InteractiveFly: GeneBrief

Odorant receptor 56a: Biological Overview | References

Flies, like all animals, need to find suitable and safe food. Because the principal food source for Drosophila melanogaster is yeast growing on fermenting fruit, flies need to distinguish fruit with safe yeast from yeast covered with toxic microbes. This study identified a functionally segregated olfactory circuit in flies that is activated exclusively by geosmin. This microbial odorant constitutes an ecologically relevant stimulus that alerts flies to the presence of harmful microbes. Geosmin activates only a single class of sensory neurons expressing the olfactory receptor Or56a. These neurons target the DA2 glomerulus and connect to projection neurons that respond exclusively to geosmin. Activation of DA2 is sufficient and necessary for aversion, overrides input from other olfactory pathways, and inhibits positive chemotaxis, oviposition, and feeding. The geosmin detection system is a conserved feature in the genus Drosophila that provides flies with a sensitive, specific means of identifying unsuitable feeding and breeding sites (Stensmyr, 2012).

Animals respond with innate behaviors to certain stimuli in their environment. Innate behaviors, in contrast to learned behaviors, are hardwired; i.e., confronted with a specific stimulus, the animal will respond with a stereotyped behavior. Many innate behaviors are triggered by odors. Prime examples are pheromones, which have been particularly well studied in insects. In the vinegar fly Drosophila melanogaster, the male-produced pheromone cis-vaccenyl acetate (cVA) activates a single class of olfactory sensory neurons (OSN), which provides input to a single glomerulus and a sexually dimorphic and functionally segregated circuit within the olfactory system. In insects, odors associated with food or oviposition substrates can also elicit innate behaviors. The smell of vinegar confers obligate attraction in flies. Although the vinegar odor activates a number of OSN classes, only a single glomerulus is sufficient and necessary for positive chemotaxis (Stensmyr, 2012).

Pathways underlying hardwired attraction have thus been well characterized. Olfactory circuits mediating odorant-induced innate avoidance are, however, poorly understood. From an evolutionary perspective, being able to detect and respond quickly to harmful features in the environment should be an essential task for the olfactory system. In the fly, CO2 elicits innate avoidance, which, like the attraction pathways, is mediated via a single glomerular circuit devoted exclusively to this stimulus. No dedicated avoidance circuit for an odorant sensu stricto (i.e., a volatile organic compound) has, however, been found in the fly or in any other insect. So far, all identified aversive odorants have activated multiple glomeruli, and their identification depends on decoding of complex combinatorial glomerular activation patterns (Stensmyr, 2012).

A volatile compound of interest in this context is geosmin (trans-1,10-dimethyl-trans-9-decalol). This substance is produced by a select number of fungi, bacteria, and cyanobacteria and to the human nose has a distinct and immediately recognizable earthy odor. A recent study found that addition of a small amount of geosmin reduced the attraction of flies to vinegar volatiles (Becher, 2010). Given its capacity to modulate innate attraction, this microbial volatile must be a very potent repellent and, as such, is possibly a candidate stimulus for a dedicated pathway for innate avoidance (Stensmyr, 2012).

This study examined the functional significance of geosmin to the fly and has shown that geosmin activates only a single class of OSNs; these neurons express an odorant receptor that is exclusively tuned to this compound. Furthermore, it was shown that the geosmin-activated circuit constitutes a functionally segregated pathway, transferring the message arising from the periphery unaltered to central processing centers. It was also demonstrated that this circuit alone is sufficient and necessary to trigger the avoidance behavior. Moreover, it was shown that, upon activation, the geosmin circuit overrides input from other circuits and inhibits positive chemotaxis. Additionally, it was shown that the peripheral part of the geosmin detection system is highly conserved across the genus Drosophila. Finally, the ecological significance of this pathway, which is to detect toxic microbes, was clearly demonstrated (Stensmyr, 2012).

The behavioral significance of geosmin was determined by using a T-maze. In this two-choice olfactory assay, geosmin on its own elicited avoidance at very low concentrations (10^-6). For comparison, benzaldehyde - a well-known repellant to flies - in the same assay required a 1,000-fold higher dose than geosmin to trigger repulsion. The actual fold difference in flies' behavioral sensitivity toward these two compounds is greater once volatility is factored in. The vapor pressure of geosmin is 1,000-fold lower than for benzaldehyde. Thus, at a given dose and temperature, the number of geosmin molecules in vapor phase is substantially lower than for benzaldehyde. Geosmin is accordingly not only repellent but is also repellent when present in exceedingly low amounts (Stensmyr, 2012).

Flies are evidently equipped with a sensitive detection system for geosmin. Electrophysiology was used to identify the population of OSNs that is activated by geosmin. Specifically, single-sensillum recording (SSR) measurements, a method that allowed assessing odor-induced OSN activity extracellularly, was used. The goal was to obtain SSR measurements from all antennal olfactory sensillum types while stimulating the contacted OSNs with geosmin. The 450 olfactory sensilla of the fly antennae can be divided into 17 functional types, which in total house 46 functionally distinct OSN classes (see Benton, 2009). In addition to these well-classified sensilla, morphological data indicate that the antennae also contain one more type, the so-called intermediate sensilla; these sensilla house an unknown number of functional OSN classes. The second olfactory organ of the fly, the maxillary palp, houses an additional three types for a total of six distinct OSN classes. By performing a considerable number of SSR measurements (n > 1000) using diagnostic odors and by comparing the response properties of contacted OSNs with previously published ligand affinities, it was possible to locate and record from all sensillum types present on the antennae (including two types of intermediate sensilla), as well as from the three types found on the maxillary palps (Stensmyr, 2012).

Response to geosmin came from just a single class of antennal OSNs, namely, the ab4B OSNs. These neurons express the odorant receptors (OR) Or56a and Or33a (Couto, 2005; Fishilevich, 2005), of which only the former is functional in the Canton-S strain used in this study (Kreher, 2008). Although ab4B OSNs have been measured from previously, geosmin is the first ligand reported for this neuron class. To confirm that Or56a is indeed the geosmin receptor, this protein was expressed in Chinese hamster ovary (CHO) cells that stably expressed the OR coreceptor Orco. Because insect ORs are Ca2+-permeable ionotropic receptors, OR activation can be monitored by measuring the free intracellular Ca2+ concentration [Ca2+]i. The application of geosmin transiently increased [Ca2+]i in a concentration-dependent manner. The cells responding to geosmin were seen to respond to the Orco agonist VUAA1 (Jones, 2011), although there was no response to control application of saline. Or33a was then expressed in the same CHO cell line. Although the cells responded to VUAA1, no responses were found to geosmin. CHO cells not expressing Orco or either of the two tuning ORs produced no Ca2+ signals in response to the application of geosmin or VUAA1. Loss of function of Or56a should render ab4B OSNs insensitive to geosmin. SSR was used to examine the function of ab4B OSNs expressing a UAS-RNA interference (RNAi) construct against Or56a. The expression of UAS-Or56aRNAi reduced the response to geosmin in a dose-dependent manner. In flies carrying one copy each of Or56a-Gal4 and UAS-Or56aRNAi, the response to geosmin was reduced by 50% compared to the response displayed by the parental lineages. With two copies of each, the response was essentially abolished (98% reduction). Thus, it is concluded that Or56a alone underlies the ability of the ab4B cells to detect geosmin (Stensmyr, 2012).

To further verify that geosmin is detected only by a single class of OSNs, functional imaging was performed to examine the activity pattern in the antennal lobe (AL) evoked by geosmin. The Gal4-UAS system was used to express the Ca2+-sensitive reporter gene GCaMP3.0 from the Orco promoter, thereby labeling all OSNs except those relying on ionotropic receptors (Benton, 2009) for odorant detection. Activated glomeruli were then identified by comparing the activation pattern with the map of the fly AL (Couto, 2005; Fishilevich, 2005). Flies were stimulated with diagnostic odors to assist glomerular identification (and with geosmin at 10
^-3 and 10
^-5 dilutions. At 10^-5, geosmin elicited repeatable signals from only a single locus in the AL - the DA2 glomerulus, which receives input from ab4B neurons (Couto, 2005; Fishilevich, 2005). It is noted that DA2 is also situated in the same lateral part of the AL that has previously been implicated in handling aversive odors. In a number of recordings, activity was also noted from VM2; however, these signals were not consistently reproducible. In the SSR screen, activity was ever observed in response to geosmin from OSNs innervating VM2; these OSNs are housed in the ab8 sensillum. Hence, the activity noted from VM2 most likely does not reflect actual peripheral input but, rather, may stem from intrinsic AL processes. It is therefore concluded that geosmin is indeed detected by a single class of OSNs. It should be stressed that the level of specificity shown in this study toward a non-pheromonal odor is most unusual, if not unique, among the olfactory systems investigated to date (Stensmyr, 2012).

If the behavior triggered by geosmin is solely derived from the activity of ab4B neurons, silencing this OSN subpopulation should also abolish the aversive behavior. To silence these neurons, the temperature-sensitive mutant dynamin Shibire^ts was expressed from the Or56a promoter. At the restrictive temperature (32°C), flies carrying this construct displayed no aversive behavior toward geosmin. The same flies, tested at a permissive temperature (25°C), showed a strong aversion to geosmin. Parental lines tested at the nonpermissive temperature showed a somewhat increased repellency, which was likely caused by the increased volatility of geosmin at the higher temperature. Silencing the ab4B neurons had no effect on flies' behavior in response to benzaldehyde. In line with the SSR experiments, silencing input to VM2 -- via the expression of Shibire^ts from the Or43b promoter -- did not affect flies' behavior in response to geosmin. The ab4B OSNs are evidently necessary for the aversive behavior (Stensmyr, 2012).

It was next asked whether selectively activating these neurons is sufficient to cause aversion. The temperature-sensitive cation channel dTRPA1 was expressed in the ab4B neurons, a procedure that allowed conditional activation these OSNs at temperatures >26°C (Hamada, 2008). As a control, the temperature preference (26°C versus 22°C) of wild-type (WT) flies was measured in a T-maze assay. WT flies showed a tendency toward aversion against the higher temperature. Having established baseline behavior in the assay, it was next asked whether flies bearing the Or56a-Gal4, UASdTRPA1 construct displayed a stronger aversion toward the higher temperature. In fact, flies expressing dTRPA1 in ab4B OSNs showed significant avoidance toward the warm side, whereas parental control flies showed moderate (but insignificant) aversion. Thus, specifically activating these neurons induces aversion in flies. In summary, these experiments demonstrate that the aversive behavior caused by geosmin is mediated solely through a single class of OSNs (Stensmyr, 2012).

As seen, geosmin is detected by a single class of OSNs, ab4B. It was next asked whether or not these neurons are exclusively tuned to geosmin. SSR was again used but now screened with 10³ structurally diverse odorants (tested at 10
^-2 dilution). The larger spiking neuron in the ab4 sensillum responded to a range of compounds. Interestingly, it is noted that the most potent ligands for these OSNs are all known repellants. The functional significance, if any, of having two neurons both responding to aversive odorants that are co-compartmentalized is unclear. The ab4B neurons, in contrast, displayed a striking degree of selectivity, as none of the screened odorants - apart from geosmin - elicited any increased spike firing. Showing specificity in the context of the olfactory system is, however, difficult, as there are thousands of volatile chemicals in nature. The tested set thus represents only a fraction of the volatile chemicals potentially present in the natural habitat of D. melanogaster (Stensmyr, 2012).

To address this issue and to more firmly examine the specificity of these neurons, the SSR investigation was expanded by using a gas chromatograph (GC) for stimulus delivery. GC-linked SSR enables the screening of headspace collections from complex odor sources and, consequently, enables the probing of large numbers of volatiles. Odors were first sampled from a wide range of sources present in the natural habitat of D. melanogaster in native Africa as well as in the 'Diaspora.' Odors were collected from 14 sources, including avoided ones, such as feces (from African mammals) and rotting meat, as well as attractive ones, such as fruits and vinegar. The total number of volatiles present in these samples is difficult to firmly establish, but the number of distinguishable flame ionization detection (FID) peaks amounts to 2,900 in total. The actual number of compounds present is, however, likely considerably higher. The headspace of many fruits typically contains > 400 volatiles; hence, in this study's samples, many more compounds were presumably present but only in amounts below the FID limit. These compounds were nevertheless effectively screened, as insects, including Drosophila, are capable of detecting compounds present well below the FID limit (Stensmyr, 2012).

Having collected and verified the odor samples, GC-SSR measurements were then performed from ab4B neurons. Out of the 14 odor samples that were screened, only three evoked responses namely the headspace of a moldy tomato, a moss tussock, and isolated cultures of the common soil bacterium Streptomyces coelicolor. In each of the active samples, only a single FID peak elicited a response. GC-linked mass spectroscopy (GC-MS) combined with synthetic standards were used to identify the functionally relevant peaks in these three samples; in all cases, these turned out to be geosmin. Thus, the ab4B neurons are indeed extremely specific, and it is reasonable to conclude that the sole function of these neurons is to detect geosmin (Stensmyr, 2012).

How sensitive are the ab4B neurons toward geosmin? T-maze experiments had already shown that the flies respond behaviorally at very low concentrations. Indeed, the ab4B neurons respond to geosmin at 10
8 dilution (corresponding to 100 pg of substance in the stimulus pipette), which is in good agreement with the dilution of geosmin
causing reduced upwind flight attraction to vinegar headspace when vaporized in the wind tunnel (Stensmyr, 2012).

How is the specific tuning in flies to geosmin seen in the peripheral sensory neurons transferred to higher brain centers? In Drosophila, the OSNs form synapses with projection neurons (PNs) and local interneurons within the AL. Most PNs innervate only a single glomerulus, whereas local interneurons typically show broad innervation throughout the AL. The PNs send their axons to the mushroom body and lateral horn. PNs tend to respond to a somewhat broader range of odors than do their corresponding OSNs. For instance, the PNs connected to OSNs that respond only to geranyl acetate respond to additional odors as well. However, PNs connected to OSNs that respond to the sex pheromone cVA do not show a broad response pattern and are just as specific as their cognate OSNs. It was thus asked: how specific is the response of PNs that respond to geosmin? Whole-cell patch-clamp recordings were carried out from a large number of randomly selected uniglomerular PNs, stimulating with 17 chemicals, including geosmin. Recordings and fills were obtained from 66 PNs (from 66 individual flies), which covered 31 different glomeruli. Geosmin elicited significant responses only from two PNs, both of which innervated the DA2 glomerulus. Although not all glomeruli were covered, this result strongly suggests that geosmin information does not diffuse broadly across the AL to other glomeruli. Moreover, DA2 PNs appear to be as selective as the input OSNs because these PNs responded exclusively to geosmin and not to any of the other screened compounds. To further examine the specificity of the AL output, flies were imaged carrying the GH146-Gal4 and UAS-GCaMP3.0 constructs in which 1/2 of the PNs express the GCaMP3.0 activity reporter. Stimulation with geosmin again exclusively activated the DA2 glomerulus. Thus, it is concluded that, like the labeled line pheromone pathway, the geosmin circuit forms a dedicated functionally segregated pathway, at least to the point of the calyx and lateral horn. The fate of the signal past this point remains to be elucidated (Stensmyr, 2012).

As mentioned before, the addition of geosmin to vinegar significantly reduced positive chemotaxis in flies' response to this innately attractive odor. To verify that geosmin indeed has the capacity to reduce flies' attraction to vinegar, the wind tunnel experiments were repeated with an alternative bioassay, the Flywalk (Steck, 2012). This assay enables high-resolution quantification of behavior from individual flies in response to short pulses of an odor stimulus repeated during an extended period of time. The Flywalk results parallel the findings from the wind tunnel. Exposing flies to pulses of balsamic vinegar induced bursts of positive chemotaxis, which were significantly reduced when geosmin was added to the vinegar volatiles. Geosmin alone induced a 'freezing' behavior, i.e., a decrease of the flies' activity, which, in this assay, reflects aversion (Steck, 2012). The ability of geosmin to reduce the attractiveness of vinegar is robust and can be repeated with both the trap assay and the T-maze (Stensmyr, 2012).

In light of the physiology findings, the cause of the reduced attractiveness of the geosmin-vinegar mix should stem from activation of the DA2 pathway. This circuit should consequently have the capacity to override and modulate an innate behavior. To test this notion, the Or56a-Gal4 line was used to drive the expression of an additional odorant receptor (Or22a targeting glomerulus DM2) in ab4B OSNs, enabling manipulation of the activity of the DA2 circuit in the absence of geosmin and thereby to separate the chemical from the actual effect. In flies expressing Or22a under the Or56a promoter, stimulation with ethyl butyrate, a potent ligand for Or22a that is highly attractive to flies, should result in the activation of both DM2 and DA2, in turn reducing the flies' attraction to ethyl butyrate. Through SSR, it was first verified that the misexpression of Or22a conferred sensitivity toward ethyl butyrate in ab4B neurons. Having established physiological function, the flies' behavioral response toward ethyl butyrate was then tested by using a T-maze. The parental control lines showed the expected strong positive response of WT flies toward this fruit ester. On the other hand, flies additionally expressing Or22a in the ab4B OSNs showed no attraction toward ethyl butyrate. Thus, activating DA2 and the associated pathway can modulate and override innate attractive behavior (Stensmyr, 2012).

It was next asked what the possible evolutionary and ecological reason might be for the strong and hard-wired chemosensory avoidance of geosmin. Because geosmin itself is nontoxic to invertebrates as well as mammals, the function of the circuit is not just to alert D. melanogaster to the presence of this compound. With some exceptions, the majority of volatiles flies detect are widely produced in nature and, thus, are difficult to firmly associate with a specific source. Geosmin, although very abundant in nature, is solely produced by a narrow range of microbes, in particular Penicillium fungal molds and Streptomyces soil bacteria. Has the system for detecting geosmin evolved to identify these specific microorganisms? It was first examined whether flies could survive on these types of microbes. Newly eclosed flies were transferred to vials with a yeast-containing medium or to vials additionally containing cultures of either Streptomyces coelicolor or Penicillium expansum. Flies were unable to survive in the presence of either of these microbes, presumably due to the accumulation of toxins. Many fungal molds, including P. expansum, produce a range of toxic secondary metabolites, several of which have been shown to have strong insecticidal activity. Many geosmin-producing microbes are not only toxic but are also known to outcompete or even kill the yeasts flies graze on. Thus, for the fly, being able to detect and avoid fruit colonized by harmful molds and bacteria should be an essential skill (Stensmyr, 2012).

Because many geosmin-producing microbes are detrimental to flies, it was suspected that substrates colonized by this type of microbe are avoided for oviposition. Thus, an olfactory-based oviposition preference was sought in flies by using a two-choice assay in which flies were given the option of laying eggs on plates containing either standard Drosophila yeast medium or on plates additionally inoculated with S. coelicolor. Indeed, flies avoided laying eggs on plates containing S. coelicolor. Is the avoidance of the bacterial plates mediated via geosmin? To address this question, the oviposition experiments were subsequently repeated. One of the plates was innoculated with a gene-targeted S. coelicolor strain (J3001), which carries a deletion in a key gene involved in the geosmin synthesis pathway. The J3001 strain is thus identical to WT S. coelicolor except for its inability to produce geosmin, the lack of which was also confirmed via GC-MS and GC-SSR. Abolishing the production of geosmin completely eliminated the avoidance in response to S. coelicolor. In the absence of geosmin, flies readily oviposited on the harmful media. Eggs deposited onto S. coelicolor did not develop into adult flies, and survival on the J3001 strain did not differ from survival on WT S. coelicolor. In a pure olfactory choice assay, the trap assay, flies also discriminated between the two strains, preferring J3001 over WT (Stensmyr, 2012).

It was next asked whether the reluctance to oviposit in the presence of (WT) S. coelicolor is dependent on the DA2 circuit. To address this question, the oviposition preference was measured of flies carrying the previously used Or56a-Gal4, UAS-Shibire^ts construct. At permissive temperatures, these flies strongly avoided plates containing S. coelicolor, whereas at restrictive temperatures, there was no avoidance, and the flies even showed a slight preference for the bacterial substrate. In line with the hypothesis, the presence of geosmin alone should also prevent egg laying, which it did. Plates containing geosmin were avoided as an oviposition substrate. One could speculate that the presence of any strongly repellent odor would also prevent oviposition from occurring. However, benzaldehyde did not inhibit oviposition from occurring at 10
^-4 and 10
^-2 dilutions and barely did so even when tested as a pure substance (Stensmyr, 2012).

Are flies also hesitant to consume food contaminated with this type of microbe? Feeding preference was examined by using a capillary feeder assay; here, flies could choose between two 5% sucrose solutions, one of which was based on a wash from WT S. coelicolor colonies. Indeed, flies clearly preferred the pure sucrose solution. These experiments were then repeated, replacing the WT S. coelicolor with the J3001 strain. The solution containing J3001 did not reduce feeding but was slightly preferred over the sucrose-only solution, suggesting that the aversion is due to the presence of geosmin. In line with this observation, adding geosmin (0.1%) also reduced feeding. The addition of another aversive odor, benzaldehyde (0.1%), had no effect on feeding. It was next asked whether the feeding aversion is due to olfactory input to the DA2 pathway. Indeed, the reduced feeding stems not from geosmin having an aversive taste but from the activation of ab4B OSNs because silencing input to this pathway (via Shibire^ts) also fully abolished the geosmin-induced feeding aversion. Thus, geosmin also functions as an antifeedant, operating via the olfactory system. Taken together, these findings strongly suggest that the ecological significance of geosmin is to alert flies to the presence of toxic molds and bacteria. The geosmin circuit performs a critical task, providing flies with a reliable and sensitive means of identifying unsuitable hosts (Stensmyr, 2012).

To shed light on the origin and evolution of the geosmin detection system circuit, a comparative approach was taken. Eight drosophilid species, chosen based on genome availability and phylogenetic and ecological considerations, were tested for their capacity to detect geosmin. Attempts were made to identify neurons able to detect geosmin via SSR, stimulating with a set of 37 chemically diverse odorants (at 10
^-2 dilution). OSNs were located tuned to geosmin in all the screened species except D. elegans. Electroantennogram recordings from this species also showed no response to geosmin and neither does this species respond behaviorally to geosmin in a T-maze assay. As in D. melanogaster, in each of the species responding to geosmin, detection was noted only from a single class of OSNs, which also responded exclusively to geosmin. The geosmin OSNs found in the other species may well serve the same function that they serve in D. melanogaster. The lack of a geosmin detection system in D. elegans may be a consequence of the low susceptibility to mold growth of this species' breeding substrate, namely, fresh flowers. Putatively functional orthologs of Or56a are also present across the species in which OR repertoires have been completed (Guo, 2007). Intact orthologs of Or56a were localized in draft genome assemblies from an additional eight drosophilids, including D. biarmipes and D. elegans. The function (if any) of the Or56a ortholog in the latter remains unknown. Analysis of selection pressure also showed that the Or56a genes are under overall purifying selection. The response properties of the second neuron residing in these sensilla are much less conserved. These neurons also do not express orthologous receptors across the examined species. In D. melanogaster, the ab4A neurons express Or7a, orthologs of which are, however, found only in the subgenus Sophophora (Guo, 2007). Yet, also in species in which it can be assumed that Or7a underlies the response property, variation was noted in ligand affinity. The function of the ab4A OSNs hence likely reflects species-specific requirements. The striking specificity toward geosmin seen in the olfactory system of D. melanogaster is accordingly a basal feature of the genus Drosophila, conserved for at least 40 million years (Stensmyr, 2012).

The manner in which flies decode and rely upon geosmin has few, if any, direct parallels. Comparable circuits are essentially found only within the subset of the olfactory nervous system that relays pheromone information. However, also within this context, it is exceedingly rare for animals to rely on just a single chemical to identify a critical resource. Almost all pheromones characterized to date have been complex blends processed by multiple neuronal pathways. Moreover, the specificity toward geosmin shown in this study surpasses many pheromone-tuned neurons; if presented with enough odorants or with odorants in sufficient concentration, these neurons will also display responses to other substances (Stensmyr, 2012).

The closest match to the geosmin pathway is found outside of the regular olfactory system, namely in the detection and processing machinery for the atmospheric trace gas CO2. Although CO2 is a fundamentally different chemical from geosmin, the similarity in which these two stimuli are decoded is striking. In flies, the CO2 circuit forms a functionally segregated pathway that mediates innate avoidance. Input to the CO2 circuit is likewise fed by sensory neurons exclusively tuned to a single stimulus. Although organized similarly, the ecological significance of these two circuits seems to differ. Geosmin is used by flies as a universal warning sign for the presence of toxic compounds that are co-morbid with geosmin. The evolutionary significance of this circuit is clear: it provides flies with a sensitive and specific means to identify unsuitable hosts. The ecological meaning of CO2 for D. melanogaster is, however, unclear. In fact, it is puzzling why flies would be repelled by CO2 at all. D. melanogaster is highly adapted toward breeding (and feeding) on substrates with high ethanol content. Because CO2 is a ubiquitous byproduct of alcoholic fermentation, it would make an ideal cue for flies to follow when searching for suitable hosts. Elucidating the role of CO2 from the point of view of flies and using assays that better reflect the natural setting should be a focus of future studies (Stensmyr, 2012).

Circuits analogous to the geosmin pathway are a likely feature in the olfactory systems of most, if not all, insects. Although these circuits are probably similar mechanistically and functionally (i.e., selective with regards to input, mediating innate aversion, and abolishing attraction), the identity of the eliciting stimulus will differ, reflecting the demands raised by the taxon-specific ecology (Stensmyr, 2012).

Search PubMed for articles about Odorant receptor 56a

Becher, P. G., Bengtsson, M., Hansson, B. S. and Witzgall, P. (2010). Flying the fly: long-range flight behavior of Drosophila melanogaster to attractive odors. J Chem Ecol 36: 599-607. PubMed ID: 20437263

Benton, R., Vannice, K. S., Gomez-Diaz, C. and Vosshall, L. B. (2009). Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila. Cell 136: 149-162. PubMed ID: 19135896

Couto, A., Alenius, M. and Dickson, B. J. (2005). Molecular, anatomical, and functional organization of the Drosophila olfactory system. Curr Biol 15: 1535-1547. PubMed ID: 16139208

Fishilevich, E. and Vosshall, L. B. (2005). Genetic and functional subdivision of the Drosophila antennal lobe. Curr Biol 15: 1548-1553. PubMed ID: 16139209

Guo, S. and Kim, J. (2007). Molecular evolution of Drosophila odorant receptor genes. Mol Biol Evol 24: 1198-1207. PubMed ID: 17331958

Hamada, F. N., Rosenzweig, M., Kang, K., Pulver, S. R., Ghezzi, A., Jegla, T. J. and Garrity, P. A. (2008). An internal thermal sensor controlling temperature preference in Drosophila. Nature 454: 217-220. PubMed ID: 18548007

Jones, P. L., Pask, G. M., Rinker, D. C. and Zwiebel, L. J. (2011). Functional agonism of insect odorant receptor ion channels. Proc Natl Acad Sci U S A 108: 8821-8825. PubMed ID: 21555561

Kreher, S. A., Mathew, D., Kim, J. and Carlson, J. R. (2008). Translation of sensory input into behavioral output via an olfactory system. Neuron 59: 110-124. PubMed ID: 18614033

Steck, K., Veit, D., Grandy, R., Badia, S. B., Mathews, Z., Verschure, P., Hansson, B. S. and Knaden, M. (2012). A high-throughput behavioral paradigm for Drosophila olfaction - The Flywalk. Sci Rep 2: 361. PubMed ID: 22511996

Stensmyr, M. C., Dweck, H. K., Farhan, A., Ibba, I., Strutz, A., Mukunda, L., Linz, J., Grabe, V., Steck, K., Lavista-Llanos, S., Wicher, D., Sachse, S., Knaden, M., Becher, P. G., Seki, Y. and Hansson, B. S. (2012). A conserved dedicated olfactory circuit for detecting harmful microbes in Drosophila. Cell 151: 1345-1357. PubMed ID: 23217715

date revised: 26 June 2013

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