The goal of this proposal is to study the mechanisms by which insulin-like peptides and the insulin receptor pathway regulate ethanol-induced behaviors in Drosophila and in mice This idea emerged from the convergence of two independent lines of investigation. First, previous genetic screens for Drosophila mutants with altered ethanol sensitivity identified mutations in several components of the insulin receptor signaling pathway. Second, neuroanatomical mapping experiments in Drosophila revealed that a group of insulin producing neurosecretory cells controls normal ethanol sensitivity. We therefore postulate that the insulin pathway, well known for its role in regulating metabolism, growth, and life span, is also involved in the regulation of ethanol-related behaviors. Here we propose to use genetic, and molecular approaches to define how, when, and where insulin functions in ethanol sensitivity in Drosophila and to begin the translation of this information to a mammalian system. First, we will study the role of insulin-producing cells in ethanol-related behaviors. Second, we will use a collection of existing mutants and transgenic fly strains, which are known to inhibit or activate various components of the insulin receptor pathway, to define additional signaling molecules and to establish their functional relationships. Third, we will use inducible gene expression strategies to determine if the insulin pathway functions during development or adulthood to regulate ethanol-induced behaviors. Fourth, we will study the functional relationship between insulin-like peptides and the neuropeptide encoded by the amnesiac gene, which was previously shown to regulate ethanol sensitivity. Finally, we will test if this signaling pathway plays a role ethanol-related behaviors in mice. ? ? The role of the insulin pathway in regulating growth, metabolism, and life span has been shown to be conserved from invertebrates to mammals. We predict that this functional conservation will hold for ethanol related phenomena. As drugs that target components of the insulin pathway are already available, information gained from studies in flies and mice could be readily transferred to people with alcohol abuse or alcoholism problems. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010035-13
Application #
7324124
Study Section
Genetics Study Section (GEN)
Program Officer
Noronha, Antonio
Project Start
1999-02-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
13
Fiscal Year
2008
Total Cost
$323,210
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Yang, Cindy F; Shah, Nirao M (2014) Representing sex in the brain, one module at a time. Neuron 82:261-78
Kapfhamer, D; Taylor, S; Zou, M E et al. (2013) Taok2 controls behavioral response to ethanol in mice. Genes Brain Behav 12:87-97
McClure, Kimberly D; Heberlein, Ulrike (2013) A small group of neurosecretory cells expressing the transcriptional regulator apontic and the neuropeptide corazonin mediate ethanol sedation in Drosophila. J Neurosci 33:4044-54
Shohat-Ophir, G; Kaun, K R; Azanchi, R et al. (2012) Sexual deprivation increases ethanol intake in Drosophila. Science 335:1351-5
Eddison, Mark; Belay, Amsale T; Sokolowski, Marla B et al. (2012) A genetic screen for olfactory habituation mutations in Drosophila: analysis of novel foraging alleles and an underlying neural circuit. PLoS One 7:e51684
Maiya, Rajani; Lee, Seonok; Berger, Karen H et al. (2012) DlgS97/SAP97, a neuronal isoform of discs large, regulates ethanol tolerance. PLoS One 7:e48967
Joseph, Ryan M; Heberlein, Ulrike (2012) Tissue-specific activation of a single gustatory receptor produces opposing behavioral responses in Drosophila. Genetics 192:521-32
Devineni, Anita V; Heberlein, Ulrike (2012) Acute ethanol responses in Drosophila are sexually dimorphic. Proc Natl Acad Sci U S A 109:21087-92
Kapfhamer, David; King, Ian; Zou, Mimi E et al. (2012) JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity. PLoS One 7:e50594
Kaun, Karla R; Azanchi, Reza; Maung, Zaw et al. (2011) A Drosophila model for alcohol reward. Nat Neurosci 14:612-9

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