The central nervous system is made from a limited number of microcircuit motifs. Our long-term goal is to unravel the general principles of the elementary microcircuits. In this study, we focus on the contribution of synaptic modulation to circuit function, sensory processing and animal behavior. GABA is the major inhibitory neurotransmitter in the central nervous system and plays a key role in synaptic modulation. GABA exerts its modulatory role via two distinct receptor systems, the fast ionotropic GABAA and the slow metabotropic GABAB receptors. There is good evidence from human clinical trials and animal experiments to suggest that GABAB receptor agonists reduce the craving for drugs such as cocaine, heroin, alcohol, and nicotine. The molecular cloning of GABAB receptors report a lack of heterogeneity, suggesting limited possibilities for selective interference with the GABAB receptors to avoid side effects in pharmacotherapy. Selection of alternative targets in the GABAB system could be aided by a deeper understanding of the GABAB receptor mediated synaptic modulation in basic neural circuits. GABAB receptor mediated synaptic modulation is the focus of this study. The anatomical simplicity and the power of genetics make Drosophila a particularly amenable system to investigate the contribution of synaptic modulation to circuit function as well as behavioral output. We have obtained evidence showing that Drosophila odorant receptor neurons express GABAB receptors and the activation of GABAB receptors causes presynaptic inhibition. We adopt a multidisciplinary approach that combines molecular genetics, behavioral studies, and optical imaging to study GABAB receptor mediated feedback inhibition in the olfactory system, and also its contribution to olfactory behaviors. Studies of such defined olfactory circuit should shed light on the general principles of synaptic modulation and feedback inhibition. These general principles should also guide target selection for future therapeutic interventions.

Public Health Relevance

There is good evidence from human clinical trials and animal experiments to suggest that GABAB receptor agonists reduce the craving for drugs such as cocaine, heroin, alcohol, and nicotine. However, a selective interference with the GABAB receptors without side effect is limited by the lack of receptor heterogeneity. The work of this proposal is basic science that seeks to reveal the mechanisms of the GABAB system in synaptic modulation and circuit function, creating a knowledge base from which alternative targets in the GABAB system can be evaluated for future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009597-05
Application #
8274322
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Sullivan, Susan L
Project Start
2008-06-20
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$288,209
Indirect Cost
$96,545
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lin, Hui-Hao; Cao, De-Shou; Sethi, Sachin et al. (2016) Hormonal Modulation of Pheromone Detection Enhances Male Courtship Success. Neuron 90:1272-85
Kim, Susy M; Wang, Jing W (2016) Hygrosensation: Feeling Wet and Cold. Curr Biol 26:R408-10
Ko, Kang I; Root, Cory M; Lindsay, Scott A et al. (2015) Starvation promotes concerted modulation of appetitive olfactory behavior via parallel neuromodulatory circuits. Elife 4:
Sen, Sonia; Cao, Deshou; Choudhary, Ramveer et al. (2014) Genetic transformation of structural and functional circuitry rewires the Drosophila brain. Elife 3:
Chihara, Takahiro; Kitabayashi, Aki; Morimoto, Michie et al. (2014) Caspase inhibition in select olfactory neurons restores innate attraction behavior in aged Drosophila. PLoS Genet 10:e1004437
Su, Chih-Ying; Wang, Jing W (2014) Modulation of neural circuits: how stimulus context shapes innate behavior in Drosophila. Curr Opin Neurobiol 29:9-16
Root, Cory M; Wong, Allan M; Flores, Jorge et al. (2013) Calcium imaging in the Drosophila olfactory system with a genetic indicator. Cold Spring Harb Protoc 2013:
Zaninovich, Orel A; Kim, Susy M; Root, Cory R et al. (2013) A single-fly assay for foraging behavior in Drosophila. J Vis Exp :e50801
Wang, Jing W (2012) Presynaptic modulation of early olfactory processing in Drosophila. Dev Neurobiol 72:87-99
Zhou, Chuan; Huang, Hai; Kim, Susy M et al. (2012) Molecular genetic analysis of sexual rejection: roles of octopamine and its receptor OAMB in Drosophila courtship conditioning. J Neurosci 32:14281-7

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