Abstract: This unit presents two basic protocols that offer rapid assessments of anosmia (the absence of a sense of smell) in mice The buried food test is used to check for the ability to smell volatile odors The olfactory habituation/dishabituation test is used to test whether the animal can detect and differentiate different odors, including both nonsocial and social odors A non-contact method of odor presentation, along with a general method for collecting urine samples, is given as an alternate protocol The tests described in this unit only require simple equipment and can be adopted readily by most laboratories

Abstract: Olfaction is a critical sensory modality that allows living things to acquire chemical information from the external world. The olfactory system processes two major classes of stimuli: (a) general odorants, small molecules derived from food or the environment that signal the presence of food, fire, or predators, and (b) pheromones, molecules released from individuals of the same species that convey social or sexual cues. Chemosensory receptors are broadly classified, by the ligands that activate them, into odorant or pheromone receptors. Peripheral sensory neurons expressing either odorant or pheromone receptors send signals to separate odor- and pheromone-processing centers in the brain to elicit distinct behavioral and neuroendocrinological outputs. General odorants activate receptors in a combinatorial fashion, whereas pheromones activate narrowly tuned receptors that activate sexually dimorphic neural circuits in the brain. We review recent progress on chemosensory receptor structure, function, and circuitry in vertebrates and invertebrates from the point of view of the molecular biology and physiology of these sensory systems.

Abstract: Objectives: Olfactory function is known to be modulated by repeated exposure to odors. The aim of this investigation was whether patients with olfactory loss would benefit from “Training” with odors in terms of an improvement of their general olfactory function. It was hypothesized that olfactory Training should produce both an improved sensitivity towards the odors used in the Training process and an overall increase of olfactory function. Study Design: The prospective study was performed in patients with olfactory dysfunction. Methods: One group of patients performed the Training (n = 40), whereas another part did not (n = 16). Exclusion criteria for patients were sinunasal disease. Olfactory training was performed over a period of 12 weeks. Patients exposed themselves twice daily to four intense odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves). Olfactory testing was performed before and after training using the “Sniffin' Sticks” (thresholds for phenyl ethyl alcohol, tests for odor discrimination and odor identification) in addition to threshold tests for the odors used in the training process. Results: Compared to baseline, training patients experienced an increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. In contrast, olfactory function was unchanged in patients who did not perform olfactory training. The present results indicate that the structured, short-term exposure to selected odors may increase olfactory sensitivity. Laryngoscope, 119:496–499, 2009

Abstract: Chemoreception is a crucial biological process that is essential for the survival of animals. In insects, olfaction allows the organism to recognise volatile cues that allow the detection of food, predators and mates, whereas the sense of taste commonly allows the discrimination of soluble stimulants that elicit feeding behaviours and can also initiate innate sexual and reproductive responses. The most important proteins involved in the recognition of chemical cues comprise moderately sized multigene families. These families include odorant-binding proteins (OBPs) and chemosensory proteins (CSPs), which are involved in peripheral olfactory processing, and the chemoreceptor superfamily formed by the olfactory receptor (OR) and gustatory receptor (GR) families. Here, we review some recent evolutionary genomic studies of chemosensory gene families using the data from fully sequenced insect genomes, especially from the 12 newly available Drosophila genomes. Overall, the results clearly support the birth-and-death model as the major mechanism of evolution in these gene families. Namely, new members arise by tandem gene duplication, progressively diverge in sequence and function, and can eventually be lost from the genome by a deletion or pseudogenisation event. Adaptive changes fostered by environmental shifts are also observed in the evolution of chemosensory families in insects and likely involve reproductive, ecological or behavioural traits. Consequently, the current size of these gene families is mainly a result of random gene gain and loss events. This dynamic process may represent a major source of genetic variation, providing opportunities for FUTURE specific adaptations.

Abstract: To date, four types of olfactory receptors have been described in mammals — odorant receptors, trace amine-associated receptors and vomeronasal type 1 and type 2 receptor superfamilies. Riviere et al. now report the identification of a additional novel olfactory receptor family, expressed by mouse vomeronasal sensory neurons. This family is encoded by five members of the formyl peptide receptor-related gene family (FPRs), which are otherwise known to mediate immune cell response to infection Cells expressing FPRs respond to ligands associated with disease and inflammation, which are excreted in urine, raising the possibility that FPRs detect the health status of individuals. Two different G-protein-coupled receptor families are known to mediate pheromonal cues in the mammalian vomeronasal organ. Here, members of a third family of receptors, the formyl peptide receptor-related gene family (FPRs), are shown to be expressed in the vomeronasal epithelium, with those cells expressing FPRs responding to ligands associated with disease and inflammation. This raises the possibility that FPRs detect the health status of individuals. Mammals rely heavily on olfaction to interact adequately with each other and with their environment1. They make use of seven-transmembrane G-protein-coupled receptors to identify odorants and pheromones. These receptors are present on dendrites of olfactory sensory neurons located in the main olfactory or vomeronasal sensory epithelia, and pertain to the odorant2, trace amine-associated receptor3 and vomeronasal type 1 (ref. 4) or 2 (refs 5–7) receptor superfamilies. Whether these four sensor classes represent the complete olfactory molecular repertoire used by mammals to make sense of the outside world is unknown. Here we report the expression of formyl peptide receptor-related genes by vomeronasal sensory neurons, in multiple mammalian species. Similar to the four known olfactory receptor gene classes, these genes encode seven-transmembrane proteins, and are characterized by monogenic transcription and a punctate expression pattern in the sensory neuroepithelium. In vitro expression of mouse formyl peptide receptor-like 1, 3, 4, 6 and 7 provides sensitivity to disease/inflammation-related ligands. Establishing an in situ approach that combines whole-mount vomeronasal preparations with dendritic calcium imaging in the intact neuroepithelium, we show neuronal responses to the same molecules, which therefore represent a new class of vomeronasal agonists. Taken together, these results suggest that formyl peptide receptor-like proteins have an olfactory function associated with the identification of pathogens, or of pathogenic states.

Abstract: From Odors to Behaviors in Caenorhabditis elegans Anne C. Hart and Michael Y. Chao Odor Coding in Insects C. Giovanni Galizia and Silke Sachse Olfactory Information Processing in Moths S. Shuichi Haupt, Takeshi Sakurai, Shigehiro Namiki, Tomoki Kazawa, and Ryohei Kanzaki Olfactory Coding in Larvae of the African Clawed Frog Xenopus laevis Ivan Manzini and Detlev Schild Development of the Olfactory System Helen B. Treloar, Alexandra M. Miller, Arundhati Ray, and Charles A. Greer Pheromones and Mammalian Behavior Peter A. Brennan Odorant Receptors Bettina Malnic, Daniela C. Gonzalez-Kristeller, and Luciana M. Gutiyama Signal Transduction in Vertebrate Olfactory Cilia Simone Pifferi, Anna Menini, and Takashi Kurahashi Multiple Olfactory Subsystems Convey Various Sensory Signals Minghong Ma Feedback Regulation of Neurogenesis in the Mammalian Olfactory Epithelium: New Insights from Genetics and Systems Biology Kimberly K. Gokoffski, Shimako Kawauchi, Hsiao-Huei Wu, Rosaysela Santos, Piper L.W. Hollenbeck, Arthur D. Lander, and Anne L. Calof Neurogenesis in the Adult Olfactory Bulb Angela Pignatelli and Ottorino Belluzzi Active Sensing in Olfaction Matt Wachowiak Temporal Coding in Olfaction Brice Bathellier, Olivier Gschwend, and Alan Carleton Cortical Activity Evoked by Odors Donald A. Wilson and Robert L. Rennaker Memory and Plasticity in the Olfactory System: From Infancy to Adulthood Anne-Marie Mouly and Regina Sullivan New Perspectives on Olfactory Processing and Human Smell Gordon M. Shepherd

Abstract: The mammalian olfactory system senses an almost unlimited number of chemical stimuli and initiates a process of neural recognition that influences nearly every aspect of life. This review examines the organizational principles underlying the recognition of olfactory stimuli. The olfactory system is composed of a number of distinct subsystems that can be distinguished by the location of their sensory neurons in the nasal cavity, the receptors they use to detect chemosensory stimuli, the signaling mechanisms they employ to transduce those stimuli, and their axonal projections to specific regions of the olfactory forebrain. An integrative approach that includes gene targeting methods, optical and electrophysiological recording, and behavioral analysis has helped to elucidate the functional significance of this subsystem organization for the sense of smell.

Abstract: Accumulating evidence suggests that sporadic Parkinson's disease (sPD) has a long prodromal period during which several nonmotor features develop; in particular, impairment of olfaction, vagal dysfunction, and sleep disorder Early sites of Lewy pathology are the olfactory bulb and enteric plexuses of the foregut We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (a) nasal, with anterograde progression into the temporal lobe; and (b) gastric, secondary to swallowing of nasal secretions in saliva These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and via transsynaptic transmission reach the preganglionic parasympathetic motor neurons of the vagus nerve This would allow retrograde transport into the medulla and from here into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed and the possible routes of pathogenic invasion are considered It is concluded that the most parsimonious explanation for the initial events of sPD is pathogenic access to the brain through the foregut and nose-hence the term "dual hit"

Abstract: In most insects with olfactory glomeruli, each side of the brain possesses a mushroom body equipped with calyces supplied by olfactory projection neurons. Kenyon cells providing dendrites to the calyces supply a pedunculus and lobes divided into subdivisions supplying outputs to other brain areas. It is with reference to these components that most functional studies are interpreted. However, mushroom body structures are diverse, adapted to different ecologies, and likely to serve various functions. In insects whose derived life styles preclude the detection of airborne odorants, there is a loss of the antennal lobes and attenuation or loss of the calyces. Such taxa retain mushroom body lobes that are as elaborate as those of mushroom bodies equipped with calyces. Antennal lobe loss and calycal regression also typify taxa with short nonfeeding adults, in which olfaction is redundant. Examples are cicadas and mayflies, the latter representing the most basal lineage of winged insects. Mushroom bodies of another basal taxon, the Odonata, possess a remnant calyx that may reflect the visual ecology of this group. That mushroom bodies persist in brains of secondarily anosmic insects suggests that they play roles in higher functions other than olfaction. Mushroom bodies are not ubiquitous: the most basal living insects, the wingless Archaeognatha, possess glomerular antennal lobes but lack mushroom bodies, suggesting that the ability to process airborne odorants preceded the acquisition of mushroom bodies. Archaeognathan brains are like those of higher malacostracans, which lack mushroom bodies but have elaborate olfactory centers laterally in the brain.

Abstract: Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3−/− mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR.

Abstract: Fruitflies instinctively avoid CO2, for example that produced by stressed fellow flies, but they overcome this innate repulsion when CO2 is combined with other odorants, such as those produced by ripening fruits. Stephanie Turner and Anandasankar Ray report that such behaviour-modifying food odorants act directly on CO2-sensitive neurons in the fly antenna — not, as one would expect, indirectly via other olfactory pathways. Other naturally occurring odorants also blocked the action of CO2-responsive neurons from Culex mosquitoes, the insect vector for West Nile virus and filariasis. Given that these insects are drawn to CO2 emitted in human breath, these inhibitors of mosquito CO2-sensitive neurons could aid the search for repellent drugs that work by blocking this pathway. Fruitflies instinctively avoid CO2, for example that produced by stressed fellow flies, but they overcome this avoidance response in some environments that contain CO2, such as ripening fruits. Here, a new class of odorants present in food is identified that directly inhibit CO2-sensitive neurons in the antenna — not, as one would expect, indirectly via other olfactory pathways. The fruitfly Drosophila melanogaster exhibits a robust and innate olfactory-based avoidance behaviour to CO2, a component of odour emitted from stressed flies1. Specialized neurons in the antenna and a dedicated neuronal circuit in the higher olfactory system mediate CO2 detection and avoidance1,2. However, fruitflies need to overcome this avoidance response in some environments that contain CO2 such as ripening fruits and fermenting yeast, which are essential food sources. Very little is known about the molecular and neuronal basis of this unique, context-dependent modification of innate olfactory avoidance behaviour. Here we identify a new class of odorants present in food that directly inhibit CO2-sensitive neurons in the antenna. Using an in vivo expression system we establish that the odorants act on the Gr21a/Gr63a CO2 receptor3. The presence of these odorants significantly and specifically reduces CO2-mediated avoidance behaviour, as well as avoidance mediated by ‘Drosophila stress odour’. We propose a model in which behavioural avoidance to CO2 is directly influenced by inhibitory interactions of the novel odours with CO2 receptors. Furthermore, we observe differences in the temporal dynamics of inhibition: the effect of one of these odorants lasts several minutes beyond the initial exposure. Notably, animals that have been briefly pre-exposed to this odorant do not respond to the CO2 avoidance cue even after the odorant is no longer present. We also show that related odorants are effective inhibitors of the CO2 response in Culex mosquitoes that transmit West Nile fever and filariasis. Our findings have broader implications in highlighting the important role of inhibitory odorants in olfactory coding, and in their potential to disrupt CO2-mediated host-seeking behaviour in disease-carrying insects like mosquitoes.

Abstract: Sensing the chemical environment is critical for all organisms. Diverse animals from insects to mammals utilize highly organized olfactory system to detect, encode, and process chemostimuli that may carry important information critical for health, survival, social interactions and reproduction. Therefore, for animals to properly interpret and react to their environment it is imperative that the olfactory system recognizes chemical stimuli with appropriate selectivity and sensitivity. Because olfactory receptor proteins play such an essential role in the specific recognition of diverse stimuli, understanding how they interact with and transduce their cognate ligands is a high priority. In the nearly two decades since the discovery that the mammalian odorant receptor gene family constitutes the largest group of G protein-coupled receptor (GPCR) genes, much attention has been focused on the roles of GPCRs in vertebrate and invertebrate olfaction. However, is has become clear that the 'family' of olfactory receptors is highly diverse, with roles for enzymes and ligand-gated ion channels as well as GPCRs in the primary detection of olfactory stimuli.

Abstract: Olfaction is a primitive sense in organisms. Both vertebrates and insects have receptors for detecting odor molecules in the environment, but the evolutionary origins of these genes are different. Among studied vertebrates, mammals have approximately 1,000 olfactory receptor (OR) genes, whereas teleost fishes have much smaller (approximately 100) numbers of OR genes. To investigate the origin and evolution of vertebrate OR genes, I attempted to determine near-complete OR gene repertoires by searching whole-genome sequences of 14 nonmammalian chordates, including cephalochordates (amphioxus), urochordates (ascidian and larvacean), and vertebrates (sea lamprey, elephant shark, five teleost fishes, frog, lizard, and chicken), followed by a large-scale phylogenetic analysis in conjunction with mammalian OR genes identified from nine species. This analysis showed that the amphioxus has >30 vertebrate-type OR genes though it lacks distinctive olfactory organs, whereas all OR genes appear to have been lost in the urochordate lineage. Some groups of genes (theta, kappa, and lambda) that are phylogenetically nested within vertebrate OR genes showed few gene gains and losses, which is in sharp contrast to the evolutionary pattern of OR genes, suggesting that they are actually non-OR genes. Moreover, the analysis demonstrated a great difference in OR gene repertoires between aquatic and terrestrial vertebrates, reflecting the necessity for the detection of water-soluble and airborne odorants, respectively. However, a minor group (beta) of genes that are atypically present in both aquatic and terrestrial vertebrates was also found. These findings should provide a critical foundation for further physiological, behavioral, and evolutionary studies of olfaction in various organisms.

Abstract: Olfactory dysfunction is a frequent nonmotor symptom in idiopathic Parkinson's disease (PD) and may be considered as an early clinical feature of the disease preceding motor symptoms by years According to recent neuropathological staging concepts, impaired olfaction is assumed to indicate an early pathological process and might be associated with structural changes in the brain A morphometric analysis of magnetic resonance images [voxel-based morphometry (VBM)] was used to investigate gray matter atrophy related to psychophysically measured scores of olfactory function in early PD patients (n = 15, median Hoehn and Yahr stage 15), moderately advanced PD patients (n = 12, median Hoehn and Yahr stage 25), and age-matched healthy controls (n = 17) In PD patients, but not in controls, cortical atrophy in olfactory-related brain regions correlated specifically with olfactory dysfunction Positive correlations between olfactory performance and gray matter volume were observed in the right piriform cortex in early PD patients and in the right amygdala in moderately advanced patients The results provided first evidence that olfactory dysfunction in PD is related to atrophy in olfactory-eloquent regions of the limbic and paralimbic cortex In addition, olfactory-correlated atrophy in these brain regions is consistent with the assumption that olfactory impairment as an early symptom of PD is likely to be associated with extranigral pathology

Abstract: Diaphorina citri Kuwayama (Hemiptera: Psyllidae) is an important worldwide pest of citrus that vectors bacteria (Candidatus Liberibacter spp.) responsible for huanglongbing (citrus greening disease). We examined the behavioral responses of mated and unmated D. citri of both sexes to odors from host plants in a Y-tube olfactometer, with and without visual cues. The host plants tested were 'Duncan' grapefruit (Citrus paradisi Macfayden), sour orange (Citrus aurantium L.), navel orange (C. sinensis L.), and Murraya paniculata L. Jack. Responses varied by plant species, psyllid sex and mating status, and the presence of a visual cue. Evidence of attraction generally was stronger in females and in mated individuals of both sexes relative to virgins. The presence of a visual cue typically enhanced attractiveness of olfactory cues; in no case did unmated individuals show evidence of attraction to host plant odors in the absence of avisual cue. In the absence of visual cues, mated females and males showed evidence of attraction only to odors from sour orange and navel orange, respectively. Psyllids exhibited anemotactic responses when assayed with plant odors alone but showed strong evidence of attraction only when olfactory and visual cues were combined, suggesting that olfactory cues facilitate orientation to host plants but may be insufficient alone. Antennal responses to citrus volatiles were confirmed by electroantennogram. The results reported here provide evidence that D. citri uses olfactory and visual cues in orientation to host plants and suggest the possibility of using plant volatiles in monitoring and management of this pest.

Abstract: In fish, amino acids are food-related important olfactory cues to elicit an attractive response. However, the neural circuit underlying this olfactory behavior is not fully elucidated. In the present study, we applied the Tol2 transposon-mediated gene trap method to dissect the zebrafish olfactory system genetically. Four zebrafish lines (SAGFF27A, SAGFF91B, SAGFF179A, and SAGFF228C) were established in which the modified transcription activator Gal4FF was expressed in distinct subsets of olfactory sensory neurons (OSNs). The OSNs in individual lines projected axons to partially overlapping but mostly different glomeruli in the olfactory bulb (OB). In SAGFF27A, Gal4FF was expressed predominantly in microvillous OSNs innervating the lateral glomerular cluster that corresponded to the amino acid-responsive region in the OB. To clarify the olfactory neural pathway mediating the feeding behavior, we genetically expressed tetanus neurotoxin in the Gal4FF lines to block synaptic transmission in distinct populations of glomeruli and examined their behavioral response to amino acids. The attractive response to amino acids was abolished only in SAGFF27A fish carrying the tetanus neurotoxin transgene. These findings clearly demonstrate the functional significance of the microvillous OSNs innervating the lateral glomerular cluster in the amino acid-mediated feeding behavior of zebrafish. Thus, the integrated approach combining genetic, neuroanatomical, and behavioral methods enables us to elucidate the neural circuit mechanism underlying various olfactory behaviors in adult zebrafish.

Abstract: The "Sniffin' Sticks" test kit is a validated and commonly used tool for assessment of olfactory function in subjects with normal sense of smell and in individuals with smell loss. That test incorporates subtests for odor threshold, discrimination, and identification. To gain higher subtest reproducibility, tests on odor discrimination and odor identification were extended using 32 instead of the usually applied 16 single trials each. In developing the extended Sniffin' Sticks test, a number of preliminary experiments were performed in 46 healthy, normosmic individuals 1) to evaluate intensity and familiarity of the additionally selected odors, 2) to select distractors for the discrimination and identification test, and 3) to evaluate the test-retest reliability of each subtest. Furthermore, the extended test was applied to 126 patients with olfactory loss and 71 normosmic individuals. Follow-up investigation could be performed in 69 controls within an average interval of 4 days. Results revealed significant differences between patients and healthy subjects. Estimated intensity and familiarity of the newly selected 16 items of the discrimination test did not differ significantly from the 16 standard items. Test-retest reliability was found to be r = 0.80 (odor discrimination), r = 0.88 (odor identification), and r = 0.92 (odor threshold). In conclusion, the extended test kit allows a precise evaluation of olfactory function, especially when different olfactory tasks are assessed using individual subtests. Furthermore, the high test-retest reliability of both the 16 and the 32-item tests allows the evaluation of even relatively small changes of olfactory function over time by means of either test.

Abstract: The olfactory bulb collects the sensory afferents of the olfactory receptor cells located in the olfactory neuroepithelium. The olfactory bulb ends with the olfactory tract and is closely related to the olfactory sulcus of the frontal lobe. Many studies demonstrated that olfactory bulb volume assessed with magnetic resonance imaging is related to the olfactory function both in normal and pathological conditions. It has been shown that olfactory bulb volume changes with the degree of olfactory dysfunction, that it decreases with the duration of the olfactory loss and that patients with qualitative disorder such as parosmia have smaller olfactory bulbs than patients without parosmia. In this review, we will discuss the actual knowledge regarding olfactory bulb function, practical ways to measure olfactory bulb volume and olfactory sulcus depth, and report systematic observations regarding these measurements related to various causes of olfactory dysfunction, e.g. infection of the upper respiratory tract, head trauma, or neurodegenerative disease. Measurement of olfactory bulb volume may provide valuable information for patients with olfactory dysfunction.

Abstract: Postdevelopmental neurogenesis occurs in the olfactory bulb (OB), to which new interneurons are continuously recruited. However, only a subset of the adult-generated interneurons survives, as many undergo programmed cell death. As part of homeostatic processes, the removal of new neurons is required alongside the addition of new ones, to ensure a stable neuron number. In addition to a critical role in tissue maintenance, it is still unclear whether this neuronal elimination affects the functioning of adult circuits. Using focal drug delivery restricted to the OB, we investigated the significance of programmed cell death in the adult OB circuits. Cell death was effectively blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). The zVAD effect differed with newborn interneuron location, either in the superficial (periglomerular cells) or in the deep (granule cells) OB layers. Furthermore, whereas sensory experience potentiated the effect of zVAD on the survival of new granule cells, it had no additional effect on the survival of new periglomerular cells. Thus, distinct mechanisms control the survival/elimination decision of newborn interneuron subtypes. However, zVAD had no effect on the olfactory sensory neurons projecting to the bulb. Remarkably, psychophysical analyzes revealed that a normal rate of new neuron elimination was essential for optimal odorant exploration and discrimination. This study highlights the importance of cell elimination for adjusting olfactory performance. We conclude that adult-generated OB interneurons are continually turned over, rather than simply added, and the precise balance between new and mature interneurons, set through active selection/elimination processes, is essential for optimizing olfaction.

Abstract: Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system—owing to its strategic anatomic location—may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an ‘‘early warning’’ sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

Abstract: The olfactory system gives us an awareness of our immediate environment by allowing us to detect airborne stimuli. The components necessary for detection of these odorants are compartmentalized in the cilia of olfactory sensory neurons. Cilia are microtubule-based organelles, which can be found projecting from the surface of almost any mammalian cell, and are critical for proper olfactory function. Mislocalization of ciliary proteins and/or the loss of cilia cause impaired olfactory function, which is now recognized as a clinical manifestation of a broad class of human diseases, termed ciliopathies. Future work investigating the mechanisms of olfactory cilia function will provide us important new information regarding the pathogenesis of human sensory perception diseases.

Abstract: Sensory systems must be able to extract features of environmental cues within the context of the different physiological states of the organism and often temper their activity in a state-dependent manner via the process of neuromodulation. We examined the effects of the neuromodulator serotonin on a well-characterized sensory circuit, the antennal lobe of Drosophila melanogaster, using two-photon microscopy and the genetically expressed calcium indicator, G-CaMP. Serotonin enhances sensitivity of the antennal lobe output projection neurons in an odor-specific manner. For odorants that sparsely activate the antennal lobe, serotonin enhances projection neuron responses and causes an offset of the projection neuron tuning curve, most likely by increasing projection neuron sensitivity. However, for an odorant that evokes a broad activation pattern, serotonin enhances projection neuron responses in some, but not all, glomeruli. Further, serotonin enhances the responses of inhibitory local interneurons, resulti...

Abstract: The current consensus model in mammalian olfaction is that the detection of millions of odorants requires a large number of odorant receptors (ORs) and that each OR interacts selectively with a small subset of odorants, which are typically related in structure. Here, we report the odorant response properties of an OR that deviates from this model: SR1, a mouse OR that is abundantly expressed in sensory neurons of the septal organ and also of the main olfactory epithelium. Patch-clamp recordings reveal that olfactory sensory neurons (OSNs) that express SR1 respond to many, structurally unrelated odorants, and over a wide concentration range. Most OSNs expressing a gene-targeted SR1 locus that lacks the SR1 coding sequence do not show this broad responsiveness. Gene transfer in the heterologous expression system Hana3A confirms the broad response profile of SR1. There may be other mouse ORs with such broad response profiles.