Jill C. Bettinger, Ph.D.
Department: Department of Pharmacology and Toxicology
Phone: (804) 828-2072
Molecular Medicine Research Building, Room 3034
1220 East Broad Street
- University of Minnesota, 1998
My lab uses C. elegans genetics to address questions of neurobiology related to synaptic transmission and behavior, specifically as they relate to the physiological effects of alcohol. Alcohol abuse is a devastating and pervasive problem throughout the world. Current drug treatments are inadequate, and a primary difficulty with the development of novel treatments for alcoholism is that the molecular nature of the interaction of the nervous system with the drug is not completely understood. Alcohol is a small, easily diffusible molecule that probably interacts with a large number of proteins in all neurons. A cardinal challenge for researchers is to determine which interactions are important for altering nervous system function, and ultimately, for the development of addiction.
C. elegans is an excellent model for the study of the neurobiology of behavior. Its extremely simple and well-characterized nervous system — 302 neurons — contains at least 118 different neuronal cell types and uses many of the same neurotransmitters that are used by the mammalian brain. The use of C. elegans genetics provides a facile means of dissecting nervous system function and can be used effectively to address questions of drug impact on neurons.
I am particularly interested in questions of synaptic plasticity, and we have found that ethanol induces at least two types of plasticity in the worm that are also observed in humans: the development of acute tolerance and state-dependency of learned behaviors. My research focuses on understanding the molecular mechanisms of these behaviors as tractable models of neuronal plasticity.
When animals, including worms and humans, are exposed to a constant concentration of ethanol for an extended period of time, they undergo a homeostatic neural adaptation referred to as development of acute tolerance, the result of which is that animals appear to be less intoxicated over time. We have found that the NPR-1 protein, a G protein-coupled receptor of the NPY receptor family, controls the rate at which animals can develop acute tolerance to ethanol (Davies et al., 2004). We are using forward genetics to explore the mechanisms of development of acute tolerance.
I am also investigating the effects of ethanol on a more complex behavior, state-dependent learning. By pairing alcohol administration with olfactory adaptation, I demonstrated a form of state-dependent learning in C. elegans (Bettinger and McIntire, 2004). Ethanol does not interfere with olfactory adaptation; however, worms exposed to an odorant while being treated with ethanol will only show subsequent adaptation to the odorant if ethanol is again administered during chemotaxis testing. Furthermore, I demonstrated that this effect requires dopaminergic function. This system provides an opportunity to pursue a molecular understanding of state-dependent learning and the molecular mechanisms of associative learning in general. We are using the state-dependent learning paradigm as a genetic screening tool to uncover molecules involved in associative learning.
Mathies, L.D., Blackwell, G.G., Austin, M.K., Edwards, A.C., Riley, B.P., Davies, A.G., Bettinger, J.C. (2015) SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans. PNAS 2015 Mar 10;112(10):3032-7
Hawkins, E.G., Martin, I., Kondo, L.M., Judy, M.E., Brings, V.E., Chan, C.-L., Blackwell, G.G., Bettinger, J.C., Davies, A.G. (2015) A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans. Genetics Jan;199(1):135-49
Raabe, R.C., Mathies, L.D., Davies, A.G., Bettinger, J.C. (2014) The omega-3 fatty acid eicosapentaenoic acid is required for normal alcohol response behaviors in C. elegans. PLoS One 9:e105999.
Zhang Z., Tang Q.Y., Alaimo J.T., Davies A.G., Bettinger J.C., Logothetis D.E. (2013) SLO-2 isoforms with unique Ca(2+) – and voltage-dependence characteristics confer sensitivity to hypoxia in C. elegans. Channels (Austin) 7: 194-205.
Davies, A.G., Friedberg, R.I., Gupta, H., Chan, C.-L., Shelton, K.L., Bettinger, J.C. (2012) Different genes influence toluene- and ethanol-induced locomotor impairment in C. elegans. Drug Alcohol Depend. 122: 47-54.
Bhandari, P., Hill, J.S., Farris, S.P., Costin, B., Martin, I., Chan, C.-L., Alaimo, J.T., Bettinger, J.C., Davies, A.G., Miles, M.F., Grotewiel, M. (2012) Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, C. elegans and mice. Genes Brain Behav. 11:387-397.
Bettinger, J.C., Leung, K. Bolling, M.H., Goldsmith, A.D., Davies, A.G. (2012) Lipid environment modulates the development of acute tolerance in Caenorhabditis elegans. PLoS One 7(5):e35192.
Alaimo, J.T., Davis, S.J., Song, S.S., Burnette, C.R., Grotewiel, M., Shelton, K.L., Pierce-Shimomura, J.T., Davies, A.G., Bettinger, J.C. (2012) Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans. Alcohol. Clin. Exp. Res. 36:1840-1850.