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...

SUMMARY In natural environments where food abundance and quality can change drastically over time, animals must continuously alter their food acquisition strategies. Although genetic variation contributes to this plasticity, the specific genes involved and their interactions with the environment are poorly understood. Here we report that natural variation in the Drosophilagene, foraging (for), which encodes a cGMP-dependent protein kinase (PKG), affects larval food acquisition in an environmentally dependent fashion. When food is plentiful, the wild-type rover(forR) allele confers lower food intake and higher glucose absorption than both the wild-type sitter (fors) allele and the mutant fors2 allele. When food is scarce, forR, fors and fors2 larvae increase food intake to a common maximal level, but forRlarvae retain their increased absorption efficiency. Changes in forexpression can induce corrective behavioral modifications in response to food deprivation. When reared in environments with low food levels, forR larvae have higher survivorship and faster development than fors and fors2larvae. Together, these results show that natural variation in forhas far reaching implications affecting a suite of phenotypes involved in the regulation of food acquisition.

The ability to identify and respond to food is essential for survival, yet little is known about the neural substrates that regulate natural variation in food-related traits. The foraging (for) gene in Drosophila melanogaster encodes a cGMP-dependent protein kinase (PKG) and has been shown to function in food-related traits. To investigate the tissue distribution of FOR protein, we generated an antibody against a common region of the FOR isoforms. In the adult brain we localized FOR to neuronal clusters and projections including neurons that project to the central complex, a cluster within the dorsoposterior region of the brain hemispheres, a separate cluster medial to optic lobes and lateral to brain hemispheres, a broadly distributed frontal-brain cluster, axon bundles of the antennal nerve and of certain subesophageal-ganglion nerves, and the medulla optic lobe. These newly described tissue distribution patterns of FOR protein provide candidate neural clusters and brain regions for investigation of neural networks that govern foraging-related traits. To determine whether FOR has a behavioral function in neurons we expressed UAS-for in neurons using an elav-gal4 driver and measured the effect on adult sucrose responsiveness (SR), known to be higher in rovers than sitters, the two natural variants of foraging. We found that pan-neuronal expression of for caused an increase in the SR of sitters, demonstrating a neural function for PKG in this food-related behavior.

Habituation is a form of non-associative learning that enables animals to reduce their reaction to repeated harmless stimuli. When exposed to ethanol vapor, Drosophila show an olfactory-mediated startle response characterized by a transient increase in locomotor activity. Upon repeated exposures, this olfactory startle attenuates with the characteristics of habituation. Here we describe the results of a genetic screen to identify olfactory startle habituation (OSH) mutants. One mutation is a transcript specific allele of foraging (for) encoding a cGMP-dependent kinase. We show this allele of for reduces expression of a for-T1 isoform expressed in the head and functions normally to inhibit OSH. We localize for-T1 function to a limited set of neurons that include olfactory receptor neurons (ORNs) and the mushroom body (MB). Overexpression of for-T1 in ORNs inhibits OSH, an effect also seen upon synaptic silencing of the ORNs; for-T1 may therefore function in ORNs to decrease synaptic release upon repeated exposure to ethanol vapor. Overall, this work contributes to our understanding of the genes and neurons underlying olfactory habituation in Drosophila.

OBJECTIVE:To investigate whether genetic variation in the cyclic GMP-dependent protein kinase gene (PRKG1) is associated with obesity. METHODS: The study included 143 individuals from New York City area, NY, USA. The subjects were sampled on the basis of body mass index (BMI): obese (BMI ranging from 33.8 to 89.5 kg/m 2 ), and nonobese (BMI ranging from 16.0 to 29.4 kg/m 2 ). The association between C2276T polymorphism in PRKG1 gene and obesity was tested using linear regression analysis. RESULTS: BMI levels were predicted by linear regression models adjusted for demographic factors. An analysis was performed twice: in individuals of all ethnical backgrounds and in European-Americans only. In both cases, genotype did not have a significant effect. CONCLUSION: We found no evidence that the C2276T polymorphism in the PKRG1 gene is associated with obesity.