral responses to ethanol. In the result and methods section, I will describe my obtained experimental data and the methodology employed. In the discussion section, I will first illustrate on the initial part of the results dealing with neuronal Rac1, Arfip, and Arf6, which through a linear genetic pathway regulate acute ethanol sedation. Second, I will explain how Arf6 GTPase may integrate the Rho to InR signaling to control behavioral ethanol responses. Third, I will illuminate on recent data showing that Arf6 via neuronal S6K mediates behavioral sensitivity to ethanol. Moreover, I will propose a model in which Arf6 plays separable but intertwined roles in InR signaling and endocytosis, in order to regulate acute ethanol behaviors.Item Causes of Naive Ethanol Avoidance in Drosophila Melanogaster(2016-06-22) Ritz, Morgan Paige; Rothenfluh, Adrian; Rodan, Aylin; Self, David W.BACKGROUND: Alcohol dependence is a pressing public health concern, yet little is still known about its molecular causes. Although current studies have started to understand human addiction, Drosophila research is used as a tool to carry out more genetic and behavioral approaches that are crucial in learning about the addiction process. OBJECTIVE: The aim of this project was to understand the mechanisms of ethanol avoidance in Drosophila. METHODS: I applied quantitative ingestion assays to determine the amounts of food flies ate, with or without supplemented ethanol. I also used a choice assay, the FRAPPE, to determine whether naive flies exhibited preference for 15% ethanol. To interfere with neuronal function, I used the Gal4/UAS system, which allows for tissue specific manipulation of the activity of both neurons and genes. RESULTS: On average, Drosophila flies ate less sucrose when ethanol was added. One reason for this was that fewer flies initiated feeding. Upon silencing of gustatory neurons that perceive aversive tastes, flies showed less aversion to ethanol-containing food in the choice FRAPPE assay. As I increased the starvation time, almost all flies initiated feeding, but consumption amounts were still lowered when ethanol was supplemented. Additional feeding experiments where flies were only exposed to ethanol odor, but were unable to touch it, suggested that ethanol odor also suppresses food intake. I corroborated this with ethanol vapor exposures of defined intensity and duration: during the first minute of exposure, ethanol vapor stimulated food intake, but beyond that, it caused a suppression. Mutation in the ics gene affected ethanol-induced food suppression, but had no effect on the initial ethanol-induced stimulation of food intake. CONCLUSION: Drosophila flies show multimodal suppression of food intake by ethanol. Both the taste and smell of ethanol can reduce sucrose consumption. Interestingly, ethanol odor initially enhanced, but with continued exposure suppressed food intake. This suppression was abolished in ics mutants. This gene, whose human ortholog is linked to alcohol abuse disorders, is therefore critical for alcohol aversion, explaining how ics mutant flies show high, naive preference for ethanol-containing food.Item Defining Genes and Circuits Affecting Naïve and Experience-Dependent Alcohol Preference in Drosophila melanogaster(2015-07-22) Ojelade, Shamsideen Adeniyi; Krämer, Helmut; Terman, Jonathan R.; Self, David W.; Rothenfluh, AdrianDespite alcohol being one of the most used and abused drugs in the world, the molecular mechanisms underlying alcohol abuse disorders remain largely unknown. In this dissertation, I utilized the model system Drosophila melanogaster to identify genes and circuits affecting ethanol-induced behaviors. From an unbiased genetic screen, I identified a novel gene that affects ethanol consumption in both flies and humans. Ras suppressor 1 (Rsu1) is required in the adult Drosophila nervous system for normal sensitivity to ethanol-induced sedation, and acts upstream of Rac1 and downstream of integrin to regulate the actin cytoskeleton. In a two bottle choice assay called the capillary feeding (Café) assay, loss of Rsu1 causes immediate heightened alcohol preference compared to wild type's initial naïve aversion. In contrast, flies specifically lacking Rsu1 in the mushroom bodies show normal initial aversion to alcohol, but then fail to acquire ethanol preference like normal flies do. Our data show that not only is Rsu1 required for normal alcohol responses, it suggests that different anatomical brain structures in flies control distinct alcohol behavioral responses. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption in flies and humans. Using a modified Café paradigm, we investigated whether dopamine plays a role in both the aversive and experience-dependent properties of alcohol. I show that distinct subsets of DA neurons innervating the Fan-shaped body (FSB) and Mushroom body (MB) mediate naïve alcohol aversion (NAA) and experience-dependent alcohol preference (EDAP) respectively in flies. Furthermore, Rac1-dependent actin alteration in these anatomical structures (FSB and MB) also mirror dopaminergic-induced neuronal activity in these circuits suggesting that dopamine functions upstream of Rac1-signaling to affect alcohol preference in flies. Taken together, my dissertation suggests a conserved role for dopamine and the integrin/Rsu1/Rac1/Cofilin/Actin signaling pathway in modulating drug-induced behavioral plasticity across phyla, and highlights Drosophila as an effective model for integrative translational research.Item EFA6/PSD3, Arf6 Modulator, Regulates Ethanol-Induced Behaviors Via the Insulin Receptor Signaling Pathway in Flies and Humans(2015-12-28) Gonzalez, Dante Alan; Huber, Kimberly M.; Powell, Craig M.; Krämer, Helmut; Rothenfluh, AdrianDespite the tremendous hazard that alcohol (ethanol) poses to society world-wide, our progress on the molecular and physiological understanding of how ethanol use disorders (AUD) develop has been marginal. Our limited progress can be credited to the wide range of effects that ethanol has on the body, absence of a known high affinity receptor to ethanol, and large phenotypic heterogeneities, which have been shown in genome wide association studies (GWAS). In the United States alone, AUD are highly prevalent with approximately ~18 million adults aged 18 and up and ~1 million adolescents ages 12-17 diagnosed with AUD in 2012. AUD have profound clinical significance and show to be strongly heritability, up to ~60% based on family, adoption, and twin studies. My focus in the laboratory was to understand the mechanisms by which ethanol-induced behaviors are regulated. Some of the most recognizable effects of ethanol include: sedation, tolerance, and voluntary alcohol preference (the most salient aspect of alcohol dependence). To study these behaviors, I used Drosophila melanogaster as a model organism. Drosophila displays behavioral ethanol-induced behaviors just like humans, and it has high genetic conservation with humans. Furthermore, from a pragmatic aspect, flies are easy to maintain, yield high numbers of progeny, and can be easily Here I provide evidence that in Drosophila, a guanine nucleotide exchange factor (GEF) of Arf6, EFA6, molecularly regulates the activity of Arf6 as well as the behavioral output of Arf6. I show that EFA6 mutant flies are 1) hypersensitive to the effects of ethanol 2) they do not develop tolerance following a pre-exposure, and 3) altered in their preference for ethanol. Arf6 mutant flies also show similar alcohol-induced behaviors as EFA6 mutants, which can be rescued to wild type levels when Arf6 is re-expressed in Arf6 expressing cells. These results are also translatable to human behavior. In collaboration with Dr. Gunter Schummann from King's College London, we show that 1 out of the 4 human homologues (PSD1-4) of EFA6, PSD3 (pleckstrin Sec7 domain 3) is associated with frequency of drinking in 14 year old adolescents from the IMAGEN consortium. . Furthermore, I show that p70 S6 kinase (S6k), acting downstream of the insulin receptor tyrosine kinase (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular correlate of sedation and overall neuronal activity; P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation, and they are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, while neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, I show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol. Taken together, my data significantly expand our knowledge of ethanol-induced behaviors; they give us great insights into AUD development, and may serve in the development of better treatments or therapies for alcoholism.Item The effect of alcohol in the nervous system(1967-01-05) Schenker, StevenItem Effects of Alcohol Use on Cognition During Later Adulthood(2020-12-01T06:00:00.000Z) Becker, Joshua Eric; Brown, E. Sherwood; Rossetti, Heidi; Denney, David; Palka, Jayme; Cullum, C. Munro; Adinoff, Byron H.Alcohol is one of the most widely used psychoactive substance in the world, yet there are conflicting findings related to its long-term effect on cognition. Some research has identified a U-shaped relationship between alcohol consumption and cognition, while negative relationships have been identified in other studies. Methodological issues, particularly the time at which alcohol consumption was measured relative to when cognition was measured, wide variability in definitions of "moderate" alcohol consumption, and selecting appropriate comparison groups, have made exploring the effects of alcohol on cognition during aging difficult. The current study examined the relationship between drinking at three separate time points (between the ages of 50 and 74) and cognition in older adulthood. Results revealed that the quantity of self-reported drinks over the three time points was a significant predictor of cognition in older adulthood (b=0.001; p<.001), although the effect sizes were very small and not meaningful. Subsequent analyses examined this relationship among heavy drinkers and binge drinkers compared to moderate drinkers and non-binge drinkers, but heavy and binge drinking were not significant predictors of cognition in older adulthood (all ps>0.05). Overall, the results suggest no that there is not a meaningful relationship between alcohol consumption and cognitive functioning in older adulthood in this sample. There were few consistent heavy drinkers (n=71), but a large number of consistent moderate drinkers (n=1,847), although even the moderate drinkers did not consume much alcohol (mean alcohol consumption = 15.3 drinks/month; median alcohol consumption = 5.0 drinks/month). This may have limited the ability to detect clinically meaningful differences. Future studies should rely on more standardized alcohol measures, large, diverse samples, and inclusion of cognitive measures assessing visuospatial abilities and executive functioning, in order to better explore the relationship of alcohol in the aging brain.Item Minimally invasive treatment options for benign thyroid nodules(2023-03-17) Hussain, IramItem [News](1982-12-03) Friar, JamieItem [News](1978-04-27) Land, Chris