The trace amine, tyramine, has been implicated in a variety of human neurological disorders, including depression, migraine, schizophrenia and drug abuse. Although the role of tyramine in the CNS is poorly understood, the recent characterization of mammalian G-protein coupled receptors that can be activated by tyramine has aroused new interest in the role of tyramine in human physiology and disease. The long-term objective of this proposal is to understand how tyramine operates at the molecular, cellular, and neural circuit level to control behaviors. To this end, mechanisms of tyraminergic signaling will be analyzed in the simple nervous system of the nematode Caenorhabditis elegans. Our analysis has established that C. elegans has distinct tyraminergic cells and that tyramine regulates several behaviors. This project will use a combination of pharmacological, genetic, and electrophysiological techniques to understand tyramine function. Analysis of the pharmacological and expression profile of SHO-1, a novel ionotropic tyramine receptor isolated in our laboratory, will provide insight into how it modulates the output of distinct neural circuits. Behavioral analysis of sho-1 mutants, together with that of mutants for the G-protein coupled tyramine receptors ser-2 and tyra-2, should reveal how ionotropic and metabotropic pathways coordinately control tyramine dependent behaviors. Electrophysiological analysis of tyramine synaptic transmission at the neuromuscular junction should establish how tyramine affects postsynaptic properties. Lastly, an unbiased genetic screen will be conducted to search for mutants resistant to exogenous tyramine. Characterization of such mutants should identify novel signaling components and elucidate the signaling events downstream of tyramine receptors. These experiments will provide a multi-level perspective on how tyramine changes the output of neural circuits and controls animal behavior. Given tyramine's link with neurological disorders, these studies should ultimately accelerate our understanding of tyramine function in human physiology and disease.

Public Health Relevance

Although the brain chemical, tyramine, is linked to a large variety of neurological disorders, including drug addiction, depression, attention hyper deficit disorders, Parkinson's disease, schizophrenia and headaches, little is known about its function. Since much of our understanding in human disease has come from studies of simple organisms like the round worm, Caenorhabditis elegans, we propose to study how tyramine controls behavior of this animal at the molecular and cellular level. Our studies will provide a better understanding of the functional role of tyramine in the brain, with the ultimate goal of treatment and prevention of human neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084491-05
Application #
8214652
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Gindhart, Joseph G
Project Start
2008-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$322,453
Indirect Cost
$126,433
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Venkatachalam, Vivek; Ji, Ni; Wang, Xian et al. (2016) Pan-neuronal imaging in roaming Caenorhabditis elegans. Proc Natl Acad Sci U S A 113:E1082-8
Pirri, Jennifer K; Rayes, Diego; Alkema, Mark J (2015) A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior. PLoS Biol 13:e1002238
Nagy, Stanislav; Huang, Yung-Chi; Alkema, Mark J et al. (2015) Caenorhabditis elegans exhibit a coupling between the defecation motor program and directed locomotion. Sci Rep 5:17174
Fang-Yen, Christopher; Alkema, Mark J; Samuel, Aravinthan D T (2015) Illuminating neural circuits and behaviour in Caenorhabditis elegans with optogenetics. Philos Trans R Soc Lond B Biol Sci 370:20140212
Oh, Kelly H; Abraham, Linu S; Gegg, Chandler et al. (2015) Presynaptic BK channel localization is dependent on the hierarchical organization of alpha-catulin and dystrobrevin and fine-tuned by CaV2 calcium channels. BMC Neurosci 16:26
Sun, Lin; Shay, James; McLoed, Melissa et al. (2014) Neuronal regeneration in C. elegans requires subcellular calcium release by ryanodine receptor channels and can be enhanced by optogenetic stimulation. J Neurosci 34:15947-56
Shipley, Frederick B; Clark, Christopher M; Alkema, Mark J et al. (2014) Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans. Front Neural Circuits 8:28
Bhattacharya, Raja; Touroutine, Denis; Barbagallo, Belinda et al. (2014) A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior. PLoS Genet 10:e1004584
Donnelly, Jamie L; Clark, Christopher M; Leifer, Andrew M et al. (2013) Monoaminergic orchestration of motor programs in a complex C. elegans behavior. PLoS Biol 11:e1001529
Homberg, Uwe; Seyfarth, Jutta; Binkle, Ulrike et al. (2013) Identification of distinct tyraminergic and octopaminergic neurons innervating the central complex of the desert locust, Schistocerca gregaria. J Comp Neurol 521:2025-41

Showing the most recent 10 out of 16 publications