Caenorhabditis elegans senses multiple environmental stimuli through sensory systems and rapidly changes its behaviors for survival. With a simple and wellcharacterized nervous system, C. elegans is a suitable animal model for studying behavioral plasticity. Previous studies have shown acute neurodepressive effects of ethanol on multiple behaviors of C. elegans similar to the effect of ethanol on other organisms. Caenorhabditis elegans also develops ethanol tolerance during continuous exposure to ethanol. In mammals, chronic ethanol exposure leads to ethanol tolerance as well as increased ethanol consumption. Ethanol preference is associated with the development of tolerance and may lead to the development of ethanol dependence. In this study, we show that C. elegans is a useful model organism for studying chronic effects of ethanol, including the development of ethanol preference. We designed a behavioral assay for testing ethanol preference after prolonged ethanol exposure. Despite baseline aversive responses to ethanol, animals show ethanol preference after 4 h of pre-exposure to ethanol and exhibit significantly enhanced preference for ethanol after a lifetime of ethanol exposure. The cat-2 and tph-1 mutant animals have defects in the synthetic enzymes for dopamine and serotonin, respectively. These mutants are deficient in the development of ethanol preference, indicating that dopamine and serotonin are required for this form of behavioral plasticity.
The CRF (corticotropin releasing factor) system is a key mediator of the stress response. Alterations in CRF signaling have been implicated in drug craving and ethanol consumption. The development of negative reinforcement via activation of brain stress systems has been proposed as a mechanism that contributes to alcohol dependence. Here we isolated a gain-of-function allele of seb-3, a CRF receptor-like GPCR in C. elegans, providing an in vivo model of a constitutively activated stress system. We also characterized a loss-of-function allele of seb-3 and showed that SEB-3 positively regulates a stress response that leads to an enhanced active state of locomotion, behavioral arousal, and tremor. SEB-3 also contributed to acute tolerance to ethanol and to the development of tremor during ethanol withdrawal. Furthermore, we found that a specific CRF1 receptor antagonist reduced acute functional tolerance to ethanol in mice. These findings demonstrate functional conservation of the CRF system in responses to stress and to ethanol in vertebrates and invertebrates.
Thioredoxin, an oxidoreductase, is a multifunction protein. The thioredoxin system is composed of NADPH, thioredoxin reductase and thioredoxin. This enzyme is highly conserved from bacteria to humans. We have characterized TRX-1, a thioredoxin homolog in C. elegans, which has about 36% identity in amino acid sequence with human thioredoxin. By gfp reporter system, trx-1 has been shown to be restrictedly expressed in ASI and ASJ neurons and in intestine. Immunostaining confirmed the intestinal expression. Full-length cDNA of trx-1 has been isolated by cDNA library PCR and subsequently cloned and sequenced. We have shown that the encoded protein functions as a reductase in the insulin reducing assay. Moreover, we have isolated a deletion mutant by PCRbased TMP-UV mutagenesis method. Mutant animals have reduced life span and are sensitive to oxidative stress. Reintroduction of trx-1 into mutant worms fully restored the wild-type phenotype. Our results suggest that trx-1 has important functions in life span regulation and oxidative stress response in C. elegans.
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