Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL
Cell 2003 Dec;115(6):655-66
The activities of many neuronal proteins are modulated by ethanol, but the fundamental mechanisms underlying behavioral effects of ethanol remain unclear. To identify mechanisms responsible for intoxication, we screened for Caenorhabditis elegans mutants with altered behavioral responses to ethanol. We found that slo-1 mutants, which were previously recognized as having slightly uncoordinated movement, are highly resistant to ethanol in two behavioral assays. Numerous loss-of-function slo-1 alleles emerged from our screens, indicating that slo-1 has a central role in ethanol responses. slo-1 encodes the BK potassium channel. Electrophysiological analysis shows that ethanol activates the channel in vivo, which would inhibit neuronal activity. Moreover, behaviors of slo-1 gain-of-function mutants resemble those of ethanol-intoxicated animals. These results demonstrate that selective activation of BK channels is responsible for acute intoxicating effects of ethanol in C. elegans. BK channel activation may explain a variety of behavioral responses to ethanol in invertebrate and vertebrate systems.
Davies AG, Bettinger JC, Thiele TR, Judy ME, McIntire SL
Neuron 2004 Jun;42(5):731-43
Variation in the acute response to ethanol between individuals has a significant impact on determining susceptibility to alcoholism. The degree to which genetics contributes to this variation is of great interest. Here we show that allelic variation that alters the functional level of NPR-1, a neuropeptide Y (NPY) receptor-like protein, can account for natural variation in the acute response to ethanol in wild strains of Caenorhabditis elegans. NPR-1 negatively regulates the development of acute tolerance to ethanol, a neuroadaptive process that compensates for effects of ethanol. Furthermore, dynamic changes in the NPR-1 pathway provide a mechanism for ethanol tolerance in C. elegans. This suggests an explanation for the conserved function of NPY-related pathways in ethanol responses across diverse species. Moreover, these data indicate that genetic variation in the level of NPR-1 function determines much of the phenotypic variation in adaptive behavioral responses to ethanol that are observed in natural populations.
Miller AC, Thiele TR, Faumont S, Moravec ML, Lockery SR
J. Neurosci. 2005 Mar;25(13):3369-78
The sensorimotor transformation underlying Caenorhabditis elegans chemotaxis has been difficult to measure directly under normal assay conditions. Thus, key features of this transformation remain obscure, such as its time course and dependence on stimulus amplitude. Here, we present a comprehensive characterization of the transformation as obtained by inducing stepwise temporal changes in attractant concentration within the substrate as the worm crawls across it. We found that the step response is complex, with multiple phases and a nonlinear dependence on the sign and amplitude of the stimulus. Nevertheless, the step response could be reduced to a simple kinetic model that predicted the results of chemotaxis assays. Analysis of the model showed that chemotaxis results from the combined effects of approach and avoidance responses to concentration increases and decreases, respectively. Surprisingly, ablation of the ASE chemosensory neurons, known to be necessary for chemotaxis in chemical gradient assays, eliminated avoidance responses but left approach responses intact. These results indicate that the transformation can be dissected into components to which identified neurons can be assigned.