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Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of Slc22a3 as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced the expression of γ-aminobutyric acid (GABA) biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

Humans have significant individual variations in odor perception, derived from their experience or sometimes from differences in the olfactory receptor (OR) gene repertoire. In several cases, the genetic variation of a single OR affects the perception of its cognate odor ligand. Musks are widely used for fragrance and are known to demonstrate specific anosmia. It, however, remains to be elucidated whether the OR polymorphism contributes to individual variations in musk odor perception. Previous studies reported that responses of the human musk receptor OR5AN1 to a variety of musks in vitro correlated well with perceptual sensitivity to those odors in humans and that the mouse ortholog, Olfr1440 (MOR215-1), plays a critical role in muscone perception. Here, we took advantage of genetic variation in OR5AN1 to examine how changes in receptor sensitivity are associated with human musk perception. We investigated the functional differences between OR5AN1 variants in an in vitro assay and measured both perceived intensity and detection threshold in human subjects with different OR5AN1 genotypes. Human subjects homozygous for the more sensitive L289F allele had a lower detection threshold for muscone and found macrocyclic musks to be more intense than subjects homozygous for the reference allele. These results demonstrate that the genetic variation in OR5AN1 contributes to perceptual differences for some musks. In addition, we found that the more functional variant of OR5A1, a receptor involved in β-ionone perception, is associated with the less functional variant of OR5AN1, suggesting that the perceived intensities of macrocyclic musks and β-ionone are inversely correlated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The rapa whelk Rapana venosa, an economically important marine fishery resource in China but a major invader all over the world, changes from a phytophagous to a carnivorous form following settlement and metamorphosis. However, the low settlement and metamorphosis rates (<1%) of larvae limit the abundance of R. venosa. This critical step (settlement and metamorphosis) remains poorly characterized but may be related to how larvae perceive the presence of shellfish, their new source of food. Here, we report that larvae may use olfactory perception to sense shellfish. Olfactory receptor (OR) genes are involved in odor sensing in animals. We identified a total of 463 OR genes, which could be grouped into nine clades based on phylogenetic analysis. When assessing the attraction of larvae at different developmental stages to oyster odor, R. venosa showed active settlement and metamorphosis behavior only at the J4 stage (competent larva, 1000-1500 μm shell length) and in the presence of shellfish odor at the same time. Expression of OR gene family members differed between stage 2 (four-spiral whorl stage) and stage 1 (single- to three-spiral whorl stage), indicating significant changes in the olfactory system during larval development. These findings broaden our understanding of olfactory perception, settlement, and metamorphosis in gastropods and can be used to improve R. venosa harvesting, as well as the sustainable development and utilization of this resource., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (β-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The study was funded in part by Unilever R&D (the Netherlands). M.A.M.S. and F.-L.L. are employees of Unilever. The other authors declare that they have no competing interests.

Insect odorant-binding proteins (OBPs) are a class of small soluble proteins that can be found in various tissues wherein binding and transport of small molecules are required. Thus, OBPs are not only involved in typical olfactory function by specific activities with odorants but also participate in other physiological processes in non-chemosensory tissues. To better understand the complex biological functions of OBPs, it is necessary to study the transcriptional regulation of their expression patterns. In this paper, an apparent gradient expression pattern of Obp19, that was highly and specifically expressed in antennae and played an essential role in the detection of camphene, was defined in the antennae of the Japanese pine sawyer. Further, the transcription factor BarH1, that also presented gradient expression pattern in antennae, was found to regulate expression of Obp19 directly through binding to its upstream DNA sequence. The condition of BarH1 gene silence, the gene expression levels of Obp19 significantly decreased. At the same time, additional olfactory genes also were regulated and thus influence camphene reception. These findings provide us an opportunity to incorporate Obps in the gene regulatory networks of insects, which contribute to a better understanding of the multiplicity and diversity of OBPs and the olfactory mediated behaviors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Olfaction underpins many insect behaviors, such as foraging, host location, mating, and predator avoidance. In the first step of insect olfaction, odorant-binding proteins (OBPs) bind hydrophobic odorants and transport them to odorant receptors. Methyl eugenol (ME) is a powerful attractant for mature males of the oriental fruit fly Bactrocera dorsalis (Hendel), one of the most destructive fruit pests. The underlying molecular mechanism is unclear, but there is in vitro evidence that BdorOBP56f-2 is involved in ME perception. We used microscale thermophoresis to confirm that BdorOBP56f-2 directly binds ME with strong affinity in vitro. We then used CRISPR/Cas9 to knock out the BdorOBP56f-2 gene, allowing us to establish a homozygous mutant B. dorsalis line. The electroantennogram response and behavioral attraction to ME were significantly reduced in the mutant, providing in vivo evidence that BdorOBP56f-2 is necessary for efficient ME perception. Our results offer insight into the molecular mechanism of ME perception in B. dorsalis and provide a theoretical basis for the functional analysis of other OBPs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

During sleep, most animal species enter a state of reduced consciousness characterized by a marked sensory disconnect. Yet some processing of the external world must remain intact, given that a sleeping animal can be awoken by intense stimuli (for example, a loud noise or a bright light) or by soft but qualitatively salient stimuli (for example, the sound of a baby cooing or hearing one's own name 1-3 ). How does a sleeping brain retain the ability to process the quality of sensory information? Here we present a paradigm to study the functional underpinnings of sensory discrimination during sleep in Drosophila melanogaster. We show that sleeping vinegar flies, like humans, discern the quality of sensory stimuli and are more likely to wake up in response to salient stimuli. We also show that the salience of a stimulus during sleep can be modulated by internal states. We offer a prototypical blueprint detailing a circuit involved in this process and its modulation as evidence that the system can be used to explore the cellular underpinnings of how a sleeping brain experiences the world., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Bardet-Biedl syndrome (BBS) is a hereditary genetic disorder that results in numerous clinical manifestations including olfactory dysfunction. Of at least 21 BBS-related genes that can carry multiple mutations, a pathogenic mutation, BBS1M390R, is the single most common mutation of clinically diagnosed BBS outcomes. While the deletion of BBS-related genes in mice can cause variable penetrance in different organ systems, the impact of the Bbs1M390R mutation in the olfactory system remains unclear. Using a clinically relevant knock-in mouse model homozygous for Bbs1M390R, we investigated the impact of the mutation on the olfactory system and tested the potential of viral-mediated, wildtype gene replacement therapy to rescue smell loss. The cilia of olfactory sensory neurons (OSNs) in Bbs1 M390R/M390R mice were significantly shorter and fewer than those of wild-type mice. Also, both peripheral cellular odor detection and synaptic-dependent activity in the olfactory bulb were significantly decreased in the mutant mice. Furthermore, to gain insight into the degree to which perceptual features are impaired in the mutant mice, we used whole-body plethysmography to quantitatively measure odor-evoked sniffing. The Bbs1 M390R/M390R mice showed significantly higher odor detection thresholds (reduced odor sensitivity) compared to wild-type mice; however, their odor discrimination acuity was still well maintained. Importantly, adenoviral expression of Bbs1 in OSNs restored cilia length and re-established both peripheral odorant detection and odor perception. Together, our findings further expand our understanding for the development of gene therapeutic treatment for congenital ciliopathies in the olfactory system., (© 2021 Federation of American Societies for Experimental Biology.)

Olfaction is an important neural system for survival and fundamental behaviors such as predator avoidance, food finding, memory formation, reproduction, and social communication. However, the neural circuits and pathways associated with the olfactory system in various behaviors are not fully understood. Recent advances in optogenetics, high-resolution in vivo imaging, and reconstructions of neuronal circuits have created new opportunities to understand such neural circuits. Here, we generated a transgenic zebrafish to manipulate olfactory signal optically, expressing the Channelrhodopsin (ChR2) under the control of the olfactory specific promoter, omp . We observed light-induced neuronal activity of olfactory system in the transgenic fish by examining c-fos expression, and a calcium indicator suggesting that blue light stimulation caused activation of olfactory neurons in a non-invasive manner. To examine whether the photo-activation of olfactory sensory neurons affect behavior of zebrafish larvae, we devised a behavioral choice paradigm and tested how zebrafish larvae choose between two conflicting sensory cues, an aversive odor or the naturally preferred phototaxis. We found that when the conflicting cues (the preferred light and aversive odor) were presented together simultaneously, zebrafish larvae swam away from the aversive odor. However, the transgenic fish with photo-activation were insensitive to the aversive odor and exhibited olfactory desensitization upon optical stimulation of ChR2. These results show that an aversive olfactory stimulus can override phototaxis, and that olfaction is important in decision making in zebrafish. This new transgenic model will be useful for the analysis of olfaction related behaviors and for the dissection of underlying neural circuits.

In mice, early exposure to environmental odors affects social behaviors later in life. A signaling molecule, Semaphorin 7A (Sema7A), is induced in the odor-responding olfactory sensory neurons. Plexin C1 (PlxnC1), a receptor for Sema7A, is expressed in mitral/tufted cells, whose dendrite-localization is restricted to the first week after birth. Sema7A/PlxnC1 signaling promotes post-synaptic events and dendrite selection in mitral/tufted cells, resulting in glomerular enlargement that causes an increase in sensitivity to the experienced odor. Neonatal odor experience also induces positive responses to the imprinted odor. Knockout and rescue experiments indicate that oxytocin in neonates is responsible for imposing positive quality on imprinted memory. In the oxytocin knockout mice, the sensitivity to the imprinted odor increases, but positive responses cannot be promoted, indicating that Sema7A/PlxnC1 signaling and oxytocin separately function. These results give new insights into our understanding of olfactory imprinting during the neonatal critical period., Competing Interests: NI, HN, RO, KM, KN, TK, HS No competing interests declared, (© 2021, Inoue et al.)

Most odors of foods and drinks are mixtures of molecules. By means of the coupled Gas Chromatography-Olfactometry (GC-O) technique, single components of flavor mixtures can be separated, identified and verbally evaluated by subjects. The number of single molecules smelled by subjects during GC-O analysis (i.e., the number of odor-active compounds) was previously found to be linearly correlated with odor Threshold (T) score. Using the "Sniffin' Sticks" test, the same subjects were classified as normosmic or hyposmic. Hydrophobic odorants are captured and transported through the mucus layer by the odorant binding proteins (OBPs), particularly expressed in the olfactory cleft and associated with the olfactory function. In this study, subjects were genotyped for the rs2590498 (A/G) polymorphism of the OBPIIa gene, whose major allele A is associated with a higher olfactory sensitivity as compared to the minor allele G. One-way ANOVA showed a significant effect of the genotype of the OBPIIa locus on the: a) T score; b) number of odor-active compounds smelled; c) intensity perceived when sniffing the complex odor of banana. In conclusion, the threshold olfactory performance, but also the individual ability to smell single molecules, can be attributed, partly at least, to the rs2590498 polymorphism of the OBPIIa gene., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Olfactory receptor (OR) genes in humans form a special class characterized by unusually high DNA sequence diversity, which should give rise to differences in perception and behavior. In the largest genome-wide association study to date based on olfactory testing, we investigated odor perception and naming with smell tasks performed by 9,122 Icelanders, with replication in a separate sample of 2,204 individuals. We discovered an association between a low-frequency missense variant in TAAR5 and reduced intensity rating of fish odor containing trimethylamine (p.Ser95Pro, p combined  = 5.6 × 10 -15 ). We demonstrate that TAAR5 genotype affects aversion to fish odor, reflected by linguistic descriptions of the odor and pleasantness ratings. We also discovered common sequence variants in two canonical olfactory receptor loci that associate with increased intensity and naming of licorice odor (trans-anethole: lead variant p.Lys233Asn in OR6C70, p combined  = 8.8 × 10 -16 and p combined  = 1.4 × 10 -9 ) and enhanced naming of cinnamon (trans-cinnamaldehyde; intergenic variant rs317787-T, p combined  = 5.0 × 10 -17 ). Together, our results show that TAAR5 genotype variation influences human odor responses and highlight that sequence diversity in canonical OR genes can lead to enhanced olfactory ability, in contrast to the view that greater tolerance for mutations in the human OR repertoire leads to diminished function., Competing Interests: Declaration of Interests R.S.G., E.V.I., A.H., N.K.H., G.R., G.A.A., A.S., B.A.J., G.L.N., M.O.U., H. Helgason, B.V.H., M.S.N., V.T., G.S., T.T., A.O., R.P.K., G.B., G. T., I. J., H. Holm, D.F.G., U.T., H.S., P.S., and K.S. are employees of deCODE genetics/Amgen, Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mosquitoes rely heavily on their olfactory systems for host seeking, selection of oviposition sites, and avoiding predators and other environmental dangers. Of these behaviors, the preferential selection of a human blood-meal host drives the vectorial capacity of anthropophilic female Anopheles coluzzii mosquitoes. Olfactory receptor neurons (ORNs) are dispersed across several appendages on the head and express an obligate odorant receptor co-receptor (Orco) coupled with a "tuning" odorant receptor (OR) to form heteromeric, odor-gated ion channels in the membrane of these neurons. To examine the mechanistic and functional contributions of Orco/OR complexes to the chemosensory processes of An. coluzzii, we utilized CRISPR/Cas9 gene editing to create a line of homozygous, Orco-knockout, mutant mosquitoes. As expected, orco -/- ORNs across both adult and larval stages of An. coluzzii display significantly lower background activity and lack nearly all odor-evoked responses. In addition, blood-meal-seeking, adult female, orco -/- mutant mosquitoes exhibit severely reduced attraction to human- and non-human-derived odors while gravid females are significantly less responsive to established oviposition attractants. These results reinforce observations in other insects that Orco is crucial in maintaining the activity of ORNs. In that light, it significantly influences a range of olfactory-driven behaviors central to the anthropophilic host preference that is critical to the vectorial capacity of An. coluzzii as a primary vector for human malaria., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

How does neural activity generate perception? Finding the combinations of spatial or temporal activity features (such as neuron identity or latency) that are consequential for perception remains challenging. We trained mice to recognize synthetic odors constructed from parametrically defined patterns of optogenetic activation, then measured perceptual changes during extensive and controlled perturbations across spatiotemporal dimensions. We modeled recognition as the matching of patterns to learned templates. The templates that best predicted recognition were sequences of spatially identified units, ordered by latencies relative to each other (with minimal effects of sniff). Within templates, individual units contributed additively, with larger contributions from earlier-activated units. Our synthetic approach reveals the fundamental logic of the olfactory code and provides a general framework for testing links between sensory activity and perception., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Odor adaptation allows the olfactory system to regulate sensitivity to different stimulus intensities, which is essential for preventing saturation of the cell-transducing machinery and maintaining high sensitivity to persistent and repetitive odor stimuli. Although many studies have investigated the structure and mechanisms of the mammalian olfactory system that responds to chemical sensation, few studies have considered differences in neuronal activation that depend on the manner in which the olfactory system is exposed to odorants, or examined activity patterns of olfactory-related regions in the brain under different odor exposure conditions. To address these questions, we designed three different odor exposure conditions that mimicked diverse odor environments and analyzed c-Fos-expressing cells (c-Fos+ cells) in the odor columns of the olfactory bulb (OB). We then measured differences in the proportions of c-Fos-expressing cell types depending on the odor exposure condition. Surprisingly, under the specific odor condition in which the olfactory system was repeatedly exposed to the odorant for 1 min at 5-min intervals, one of the lateral odor columns and the ipsilateral hemisphere of the olfactory tubercle had more c-Fos+ cells than the other three odor columns and the contralateral hemisphere of the olfactory tubercle. However, this interhemispheric asymmetry of c-Fos expression was not observed in the anterior piriform cortex. To confirm whether the anterior olfactory nucleus pars externa (AONpE), which connects the left and right OB, contributes to this asymmetry, AONpE-lesioned mice were analyzed under the specific odor exposure condition. Asymmetric c-Fos expression was not observed in the OB or the olfactory tubercle. These data indicate that the c-Fos expression patterns of the olfactory-related regions in the brain are influenced by the odor exposure condition and that asymmetric c-Fos expression in these regions was observed under a specific odor exposure condition due to synaptic linkage via the AONpE., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Salient sensory environments experienced by a parental generation can exert intergenerational influences on offspring. While these data provide an exciting new perspective on biological inheritance, questions remain about causes and consequences of intergenerational influences of salient sensory experience. We previously showed that exposing male mice to a salient olfactory experience, like olfactory fear conditioning, resulted in offspring demonstrating a sensitivity to the odor used to condition the paternal generation and possessing enhanced neuroanatomical representation for that odor. In this study, we first injected RNA extracted from sperm of male mice that underwent olfactory fear conditioning into naïve single-cell zygotes and found that adults that developed from these embryos had increased sensitivity and enhanced neuroanatomical representation for the odor (Odor A) with which the paternal male had been conditioned. Next, we found that female, but not male offspring sired by males conditioned with Odor A show enhanced consolidation of a weak single-trial Odor A + shock fear conditioning protocol. Our data provide evidence that RNA found in the paternal germline after exposure to salient sensory experiences can contribute to intergenerational influences of such experiences, and that such intergenerational influences confer an element of adaptation to the offspring. In so doing, our study of intergenerational influences of parental sensory experience adds to existing literature on intergenerational influences of parental exposures to stress and dietary manipulations and suggests that some causes (sperm RNA) and consequences (behavioral flexibility) of intergenerational influences of parental experiences may be conserved across a variety of parental experiences., (© 2020 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Various insect species including moths have shown significant foraging preference to acetic acid. However, the olfactory reception and behavioral outputs of acetic acid in moths remain unsolved. The female adults of Oriental armyworm, Mythimna separata, exhibit high preference to acetic acid enriched sweet vinegar solutions, making them good targets for exploration of acid reception and performance. We first proved that acetic acid is an essential component which elicited electrophysiological responses from volatiles of the sweet vinegar solution. Successive single sensillum recording tests showed that at least 4 types (as1, as2, as3, and as4) of sensilla were involved in acetic acid reception in the antennae. The low dosages of acetic acid elicited upwind flight and close search, and pre-contact proboscis extension responses of the fasted females, indicating it serves as a food related olfactory cue. In vivo optical imaging data showed that low dosages of acetic acid activated one ordinary glomerulus (DC3), and high dosages evoked additional two glomeruli (DC1 and AC1) in the antennal lobe. A systematic survey on olfaction related receptors in three related transcriptomes has yielded 67 olfactory receptors (ORs) and 19 ionotropic receptors (IRs). Among, MsepIR8a, MsepIR64a, MsepIR75q1, and MsepIR75q2 were chosen as putative acid receptors by blasting against known acid IRs in Drosophila and comparing essential amino acid residues which related to acid sensing. Later in situ hybridization revealed that MsepIr8a was co-expressed with each of the other 3 Irs, suggesting its putative co-receptor role. This study reveals olfactory reception of acetic acid as an attractant in M. separata, and it provides the solid basis for later deorphanization of relevant receptors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bombykol (EZ) is the single component of the female sex pheromone in the silkmoth Bombyx mori. EZ alone evokes full courtship behaviors from conspecific males; however, its geometric isomer (EE) was consistently detected in the pheromone glands (PG) of 16 B. mori strains and a field population of the wild silkmoth Bombyx mandarina, which also uses EZ as the single pheromone component. We investigated the pheromonal activities of EE using a commercial hybrid strain of B. mori, Kinshu × Showa. The behavioral assay demonstrated that a 10 4 -10 5 -fold higher dose of EE than EZ was able to elicit behavioral responses from males. To elucidate whether the trace contaminant of EZ in the EE standard is responsible for these responses, we examined the responses of male antennae to EE using a gas chromatograph-electroantennographic detector system (GC-EAD). The EE, at high doses elicited marginal responses from the male antennae. We next examined antennal and behavioral responses of B. mori whose BmOR1 gene, which is responsible for the reception of bombykol, was knocked out. The knockout of BmOR1 resulted in the complete loss of antennal and behavioral responses to EE and EZ, demonstrating that if EE itself is active, it induces these responses via the incidental stimulation of BmOR1, not via the stimulation of EE-specific receptors. The existence of EE in the PG of B. mori and B. mandarina is discussed from the viewpoints of pheromone biosynthesis and the evolution of pheromone communication systems., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Olfactory sense remains elusive regarding the primary reception mechanism. Some studies suggest that olfaction is a spectral sense, the olfactory event is triggered by electron transfer (ET) across the odorants at the active sites of odorant receptors (ORs). Herein we present a Donor-Bridge-Acceptor model, proposing that the ET process can be viewed as an electron hopping from the donor molecule to the odorant molecule (Bridge), then hopping off to the acceptor molecule, making the electronic state of the odorant molecule change along with vibrations (vibronic transition). The odorant specific parameter, Huang-Rhys factor can be derived from ab initio calculations, which make the simulation of ET spectra achievable. In this study, we revealed that the emission spectra (after Gaussian convolution) can be acted as odor characteristic spectra. Using the emission spectrum of ET, we were able to reasonably interpret the similar bitter-almond odors among hydrogen cyanide, benzaldehyde and nitrobenzene. In terms of isotope effects, we succeeded in explaining why subjects can easily distinguish cyclopentadecanone from its fully deuterated analogue cyclopentadecanone-d28 but not distinguishing acetophenone from acetophenone-d8., Competing Interests: The authors declare no competing interests.

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and its dysfunction has been linked to social deficits in neurodevelopmental disorders. Yet little is known of how the PFC encodes social information and how social representations may be altered in such disorders. Here, we show that neurons in the medial PFC of freely behaving male mice preferentially respond to socially relevant olfactory cues. Population activity patterns in this region differed between social and nonsocial stimuli and underwent experience-dependent refinement. In mice lacking the autism-associated gene Cntnap2, both the categorization of sensory stimuli and the refinement of social representations were impaired. Noise levels in spontaneous population activity were higher in Cntnap2 knockouts and correlated with the degree to which social representations were disrupted. Our findings elucidate the encoding of social sensory cues in the medial PFC and provide a link between altered prefrontal dynamics and autism-associated social dysfunction.

Insects possess highly developed olfactory systems which play pivotal roles in its ecological adaptations, host plant location, and oviposition behavior. Bactrocera minax is an oligophagous tephritid insect whose host selection, and oviposition behavior largely depend on the perception of chemical cues. However, there have been very few reports on molecular components related to the olfactory system of B. minax. Therefore, the transcriptome of B. minax were sequenced in this study, with 1 candidate chemosensory protein (CSP), 21 candidate odorant binding proteins (OBPs), 53 candidate odorant receptors (ORs), 29 candidate ionotropic receptors (IRs) and 4 candidate sensory neuron membrane proteins (SNMPs) being identified. After that, we sequenced the candidate olfactory genes and performed phylogenetic analysis. qRT-PCR was used to express and characterize 9 genes in olfactory and non-olfactory tissues. Compared with GFP-injected fly (control), dsOBP21-treated B. minax and dsCSP-treated B. minax had lower electrophysiological response to D-limonene (attractant), suggesting the potential involvement of BminOBP21 and BminCSP genes in olfactory perceptions of the fly. Our study establishes the molecular basis of olfaction, tributary for further functional analyses of chemosensory processes in B. minax., Competing Interests: The authors have declared that no competing interests exist.

Genetic variation plays a crucial role in individual differences in food preferences which ultimately influence food selection and health. Our current understanding of this pathway has been informed through twin studies (to assess the heritability of food preferences), candidate gene studies, and genome-wide association studies (GWAS). However, most of this literature is mainly focused on genes previously identified as having taste or smell functions. New data suggests that genes not associated with taste or smell perception may be involved in food preferences and contribute to health outcomes. This review highlights these emerging findings and suggests a polygenic risk assessment approach to explore new relationships between food preferences and health risks., Competing Interests: The authors declare that they have no competing interests.

Deficits in olfaction are among the most frequent non-motor symptoms in Parkinson's disease (PD) and can be detected early compared with motor symptoms. The reason for the early onset, as well as the mechanism involved remains unknown. We aimed to characterize the olfactory performance of patients with PD and age-matched healthy control (HC) participants in association with gender and a specific polymorphism in the odorant-binding protein IIa (OBPIIa) gene, which plays a crucial role in the perception of odors. The olfactory performance was assessed using the odor identification part of the Sniffin' Sticks test in 249 participants (patients with PD: n = 131 and HC participants: n = 118). All participants were genotyped for the rs2590498 polymorphism of the OBPIIa gene, whose major allele A is associated with a higher retronasal perception than the minor allele G. A higher number of men with PD than women with PD exhibited hyposmia. Importantly, OBPIIa gene polymorphism showed an effect on PD-related olfactory deficits only in women. Women with PD carrying two sensitive alleles (AA) showed a better olfactory performance than women with PD with at least one insensitive allele (G); the olfactory scores of the AA genotype women with PD were not different from those of HC participants. In conclusion, our results confirmed a sex effect on the reduced olfactory performance of patients with PD and identified the OBPIIa locus, which may provide a mechanism to determine the risk factor for olfactory deficits in women with PD at the molecular level., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception., Competing Interests: Conflict of interest statement: J.D.M is on the scientific advisory board of Aromyx and receives compensation for these activities.

Chemosensory systems mediate some of the most vital animal behaviors. However, our knowledge of the genetic mechanisms that underlie behavioral responses to olfactory cues remains fragmented. Genome-wide association mapping has greatly advanced our ability to identify candidate loci associated with variation in olfactory behavior, but functional validation of these candidates remain a necessary next step in understanding the mechanisms by which these genes influence chemoreception. In previous genome-wide association analyses, a genomic region that spans multiple polymorphic loci on the left arm of the third chromosome was found to be significantly associated with variation in olfactory behavioral responses to the odorant 2,3-butanedione, a volatile compound present in fermenting fruit. In this study, behavioral analysis of flies possessing either the major or minor haplotype for this region confirmed the association between polymorphisms in the region and variation in olfactory behavior. Moreover, functional dissection of the genes within this region using P-element insertional mutagenesis together with targeted RNAi experiments revealed that the gene CG6767, a gene of previously unknown function but predicted to encode an enzyme responsible for the synthesis and metabolism of nucleic acids, affects olfactory behavioral responses to 2,3-butanedione. Specifically, RNAi mediated knockdown of CG6767 expression in different neuroanatomical populations of the olfactory system suggests that this gene functions in local interneurons of the antennal lobe. These results reveal a new role for CG6767 and its importance in olfactory behavior.

Background: The insect olfactory system is a highly specific and sensitive chemical detector, which plays important roles in feeding, mating and finding an appropriate oviposition site. The ecological niche of Bombyx mori has changed greatly since domestication from B. mandarina, and its olfactory response to environmental odorants clearly decreased. However, the mechanisms that result in the olfactory impairment are largely unknown., Results: The antennal transcriptomes were compared between the domestic and wild silkworms. Comparison of the same sex between the domestic and wild silkworms revealed 1410 and 1173 differentially expressed genes (DEGs) in males and females, respectively. To understand the olfactory impairment, we mainly focused on the olfactory-related genes. In total, 30 olfactory genes and 19 odorant-degrading enzymes (ODEs) showed differential expression in the two comparisons, in which 19 and 14 were down-regulated in the domestic silkworm, respectively. Based on population genomic data, the down-regulated odorant receptors (ORs) showed a higher ratio of unique non-synonymous polymorphisms to synonymous polymorphisms (N/S ratio) in the domestic populations than that in the wild silkworms. Furthermore, one deleterious mutation was found in OR30 of the domestic population, which was located in transmembrane helix 6 (TM6)., Conclusions: Our results suggested that down-regulation of the olfactory-related genes and relaxed selection might be the major reasons for olfactory impairment of the domestic silkworm reared completely indoor environment. Reversely, wild silkworm may increase expression and remove deleterious polymorphisms of olfactory-related genes to retain sensitive olfaction.

The Human Leukocyte Antigen (HLA) is a gene complex that encodes important elements of the human immune system. HLA profile is communicated via olfaction and interindividual diversity is assumed to be advantageous for mate choice. Additionally, HLA diversity appears to enhance satisfaction and sexual attraction in existing romantic partnerships. However, whether this effect is transmitted via body odors and whether it results in an attraction towards HLA-dissimilar individuals and/or an avoidance of HLA-similar ones remains unclear. In the present study, we genotyped couples and asked each participant to rate a body odor sample from their partner and from three strangers of the opposite sex who expressed a similar or dissimilar HLA-B and HLA-C genotype. We found no statistically significant preference for HLA similarity or dissimilarity in men. Among women, the observed effects differed depending on hormonal contraception status. Like men, women on hormonal contraception did not exhibit significant HLA-related preferences. However, for women not using hormonal contraceptives, odors from HLA-B and HLA-C similar donors were significantly less attractive than those from HLA-dissimilar donors, regardless of whether the samples were from a partner or a stranger. Our findings support the hypothesis that HLA similarity is perceived via body odors and that such similarity affects human attraction. This mechanism may serve an evolutionarily adaptive function in preventing prospective offspring from having decreased immunocompetence, or decreasing the chance of kin mating., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The medicinal leeches have been widely utilized in medical procedures for thousands of years. Recently, there were more and more transcriptomes of leech published online including the medicinal leech (Hirudo medicinalis) and some other leeches. However, leech's genetic backgrounds are still largely unknown. In this report, transcriptomes of three phylogenetically close leeches (Poecilobdella javanica, Whitmania pigra, and Haemadipsa cavatuses) were established by RNA-seq technique for studying their genetic mechanisms of environmental adaption. Over 110 million high-quality reads were generated and assembled into unique transcriptome (reads = 200 bp). 27,138 out of de novo assembled transcripts (41.77%) were assigned to one or more GO terms. Additionally, the transcripts were detected in 217 predicted KEGG pathways. The enriched genes were involved in protein metabolism, GPCRs and pathogen-resistant pathways. The results showed that the great variations existed in gene expression of olfactory transduction pathway among three leech species. The comparisons of leech species hinted at the underlying mechanism of leeches adapting well in various environments. Our study will provide useful rationales for future studies of leeches and other annelid species., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Neighboring resources can affect insect oviposition behavior when the complexity of sensory information obscures information about host resource availability in heterogeneous resource patches. These effects are referred to as associational effects and are hypothesized to occur through constraints in the sensory processing of the insect during host search, resulting into suboptimal resource use. Because the possibilities to study these constraints on naturally occurring animals are limited, we instead used sensory mutants of Drosophila melanogaster to determine the importance of sensory information in the occurrence of associational effects. We found that oviposition was mainly governed by non-volatile chemical cues and less by volatile cues. Moreover, the loss of gustatory sensilla resulted in random resource selection and eliminated associational effects. In conclusion, our study shows that associational effects do not necessarily depend on constraints in the sensory evaluation of resource quality, but may instead be a direct consequence of distinctive selection behavior between different resources at small scales.

The importance of olfaction to human health and disease is often underappreciated. Olfactory dysfunction has been reported in association with a host of common complex diseases, including neurological diseases such as Alzheimer's disease and Parkinson's disease. For health, olfaction or the sense of smell is also important for most mammals, for optimal engagement with their environment. Indeed, animals have developed sophisticated olfactory systems to detect and interpret the rich information presented to them to assist in day-to-day activities such as locating food sources, differentiating food from poisons, identifying mates, promoting reproduction, avoiding predators, and averting death. In this context, the olfactory bulb is a vital component of the olfactory system receiving sensory information from the axons of the olfactory receptor neurons located in the nasal cavity and the first place that processes the olfactory information. We report in this study original observations on the human olfactory bulb proteome in healthy subjects, using a high-resolution mass spectrometry-based proteomic approach. We identified 7750 nonredundant proteins from human olfactory bulbs. Bioinformatics analysis of these proteins showed their involvement in biological processes associated with signal transduction, metabolism, transport, and olfaction. These new observations provide a crucial baseline molecular profile of the human olfactory bulb proteome, and should assist the future discovery of biomarker proteins and novel diagnostics associated with diseases characterized by olfactory dysfunction.

Studies on insect olfaction have increased our understanding of insect's chemosensory system and chemical ecology, and have improved pest control strategies based on insect behavior. In this study, we assembled the antennal transcriptomes of the lychee giant stink bug, Tessaratoma papillosa, by using next generation sequencing to identify the major olfaction gene families in this species. In total, 59 odorant receptors, 14 ionotropic receptors (8 antennal IRs), and 33 odorant binding proteins (28 classic OBPs and 5 plus-C OBPs) were identified from the male and female antennal transcriptomes. Analyses of tissue expression profiles revealed that all 59 OR transcripts, 2 of the 8 antennal IRs, and 6 of the 33 OBPs were primarily expressed in the antennae, suggesting their putative role in olfaction. The sex-biased expression patterns of these antenna-predominant genes suggested that they may have important functions in the reproductive behavior of these insects. This is the first report that provides a comprehensive resource to future studies on olfaction in the lychee giant stink bug.

There is growing evidence in the literature suggesting that caste differentiation in the stingless bee, Melipona scutellaris, and other bees in the genus Melipona, is triggered by environmental signals, particularly a primer pheromone. With the proper amount of food and a chemical stimulus, 25% of females emerge as queens, in agreement with a long-standing "two loci/two alleles model" proposed in the 1950s. We surmised that these larvae must be equipped with an olfactory system for reception of these chemical signals. Here we describe for the first time the diversity of antennal sensilla in adults and the morphology of larvae of M. scutellaris. Having found evidence for putative olfactory sensilla in larvae, we next asked whether olfactory proteins were expressed in larvae. Since the molecular basis of M. scutellaris is still unknown, we cloned olfactory genes encoding chemosensory proteins (CSP) and odorant-binding proteins (OBPs) using M. scutellaris cDNA template and primers designed on the basis CSPs and OBPs previously reported from the European honeybee, Apis mellifera. We cloned two CSP and two OBP genes and then attempted to express the proteins encoded by these genes. With a recombinant OBP, MscuOBP8, and a combinatorial single-chain variable fragment antibody library, we generated anti-MscuOBP8 monoclonal antibody. By immunohistochemistry we demonstrated that the anti-MscuOBP8 binds specifically to the MscuOBP8. Next, we found evidence that MscuOBP8 is expressed in M. scutellaris larvae and it is located in the mandibular region, thus further supporting the hypothesis of olfactory function in immature stages. Lastly, molecular modeling suggests that MscuOBP8 may function as a carrier of primer pheromones or other ligands.

Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection. Here we examined OSN cilium defects in Bbs1 mutant mice and assessed the utility of gene therapy to restore ciliation and function in young and adult mice. Bbs1 mutant mice possessed short residual OSN cilia in which BBSome protein trafficking and odorant detection were defective. Gene therapy with an adenovirus-delivered wild-type Bbs1 gene restored OSN ciliation, corrected BBSome cilium trafficking defects, and returned acute odor responses. Finally, using clinically approved AAV serotypes, we demonstrate, for the first time, the capacity of AAVs to restore ciliation and odor detection in OSNs of Bbs1 mutants. Together, our data demonstrate that OSN ciliogenesis can be promoted in differentiated cells of young and adult Bbs1 mutants and highlight the potential of gene therapy as a viable restorative treatment for congenital olfactory disorders., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are small noncoding RNAs that play posttranscriptional, regulatory roles in various biological processes. However, there has been limited investigation into the potential function of miRNAs in olfaction. The coleopteran Holotrichia parallela is an economically important pest, and miRNAs have been identified in only one coleopteran (Tribolium castaneum). Therefore, this study was conducted to identify miRNAs expressed in the antennae of H. parallela and obtain insights into their possible roles in olfaction. By combining deep sequencing and miRDeep2 software, a total of 99 miRNAs, including 76 conserved miRNAs and 23 novel miRNAs, were identified from H. parallela antennae. The 76 conserved miRNAs belong to 63 families and the other 23 may be species specific or tissue specific. The identified miRNAs have many conserved features of miRNAs. Evaluation of the conservation of the identified miRNA families across different species revealed that most of the families are insect specific. The prediction and annotation of targets suggested that 13 of the identified miRNAs participate in olfactory regulation. Gender differences in antennal expression of nine of the olfactory-related miRNAs were confirmed by quantitative real-time PCR., (© 2017 Wiley Periodicals, Inc.)

Background/aims: Picky eating is prevalent among preschoolers and is associated with risk of both underweight and overweight. Although differences in taste perception may be due to genetic variation, it is unclear whether these variations are related to picky eating behavior. The aim of this study was to investigate the association of 6 single nucleotide polymorphisms (SNPs) in 5 candidate genes related to chemosensory perception with picky eating behavior and adiposity in a cohort of preschool-aged children., Methods: Parents of 2- to 5-year-old non-Hispanic white preschoolers (n = 153) responded to survey questions on demographics, and information regarding their child's breastfeeding history and picky eating behavior. Height and weight were measured to calculate body mass index (BMI) z-scores using standard growth charts, and saliva was collected for genotyping. Generalized linear models were used to examine associations between picky eating behavior and BMI z-scores with genetic variation., Results: When controlling for child age, sex, breastfed status, and parent education level, SNPs in TAS2R38 (rs713598) and CA6 (rs2274327) were associated with picky eating behavior in children. There was no association between SNPs and BMI z-scores., Conclusion: Genes related to chemosensory perception may play a role in children's picky eating behavior., (© 2017 S. Karger AG, Basel.)

Locusts are important agricultural pests worldwide and regarded as study models for entomology. However, the absence of targeted gene manipulation systems for locusts has restricted their applications for research. Herein, we report the successful use of the CRISPR/Cas9 system to induce a targeted heritable mutagenesis of the migratory locust, Locusta migratoria. The target sequence of gRNA was designed to disrupt the gene encoding the odorant receptor co-receptor (Orco) and examine the roles of the odorant receptor pathway in the locust. Microinjection of the mixture of Cas9-mRNA and Orco-gRNA into the locust eggs resulted in efficient target-gene editing at a rate of 71.7% in G0 animals and achieved a germline efficiency of up to 88.1% in G1 animals. By a crossing strategy, we successfully established stable Orco mutant lines. EAGs and SSRs indicated that the fourth-instar nymphs of the Orco mutants showed severely impaired electrophysiological responses to multiple odors. The Orco mutant locusts lost an attraction response to aggregation pheromones under the crowding conditions. The locomotor activity and body coloration of the Orco mutant locusts did not significantly differ from those of the two other genotypes. This study provides an easy and effective approach by using the CRISPR/Cas9 system for generating loss-of-function mutants for functional genetic studies of locusts and for managing insect pests., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In the last decade, it has been demonstrated that brain functional asymmetry occurs not only in vertebrates but also in invertebrates. However, the mechanisms underlying functional asymmetry remain unclear. In the present study, we trained honeybees of the same parentage and age, on the proboscis extension reflex (PER) paradigm with only one antenna in use. The comparisons of gene expression between the left and right hemispheres were carried out using high throughput sequencing. Our research revealed that gene expression in the honeybee brain is also asymmetric, with more genes having higher expression in the right hemisphere than the left hemisphere. Our studies show that during olfactory learning, the left hemisphere is more responsible for long term memory and the right hemisphere is more responsible for the learning and short term memory.

The yellow peach moth (YPM), Conogethes punctiferalis (Guenée), is a multivoltine insect pest of crops and fruits. Antennal-expressed receptors are important for insects to detect olfactory cues for host finding, mate attraction and oviposition site selection. However, few olfactory related genes were reported in YPM until now. In the present study, we sequenced and characterized the antennal transcriptomes of male and female YPM. In total, 15 putative odorant binding proteins (OBPs), 46 putative odorant receptors (ORs) and 7 putative ionotropic receptors (IRs) were annotated and identified as olfactory-related genes of C. punctiferalis. Further analysis of RT-qPCR revealed that all these olfactory genes are primarily or uniquely expressed in male and female antennae. Among which, 3 OBPs (OBP4, OBP8 and PBP2) and 4 ORs (OR22, OR26, OR44 and OR46) were specially expressed in male antennae, whereas 4 ORs (OR5, OR16, OR25 and OR42) were primarily expressed in female antennae. The predicted protein sequences were compared with homologs in other lepidopteran species and model insects, which showed high sequence homologies between C. punctiferalis and O. furnacalis. Our work allows for further functional studies of pheromone and general odorant detection genes, which might be meaningful targets for pest management.

Phasmatodea, more commonly known as stick insects, have been poorly studied at the molecular level for several key traits, such as components of the sensory system and regulators of reproduction and development, impeding a deeper understanding of their functional biology. Here, we employ de novo transcriptome analysis to identify genes with primary functions related to female odour reception, digestion, and male sexual traits in the New Zealand common stick insect Clitarchus hookeri (White). The female olfactory gene repertoire revealed ten odorant binding proteins with three recently duplicated, 12 chemosensory proteins, 16 odorant receptors, and 17 ionotropic receptors. The majority of these olfactory genes were over-expressed in female antennae and have the inferred function of odorant reception. Others that were predominantly expressed in male terminalia (n = 3) and female midgut (n = 1) suggest they have a role in sexual reproduction and digestion, respectively. Over-represented transcripts in the midgut were enriched with digestive enzyme gene families. Clitarchus hookeri is likely to harbour nine members of an endogenous cellulase family (glycoside hydrolase family 9), two of which appear to be specific to the C. hookeri lineage. All of these cellulase sequences fall into four main phasmid clades and show gene duplication events occurred early in the diversification of Phasmatodea. In addition, C. hookeri genome is likely to express γ-proteobacteria pectinase transcripts that have recently been shown to be the result of horizontal transfer. We also predicted 711 male terminalia-enriched transcripts that are candidate accessory gland proteins, 28 of which were annotated to have molecular functions of peptidase activity and peptidase inhibitor activity, two groups being widely reported to regulate female reproduction through proteolytic cascades. Our study has yielded new insights into the genetic basis of odour detection, nutrient digestion, and male sexual traits in stick insects. The C. hookeri reference transcriptome, together with identified gene families, provides a comprehensive resource for studying the evolution of sensory perception, digestive systems, and reproductive success in phasmids.

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.

The oriental fruit fly (Bactrocera dorsalis) is a species of tephritid fruit fly, endemic to Southeast Asia but also introduced to many regions of the US, and it is one of the major pest species with a broad host range of cultivated and wild fruits. Although males of B. dorsalis respond strongly to methyl eugenol and this is used for monitoring and estimating populations, the molecular mechanism of the oriental fruit fly olfaction has not been elucidated yet. Therefore, in this project, using next generation sequencing technologies, we sequenced the transcriptome of the antennae of male and female adults of B. dorsalis. We identified a total of 20 candidate odorant binding proteins (OBPs), 5 candidate chemosensory proteins (CSPs), 35 candidate odorant receptors (ORs), 12 candidate ionotropic receptors (IRs) and 4 candidate sensory neuron membrane proteins (SNMPs). The sex-specific expression of these genes was determined and a subset of 9 OR genes was further characterized by qPCR with male and female antenna, head, thorax, abdomen, leg and wing samples. In the male antennae, 595 genes showed a higher expression, while 128 genes demonstrated a higher expression in the female antennae. Interestingly, 2 ORs (BdorOR13 and BdorOR14) were highly and specifically expressed in the antennae of males, and 4 ORs (BdorOR13, BdorOR16, BdorOR18 and BdorOR35) clustered with DmOR677, suggesting pheromone reception. We believe this study with these antennae-enriched OBPs, CSPs, ORs, IRs and SNMPs can play an important role in the detection of pheromones and general odorants, and so in turn our data improve our current understanding of insect olfaction at the molecular level and provide important information for disrupting the behavior of the oriental fruit fly using chemical communication methods.

Although neglected by science for a long time, the olfactory sense is now the focus of a panoply of studies that bring new insights and raises interesting questions regarding its functioning. The importance in the clarification of this process is of interest for science, but also motivated by the food and perfume industries boosted by a consumer society with increasingly demands for higher quality standards. In this review, a general overview of the state of art of science regarding the olfactory sense is presented with the main focus on the peripheral olfactory system. Special emphasis will be given to the deorphanization of the olfactory receptors (ORs), a critical issue because the specificity and functional properties of about 90% of human ORs remain unknown mainly due to the difficulties associated with the functional expression of ORs in high yields., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mosquito species that specialize in biting humans are few but dangerous. They include the African malaria vectors Anopheles gambiae and Anopheles coluzzii, as well as Aedes aegypti, the cosmopolitan vector of dengue, chikungunya, and yellow fever. These mosquitoes have evolved a remarkable innate preference for human odor that helps them find and bite us. Here I review what is known about this important evolutionary adaptation, from its historical documentation to its chemical and molecular basis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The complexity of the sense of smell makes adverse olfactory effects of drugs highly likely, which can impact a patient's quality of life. Here, we present a bioinformatics approach that identifies drugs with potential olfactory effects by connecting drug target expression patterns in human olfactory tissue with drug-related information and the underlying molecular drug targets taken from publically available databases. We identified 71 drugs with listed olfactory effects and 147 different targets. Taking the target-based approach further, we found additional drugs with potential olfactory effects, including 152 different substances interacting with genes expressed in the human olfactory bulb. Our proposed bioinformatics approach provides plausible hypotheses about mechanistic drug effects for drug discovery and repurposing and, thus, would be appropriate for use during drug development., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The importance of olfaction for various avian behaviors has become increasingly evident. So far, the use of olfaction for food detection among raptors has only been demonstrated for Cathartes vultures. The Oriental honey buzzard (Pernis orientalis) is a resident and migrant in Taiwan and regularly forages in apiaries. One of its foods in apiaries is yellow pollen dough, a softball-sized mixture of pollen, soybeans, and sugar that beekeepers provide as a supplementary food for bees. Given that pollen dough is not similar to any naturally occurring food, we hypothesized that buzzards identify the dough's nutritious contents using olfaction, perhaps in combination with vision. Using a series of choice experiments in which individuals could choose between two doughs, we showed that (1) buzzards almost unerringly chose pollen-containing over pollen lacking doughs when otherwise the doughs were identical in size, shape, and yellow color; (2) buzzards always preferred yellow over black or green doughs if both doughs contained pollen; (3) buzzards still preferred pollen-containing over pollen-lacking doughs when both doughs were black, but at a lower rate than in (1). We statistically excluded the possible influences of the doughs' relative brightness or of repeat visits by the same individuals. Our experiments thus suggest the use of a 'multi-modal foraging strategy' among buzzards whereby olfaction and vision are likely to be both used in identifying food at close distances. We also estimated the olfactory receptor gene repertoire size in the buzzard's genome which is almost five times as large as that of three other raptor species. Therefore, olfaction is likely of far greater ecological importance to this species than to other raptor species. We suggest that olfaction should be considered in the design of behavioral and genetic studies to better understand the use of multiple senses in avian behaviors.

Each person expresses a potentially unique subset of ∼ 400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the "olfactory fingerprint." Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10(-10)), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10(-4)), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10(-6)). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information.

The fruit fly Drosophila melanogaster is ideally suited for investigating the neural circuit basis of behavior. Due to the simplicity and genetic tractability of the fly brain, neurons and circuits are identifiable across animals. Additionally, a large set of transgenic lines has been developed with the aim of specifically labeling small subsets of neurons and manipulating them in sophisticated ways. Electrophysiology and imaging can be applied in behaving individuals to examine the computations performed by each neuron, and even the entire population of relevant neurons in a particular region, because of the small size of the brain. Moreover, a rich repertoire of behaviors that can be studied is expanding to include those requiring cognitive abilities. Thus, the fly brain is an attractive system in which to explore both computations and mechanisms underlying behavior at levels spanning from genes through neurons to circuits. This review summarizes the advantages Drosophila offers in achieving this objective. A recent neurophysiology study on olfactory behavior is also introduced to demonstrate the effectiveness of these advantages., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

The genetic underpinnings that contribute to variation in olfactory perception are not fully understood. To explore the genetic basis of variation in olfactory perception, we measured behavioral responses to 14 chemically diverse naturally occurring odorants in 260400 flies from 186 lines of the Drosophila melanogaster Genetic Reference Panel, a population of inbred wild-derived lines with sequenced genomes. We observed variation in olfactory behavior for all odorants. Low to moderate broad-sense heritabilities and the large number of tests for genotype-olfactory phenotype association performed precluded any individual variant from reaching formal significance. However, the top variants (nominal P < 5×10(-5)) were highly enriched for genes involved in nervous system development and function, as expected for a behavioral trait. Further, pathway enrichment analyses showed that genes tagged by the top variants included components of networks centered on cyclic guanosine monophosphate and inositol triphosphate signaling, growth factor signaling, Rho signaling, axon guidance, and regulation of neural connectivity. Functional validation with RNAi and mutations showed that 15 out of 17 genes tested indeed affect olfactory behavior. Our results show that in addition to chemoreceptors, variation in olfactory perception depends on polymorphisms that can result in subtle variations in synaptic connectivity within the nervous system., (© The Author 2015. Published by Oxford University Press.)

Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder with a characteristic triad of cognitive, affective and motor symptoms. Transgenic HD mice show excellent construct and face validity for many of these symptoms, however the decline in some facets of every day activity in humans is difficult to model. One approach is the assessment of species-relevant behaviors. Here we described three ethologically appropriate tests in the mouse-olfactory sensitivity, nest-building and sexually-motivated vocalizations. In R6/1 HD mice, olfactory and nest-building tests were sensitive to early dysfunctions induced by the HD mutation. Male vocalization testing revealed a late-stage sexual disinterest in R6/1 HD mice compared to WT littermates. We show that essential, species-relevant functions are disrupted by the HD mutation. The development of integrative behavioral assays which more closely model 'activities of daily living' (ADL) will facilitate the testing of novel therapeutic interventions in animal models as well as their clinical translation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first-degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways.