Knowing which genes contribute to natural variation in learning and memory would help us understand how differences in these cognitive traits evolve among populations and species. We show that a natural polymorphism at the foraging (for) locus, which encodes a cGMP-dependent protein kinase (PKG), affects associative olfactory learning in Drosophila melanogaster. In an assay that tests the ability to associate an odor with mechanical shock, flies homozygous for one natural allelic variant of this gene (for R ) showed better short-term but poorer long-term memory than flies homozygous for another natural allele (for s ). The for s allele is characterized by reduced PKG activity. We showed that for R -like levels of both short-term learning and long-term memory can be induced in for s flies by selectively increasing the level of PKG in the mushroom bodies, which are centers of olfactory learning in the fly brain. Thus, the natural polymorphism at for may mediate an evolutionary tradeoff between short-and long-term memory. The respective strengths of learning performance of the two genotypes seem coadapted with their effects on foraging behavior: for R flies move more between food patches and so could particularly benefit from fast learning, whereas for s flies are more sedentary, which should favor good long-term memory.behavior ͉ evolution ͉ genetics ͉ rover-sitter ͉ cGMP-dependent protein kinase L earning and memory allow an individual to develop an adaptive behavioral response to a novel situation, even one never encountered in the evolutionary past of the species. The ability to learn may thus be regarded as one of the more remarkable products of biological evolution. Yet, our understanding of how changes in learning ability evolve remains rudimentary (1). In particular, we know almost nothing about the genetic and molecular nature of heritable variation in learning performance. This variation is the raw material of evolution. Thus, knowing which genes contribute to natural variation in learning ability would help us understand how differences in learning ability and memory evolve among populations and species. It would also offer insights into the tradeoffs constraining the evolution of improved learning performance (1-3).That natural populations harbor heritable variation affecting learning and memory has been demonstrated by artificial selection experiments, which succeeded in elevating learning performance in rats (4), blowflies (5), and Drosophila (6, 7). However, the genes underlying these experimentally induced evolutionary changes have not been identified. Mutants with major defects in learning or memory, a number of which are known in Drosophila (8-11), Caenorhabditis elegans (12, 13), and rodents (14, 15), tell us little about how genes contribute to the normal range of individual differences in learning abilities within a species. So far, the only polymorphic genes thought to contribute to natural variation in learning performance, in any species, have been recently identified through polymorphism-as...