Hermaphrodites respond to the presence of a bacterial lawn by slowing their rate of locomotion. Animals deprived of bacteria for 30 minutes exhibit enhanced slowing when they encounter a bacterial lawn (1). Genetic, pharmacological, and laser-ablation studies demonstrate that this modulatory response is mediated in part by the neurotransmitter serotonin (5-HT). A genetic screen for animals defective in this enhanced-slowing response yielded 16 mutants (1). One of these mutants,
mod-1(
n3034) (mod, modulation defective), exhibits a dominant phenotype of insensitivity to exogenous 5-HT in locomotion assays (exogenous 5-HT inhibits locomotion of wild-type animals).
mod-1 mutants have normal levels of 5-HT expression and are not defective in the uptake of exogenously added 5-HT. We have cloned
mod-1 and found that it encodes a member of the superfamily of ligand-gated ion channels that includes the ionotrophic 5-HT receptor subclass 5-HT3.
mod-1(
n3034) contains a missense mutation that causes an alanine-to-valine substitution in the second transmembrane region, which is predicted to line the pore of the channel. We have obtained two deletion alleles of
mod-1, generated by PCR-based screening of a chemical deletion library (generous gifts from Bob Barstead and NemaPharm), one of which completely eliminates the
mod-1 locus. Both of these deletion mutants are 5-HT resistant in locomotion assays, suggesting that
mod-1(
n3034) is a dominant-negative allele. Two mutations that define the gene
mod-5 were isolated in a screen for animals defective in 5-HT loading of the NSM neurons (2). Food-deprived
mod-5 mutants, when exposed to food, exhibit a recessive phenotype of slowing down more than do wild-type animals. Moreover,
mod-5 mutants are hypersensitive to exogenous 5-HT in locomotion assays. We have cloned
mod-5 and found that it encodes a predicted protein with sequence similarity to the mammalian 5-HT re-uptake transporters. A defect in the 5-HT re-uptake machinery is consistent with all the aforementioned characteristics of
mod-5 mutant animals. We postulate that the stimulus of food following a period of food-deprivation leads to 5-HT release by the MOD-5-expressing neurons. This 5-HT then acts through the MOD-1 channel to slow the rate of locomotion. This 5-HT pathway must be activated specifically within this behavioral paradigm, since
mod-1 and
mod-5 mutant animals do not seem to have defects in other behaviors affected by 5-HT, such as egg-laying and pharyngeal pumping. The further analysis of
mod-1 and
mod-5 and of other genes that affect the enhanced-slowing reponse should allow us to test aspects of our model and more generally should provide insights into how experience can modulate C. elegans behavior. 1. Sawin, E. R. (1996), Ph. D. Thesis, MIT. 2. Trent, C. (1982), Ph. D. Thesis, MIT.