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8 Publications

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    12/29/09 | Preferential ethanol consumption in Drosophila models features of addiction.
    Devineni AV, Heberlein U
    Current Biology. 2009 Dec 29;19(24):2126-32. doi: 10.1016/j.cub.2009.10.070

    Alcohol addiction is a common affliction with a strong genetic component [1]. Although mammalian studies have provided significant insight into the molecular mechanisms underlying ethanol consumption [2], other organisms such as Drosophila melanogaster are better suited for unbiased, forward genetic approaches to identify novel genes. Behavioral responses to ethanol, such as hyperactivity, sedation, and tolerance, are conserved between flies and mammals [3, 4], as are the underlying molecular pathways [5-9]. However, few studies have investigated ethanol self-administration in flies [10]. Here we characterize ethanol consumption and preference in Drosophila. Flies prefer to consume ethanol-containing food over regular food, and this preference increases over time. Flies are attracted to the smell of ethanol, which partially mediates ethanol preference, but are averse to its taste. Preference for consuming ethanol is not entirely explained by attraction to either its sensory or caloric properties. We demonstrate that flies can exhibit features of alcohol addiction. First, flies self-administer ethanol to pharmacologically relevant concentrations. Second, flies will overcome an aversive stimulus in order to consume ethanol. Third, flies rapidly return to high levels of ethanol consumption after a period of imposed abstinence. Thus, ethanol preference in Drosophila provides a new model for studying aspects of addiction.

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    12/08/09 | Glycogen synthase kinase-3/Shaggy mediates ethanol-induced excitotoxic cell death of Drosophila olfactory neurons.
    French RL, Heberlein U
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Dec 8;106(49):20924-9. doi: 10.1073/pnas.0910813106

    It has long been known that heavy alcohol consumption leads to neuropathology and neuronal death. While the response of neurons to an ethanol insult is strongly influenced by genetic background, the underlying mechanisms are poorly understood. Here, we show that even a single intoxicating exposure to ethanol causes non-cell-autonomous apoptotic death specifically of Drosophila olfactory neurons, which is accompanied by a loss of a behavioral response to the smell of ethanol and a blackening of the third antennal segment. The Drosophila homolog of glycogen synthase kinase-3 (GSK-3)beta, Shaggy, is required for ethanol-induced apoptosis. Consistent with this requirement, the GSK-3beta inhibitor lithium protects against the neurotoxic effects of ethanol, indicating the possibility for pharmacological intervention in cases of alcohol-induced neurodegeneration. Ethanol-induced death of olfactory neurons requires both their neural activity and functional NMDA receptors. This system will allow the investigation of the genetic and molecular basis of ethanol-induced apoptosis in general and provide an understanding of the molecular role of GSK-3beta in programmed cell death.

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    09/01/09 | Genetic aspects of behavioral neurotoxicology.
    Levin ED, Aschner M, Heberlein U, Ruden D, Welsh-Bohmer KA, Bartlett S, Berger K, Chen L, Corl AB, Eddins D, French R, Hayden KM, Helmcke K, Hirsch HV, Linney E, Lnenicka G, Page GP, Possidente D, Possidente B, Kirshner A
    Neurotoxicology. 2009 Sep;30(5):741-53. doi: 10.1016/j.neuro.2009.07.014

    Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.

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    08/13/09 | Too fat to fly? New brain circuits regulate obesity in Drosophila.
    Kaun KR, Heberlein U
    Neuron. 2009 Aug 13;63(3):279-81. doi: 10.1016/j.neuron.2009.07.023

    In mammals, fat store levels are regulated by brain centers that control food intake and metabolism. A new study by Al-Anzi and colleagues in this issue of Neuron identifies neurons with similar functions in Drosophila, further establishing the fly as a legitimate model to study obesity.

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    07/24/09 | Drosophila, a genetic model system to study cocaine-related behaviors: a review with focus on LIM-only proteins.
    Heberlein U, Tsai LT, Kapfhamer D, Lasek AW
    Neuropharmacology. 2009;56 Suppl 1:97-106. doi: 10.1016/j.neuropharm.2008.07.023

    In the last decade, the fruit fly Drosophila melanogaster, highly accessible to genetic, behavioral and molecular analyses, has been introduced as a novel model organism to help decipher the complex genetic, neurochemical, and neuroanatomical underpinnings of behaviors induced by drugs of abuse. Here we review these data, focusing specifically on cocaine-related behaviors. Several of cocaine's most characteristic properties have been recapitulated in Drosophila. First, cocaine induces motor behaviors in flies that are remarkably similar to those observed in mammals. Second, repeated cocaine administration induces behavioral sensitization a form of behavioral plasticity believed to underlie certain aspects of addiction. Third, a key role for dopaminergic systems in mediating cocaine's effects has been demonstrated through both pharmacological and genetic methods. Finally, and most importantly, unbiased genetic screens, feasible because of the simplicity and scale with which flies can be manipulated in the laboratory, have identified several novel genes and pathways whose role in cocaine behaviors had not been anticipated. Many of these genes and pathways have been validated in mammalian models of drug addiction. We focus in this review on the role of LIM-only proteins in cocaine-induced behaviors.

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    07/07/09 | Oviposition preference for and positional avoidance of acetic acid provide a model for competing behavioral drives in Drosophila.
    Joseph RM, Devineni AV, King IF, Heberlein U
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Jul 7;106(27):11352-7. doi: 10.1073/pnas.0901419106

    Selection of appropriate oviposition sites is essential for progeny survival and fitness in generalist insect species, such as Drosophila melanogaster, yet little is known about the mechanisms regulating how environmental conditions and innate adult preferences are evaluated and balanced to yield the final substrate choice for egg-deposition. Female D. melanogaster are attracted to food containing acetic acid (AA) as an oviposition substrate. However, our observations reveal that this egg-laying preference is a complex process, as it directly opposes an otherwise strong, default behavior of positional avoidance for the same food. We show that 2 distinct sensory modalities detect AA. Attraction to AA-containing food for the purpose of egg-laying relies on the gustatory system, while positional repulsion depends primarily on the olfactory system. Similarly, distinct central brain regions are involved in AA attraction and repulsion. Given this unique situation, in which a single environmental stimulus yields 2 opposing behavioral outputs, we propose that the interaction of egg-laying attraction and positional aversion for AA provides a powerful model for studying how organisms balance competing behavioral drives and integrate signals involved in choice-like processes.

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    05/29/09 | Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors.
    Corl AB, Berger KH, Ophir-Shohat G, Gesch J, Simms JA, Bartlett SE, Heberlein U
    Cell. 2009 May 29;137(5):949-60. doi: 10.1016/j.cell.2009.03.020

    The consequences of alcohol use disorders (AUDs) are devastating to individuals and society, yet few treatments are currently available. To identify genes regulating the behavioral effects of ethanol, we conducted a genetic screen in Drosophila and identified a mutant, happyhour (hppy), due to its increased resistance to the sedative effects of ethanol. Hppy protein shows strong homology to mammalian Ste20 family kinases of the GCK-1 subfamily. Genetic and biochemical experiments revealed that the epidermal growth factor (EGF)-signaling pathway regulates ethanol sensitivity in Drosophila and that Hppy functions as an inhibitor of the pathway. Acute pharmacological inhibition of the EGF receptor (EGFR) in adult animals altered acute ethanol sensitivity in both flies and mice and reduced ethanol consumption in a preclinical rat model of alcoholism. Inhibitors of the EGFR or components of its signaling pathway are thus potential pharmacotherapies for AUDs.

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    02/26/09 | Sensory neurons in the Drosophila genital tract regulate female reproductive behavior.
    Häsemeyer M, Yapici N, Heberlein U, Dickson BJ
    Neuron. 2009 Feb 26;61(4):511-8. doi: 10.1016/j.neuron.2009.01.009

    Females of many animal species behave very differently before and after mating. In Drosophila melanogaster, changes in female behavior upon mating are triggered by the sex peptide (SP), a small peptide present in the male's seminal fluid. SP activates a specific receptor, the sex peptide receptor (SPR), which is broadly expressed in the female reproductive tract and nervous system. Here, we pinpoint the action of SPR to a small subset of internal sensory neurons that innervate the female uterus and oviduct. These neurons express both fruitless (fru), a marker for neurons likely to have sex-specific functions, and pickpocket (ppk), a marker for proprioceptive neurons. We show that SPR expression in these fru+ ppk+ neurons is both necessary and sufficient for behavioral changes induced by mating. These neurons project to regions of the central nervous system that have been implicated in the control of reproductive behaviors in Drosophila and other insects.

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