@article {4525, title = {Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {31}, year = {2011}, month = {2011 Jan 19}, pages = {1139-48}, abstract = {

In both mammalian and insect models of ethanol-induced behavior, low doses of ethanol stimulate locomotion. However, the mechanisms of the stimulant effects of ethanol on the CNS are mostly unknown. We have identified tao, encoding a serine-threonine kinase of the Ste20 family, as a gene necessary for ethanol-induced locomotor hyperactivity in Drosophila. Mutations in tao also affect behavioral responses to cocaine and nicotine, making flies resistant to the effects of both drugs. We show that tao function is required during the development of the adult nervous system and that tao mutations cause defects in the development of central brain structures, including the mushroom body. Silencing of a subset of mushroom body neurons is sufficient to reduce ethanol-induced hyperactivity, revealing the mushroom body as an important locus mediating the stimulant effects of ethanol. We also show that mutations in par-1 suppress both the mushroom body morphology and behavioral phenotypes of tao mutations and that the phosphorylation state of the microtubule-binding protein Tau can be altered by RNA interference knockdown of tao, suggesting that tao and par-1 act in a pathway to control microtubule dynamics during neural development.

}, keywords = {Analysis of Variance, Animal, Animals, Behavior, Biological, Blotting, Drosophila, Drosophila Proteins, Ethanol, Hyperkinesis, Immunohistochemistry, Metamorphosis, Motor Activity, Mushroom Bodies, Neurons, Protein-Serine-Threonine Kinases, Western}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4416-10.2011}, author = {King, Ian and Tsai, Linus T-Y and Pflanz, Ralf and Voigt, Aaron and Lee, Seongsoo and J{\"a}ckle, Herbert and Lu, Bingwei and Heberlein, Ulrike} } @article {46623, title = {Drosophila, a genetic model system to study cocaine-related behaviors: a review with focus on LIM-only proteins.}, journal = {Neuropharmacology}, volume = {56 Suppl 1}, year = {2009}, month = {2009}, pages = {97-106}, abstract = {

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{\textquoteright}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{\textquoteright}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.

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, Cocaine, Cocaine-Related Disorders, Disease Models, Animal, Dopamine Uptake Inhibitors, Drosophila melanogaster, Drosophila Proteins, Homeodomain Proteins, Models, Genetic}, issn = {0028-3908}, doi = {10.1016/j.neuropharm.2008.07.023}, author = {Heberlein, Ulrike and Tsai, Linus T-Y and Kapfhamer, David and Lasek, Amy W} } @article {5487, title = {Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms.}, journal = {Cell}, volume = {127}, year = {2006}, month = {2006 Oct 6}, pages = {199-211}, abstract = {

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.

}, keywords = {Animal, Animals, Behavior, Brain, Central Nervous System Depressants, Drosophila melanogaster, Drosophila Proteins, Enzyme Activation, Ethanol, Female, GTPase-Activating Proteins, Humans, Molecular Sequence Data, Motor Activity, Mutation, Protein Isoforms, Rabbits, rho GTP-Binding Proteins, Transgenes}, issn = {0092-8674}, doi = {10.1016/j.cell.2006.09.010}, author = {Rothenfluh, Adrian and Threlkeld, Robert J and Bainton, Roland J and Tsai, Linus T-Y and Lasek, Amy W and Heberlein, Ulrike} } @article {5488, title = {Moody encodes two GPCRs that regulate cocaine behaviors and blood-brain barrier permeability in Drosophila.}, journal = {Cell}, volume = {123}, year = {2005}, month = {2005 Oct 7}, pages = {145-56}, abstract = {

We identified moody in a genetic screen for Drosophila mutants with altered cocaine sensitivity. Hypomorphic mutations in moody cause an increased sensitivity to cocaine and nicotine exposure. In contrast, sensitivity to the acute intoxicating effects of ethanol is reduced. The moody locus encodes two novel GPCRs, Moody-alpha and Moody-beta. While identical in their membrane-spanning domains, the two Moody proteins differ in their long carboxy-terminal domains, which are generated by use of alternative reading frames. Both Moody forms are required for normal cocaine sensitivity, suggesting that they carry out distinct but complementary functions. Moody-alpha and Moody-beta are coexpressed in surface glia that surround the nervous system, where they are actively required to maintain the integrity of the blood-brain barrier in the adult fly. We propose that a Moody-mediated signaling pathway functions in glia to regulate nervous system insulation and drug-related behaviors.

}, keywords = {Alternative Splicing, Animal, Animals, Behavior, Blood-Brain Barrier, Brain, Cocaine, Cocaine-Related Disorders, Disease Models, Dopamine Uptake Inhibitors, Drosophila melanogaster, Drosophila Proteins, Drug Tolerance, G-Protein-Coupled, Male, Motor Activity, Neuroglia, Nicotine, Protein Structure, Receptors, Substance-Related Disorders, Tertiary}, issn = {0092-8674}, doi = {10.1016/j.cell.2005.07.029}, author = {Bainton, Roland J and Tsai, Linus T-Y and Schwabe, Tina and DeSalvo, Michael and Gaul, Ulrike and Heberlein, Ulrike} } @article {5491, title = {Lmo mutants reveal a novel role for circadian pacemaker neurons in cocaine-induced behaviors.}, journal = {PLoS Biology}, volume = {2}, year = {2004}, month = {2004 Dec}, pages = {e408}, abstract = {

Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LN(v)s), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LN(v)function,Lmomutants also show defects in circadian rhythms of behavior. However, the role for LN(v)s in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LN(v)s reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LN(v)s to cocaine, which in turn regulate the flies{\textquoteright} behavioral sensitivity to the drug.

}, keywords = {Alleles, Animal, Animals, Behavior, Biological, Biological Clocks, Circadian Rhythm, Cocaine, Drosophila melanogaster, Drosophila Proteins, Gene Expression Regulation, Gene Silencing, Genetic, Homeodomain Proteins, Models, Mutation, Neurons, Neuropeptides, Neurotransmitter Agents, Protein Structure, Reverse Transcriptase Polymerase Chain Reaction, Tertiary}, issn = {1545-7885}, doi = {10.1371/journal.pbio.0020408}, author = {Tsai, Linus T-Y and Bainton, Roland J and Blau, Justin and Heberlein, Ulrike} } @article {5492, title = {High-resolution analysis of ethanol-induced locomotor stimulation in Drosophila.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {22}, year = {2002}, month = {2002 Dec 15}, pages = {11035-44}, abstract = {

Understanding how ethanol influences behavior is key to deciphering the mechanisms of ethanol action and alcoholism. In mammals, low doses of ethanol stimulate locomotion, whereas high doses depress it. The acute stimulant effect of ethanol has been proposed to be a manifestation of its rewarding effects. In Drosophila, ethanol exposure transiently potentiates locomotor activity in a biphasic dose- and time-dependent manner. An initial short-lived peak of activity corresponds to an olfactory response to ethanol. A second, longer-lasting period of increased activity coincides with rising internal ethanol concentrations; these closely parallel concentrations that stimulate locomotion in mammals. High-resolution analysis of the walking pattern of individual flies revealed that locomotion consists of bouts of activity; bout structure can be quantified by bout frequency, bout length, and the time spent walking at high speeds. Ethanol exposure induces both dramatic and dynamic changes in bout structure. Mutants with increased ethanol sensitivity show distinct changes in ethanol-induced locomotor behavior, as well as genotype-specific changes in activity bout structure. Thus, the overall effect of ethanol on locomotor behavior in Drosophila is caused by changes in discrete quantifiable parameters of walking pattern. The effects of ethanol on locomotion are comparable in flies and mammals, suggesting that Drosophila is a suitable model system to study the underlying mechanisms.

}, keywords = {Afferent Pathways, Animal, Animals, Automation, Behavior, Cyclic AMP, Dose-Response Relationship, Drosophila, Drug, Ethanol, Kinetics, Locomotion, Male, Mutation, Sensitivity and Specificity}, issn = {1529-2401}, author = {Wolf, Fred W and Rodan, Aylin R and Tsai, Linus T-Y and Heberlein, Ulrike} }