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94 Publications

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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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    08/01/08 | Loss of RAB-3/A in Caenorhabditis elegans and the mouse affects behavioral response to ethanol.
    Kapfhamer D, Bettinger JC, Davies AG, Eastman CL, Smail EA, Heberlein U, McIntire SL
    Genes, Brain, and Behavior. 2008 Aug;7(6):669-76. doi: 10.1111/j.1601-183X.2008.00404.x

    The mechanisms by which ethanol induces changes in behavior are not well understood. Here, we show that Caenorhabditis elegans loss-of-function mutations in the synaptic vesicle-associated RAB-3 protein and its guanosine triphosphate exchange factor AEX-3 confer resistance to the acute locomotor effects of ethanol. Similarly, mice lacking one or both copies of Rab3A are resistant to the ataxic and sedative effects of ethanol, and Rab3A haploinsufficiency increases voluntary ethanol consumption. These data suggest a conserved role of RAB-3-/RAB3A-regulated neurotransmitter release in ethanol-related behaviors.

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    05/01/08 | Ethanol sensitivity and tolerance in long-term memory mutants of Drosophila melanogaster.
    Berger KH, Kong EC, Dubnau J, Tully T, Moore MS, Heberlein U
    Alcoholism, Clinical and Experimental Research. 2008 May;32(5):895-908. doi: 10.1111/j.1530-0277.2008.00659.x

    BACKGROUND: It has become increasingly clear that molecular and neural mechanisms underlying learning and memory and drug addiction are largely shared. To confirm and extend these findings, we analyzed ethanol-responsive behaviors of a collection of Drosophila long-term memory mutants.

    METHODS: For each mutant, sensitivity to the acute uncoordinating effects of ethanol was quantified using the inebriometer. Additionally, 2 distinct forms of ethanol tolerance were measured: rapid tolerance, which develops in response to a single brief exposure to a high concentration of ethanol vapor; and chronic tolerance, which develops following a sustained low-level exposure.

    RESULTS: Several mutants were identified with altered sensitivity, rapid or chronic tolerance, while a number of mutants exhibited multiple defects.

    CONCLUSIONS: The corresponding genes in these mutants represent areas of potential overlap between learning and memory and behavioral responses to alcohol. These genes also define components shared between different ethanol behavioral responses.

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    04/01/08 | Genetic dissociation of ethanol sensitivity and memory formation in Drosophila melanogaster.
    LaFerriere H, Guarnieri DJ, Sitaraman D, Diegelmann S, Heberlein U, Zars T
    Genetics. 2008 Apr;178(4):1895-902. doi: 10.1534/genetics.107.084582

    The ad hoc genetic correlation between ethanol sensitivity and learning mechanisms in Drosophila could overemphasize a common process supporting both behaviors. To challenge directly the hypothesis that these mechanisms are singular, we examined the learning phenotypes of 10 new strains. Five of these have increased ethanol sensitivity, and the other 5 do not. We tested place and olfactory memory in each of these lines and found two new learning mutations. In one case, altering the tribbles gene, flies have a significantly reduced place memory, elevated olfactory memory, and normal ethanol response. In the second case, mutation of a gene we name ethanol sensitive with low memory (elm), place memory was not altered, olfactory memory was sharply reduced, and sensitivity to ethanol was increased. In sum, however, we found no overall correlation between ethanol sensitivity and place memory in the 10 lines tested. Furthermore, there was a weak but nonsignificant correlation between ethanol sensitivity and olfactory learning. Thus, mutations that alter learning and sensitivity to ethanol can occur independently of each other and this implies that the set of genes important for both ethanol sensitivity and learning is likely a subset of the genes important for either process.

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    11/01/07 | Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice.
    Lasek AW, Janak PH, He L, Whistler JL, Heberlein U
    Genes, Brain, and Behavior. 2007 Nov;6(8):728-35. doi: 10.1111/j.1601-183X.2007.00303.x

    Pharmacological and genetic studies have implicated the mu opioid receptor (MOR) in the regulation of ethanol intake in animal models and humans. Non-specific antagonists of opioid receptors have been shown to affect ethanol consumption when infused directly into the ventral tegmental area (VTA) of rats. However, administration of MOR-selective antagonists into the VTA has yielded mixed results. We used RNA interference (RNAi) to specifically decrease levels of MOR messenger RNA in the VTA of mice and examined the effect on ethanol consumption in a two-bottle choice paradigm. Mice were injected in the VTA with lentivirus expressing either a small hairpin RNA (shRNA) targeting MOR or a control shRNA. One week after virus injection, mice were examined for ethanol consumption in a two-bottle choice experiment with increasing concentrations of ethanol over the course of 1 month. Expression of an shRNA targeting MOR in the VTA led to a significant reduction in ethanol consumption. These results strengthen the hypothesis that MOR in the VTA is one of the key brain substrates mediating alcohol consumption. The RNAi combined with lentiviral delivery can be used successfully in brain to effect a sustained reduction in expression of specific genes for behavioral analysis.

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    03/13/07 | GSK-3/Shaggy regulates olfactory habituation in Drosophila.
    Wolf FW, Eddison M, Lee S, Cho W, Heberlein U
    Proceedings of the National Academy of Sciences of the United States of America. 2007 Mar 13;104(11):4653-7. doi: 10.1073/pnas.0700493104

    Habituation is a universal form of nonassociative learning that results in the devaluation of sensory inputs that have little information content. Although habituation is found throughout nature and has been studied in many organisms, the underlying molecular mechanisms remain poorly understood. We performed a forward genetic screen in Drosophila to search for mutations that modified habituation of an olfactory-mediated locomotor startle response, and we isolated a mutation in the glycogen synthase kinase-3 (GSK-3) homolog Shaggy. Decreases in Shaggy levels blunted habituation, whereas increases promoted habituation. Additionally, habituation acutely regulated Shaggy by an inhibitory phosphorylation mechanism, suggesting that a signal transduction pathway that regulates Shaggy is engaged during habituation. Although shaggy mutations also affected circadian rhythm period, this requirement was genetically separable from its role in habituation. Thus, shaggy functions in different neuronal circuits to regulate behavioral plasticity to an olfactory startle and circadian rhythmicity.

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    02/01/07 | Guidelines on nicotine dose selection for in vivo research.
    Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, Craig CR, Collins AC, Damaj MI, Donny EC, Gardiner PS, Grady SR, Heberlein U, Leonard SS, Levin ED, Lukas RJ, Markou A, Marks MJ, McCallum SE, Parameswaran N, Perkins KA, Picciotto MR, Quik M, Rose JE, Rothenfluh A, Schafer WR, Stolerman IP, Tyndale RF, Wehner JM, Zirger JM
    Psychopharmacology (Berl). 2007 Feb;190(3):269-319. doi: 10.1007/s00213-006-0441-0

    RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.

    OBJECTIVES: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.

    RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.

    CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

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    10/06/06 | Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms.
    Rothenfluh A, Threlkeld RJ, Bainton RJ, Tsai LT, Lasek AW, Heberlein U
    Cell. 2006 Oct 6;127(1):199-211. doi: 10.1016/j.cell.2006.09.010

    In most organisms, low ethanol doses induce increased activity, while high doses are sedating. To investigate the underlying mechanisms, we isolated Drosophila mutants with altered ethanol responsiveness. Mutations in white rabbit (whir), disrupting RhoGAP18B, are strongly resistant to the sedating effects of ethanol. This resistance can be suppressed by reducing the levels of Rho1 or Rac, implicating these GTPases in the behavioral response to ethanol. Indeed, expression of constitutively active forms of Rho1 or Rac1 in adult flies results in ethanol resistance similar to that observed in whir mutants. The whir locus produces several transcripts, RA-RD, which are predicted to encode three distinct RhoGAPs that share only the GAP domain. The RC transcript mediates the sedating effects of ethanol, while the RA transcript regulates its stimulant effects. Thus, distinct RhoGAPs, encoded by the same gene, regulate different manifestations of acute ethanol intoxication.

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