Abstract: The sense of smell is today one of the focuses of interest in aging and neurodegenerative disease research. In several neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, the olfactory dysfunction is one of the initial symptoms appearing years before motor symptoms and cognitive decline, being considered a clinical marker of these diseases’ early stages and a marker of disease progression and cognitive decline. Overall and under the umbrella of precision medicine, attention to olfactory function may help to improve chances of success for neuroprotective and disease-modifying therapeutic strategies. The use of olfaction, as clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and potentially prediction of treatment success. Understanding the mechanisms underlying olfactory dysfunction is central to determine its association with neurodegenerative disorders. Several anatomical systems and environmental factors may underlie or contribute to olfactory loss associated with neurological diseases, although the direct biological link to each disorder remains unclear and, thus, requires further investigation. In this review, we describe the neurobiology of olfaction, and the most common olfactory function measurements in neurodegenerative diseases. We also highlight the evidence for the presence of olfactory dysfunction in several neurodegenerative diseases, its value as a clinical marker for early stages of the diseases when combined with other clinical, biological, and neuroimage markers, and its role as a useful symptom for the differential diagnosis and follow-up of disease. The neuropathological correlations and the changes in neurotransmitter systems related with olfactory dysfunction in the neurodegenerative diseases are also described.

Abstract: Insects, including those which provide vital ecosystems services as well as those which are devastating pests or disease vectors, locate their resources mainly based on olfaction. Understanding insect olfaction not only from a neurobiological but also from an ecological perspective is therefore crucial to balance insect control and conservation. However, among all sensory stimuli olfaction is particularly hard to grasp. Our chemical environment is made up of thousands of different compounds, which might again be detected by our nose in multiple ways. Due to this complexity, researchers have only recently begun to explore the chemosensory ecology of model organisms such as Drosophila, linking the tools of chemical ecology to those of neurogenetics. This cross-disciplinary approach has enabled several studies that range from single odors and their ecological relevance, via olfactory receptor genes and neuronal processing, up to the insects' behavior. We learned that the insect olfactory system employs strategies of combinatorial coding to process general odors as well as labeled lines for specific compounds that call for an immediate response. These studies opened new doors to the olfactory world in which insects feed, oviposit, and mate.

Abstract: Background/objectives Loss of olfactory function is largely found with aging. Such a reduction in olfactory function affects quality of life and enhances likelihood of depressive symptoms. Furthermore, it has been shown that reduction in olfactory function is associated with cognitive impairment and several diseases such as major depression. Because several studies suggest that discontinuous exposure to odors may improve general olfactory function, the primary aim of this study was to investigate whether such “olfactory training” has positive effects on subjective well-being and cognitive function. Design We performed a controlled, unblinded, longitudinal study Setting The study took place at an outpatients' clinic of a Department of Otorhinolaryngology at a Medical University. Participants A total of 91 participants (age 50 to 84 years) completed testing. They were randomly assigned to an olfactory training (OT) group (N = 60) and a control group (N = 31). The study included two appointments at the Smell and Taste Clinic. Measurements Olfactory and cognitive function as well as subjective well-being was tested using standardized tests. Intervention During the 5-month interval between sessions, the OT group completed daily olfactory exposure. During the same time, the control group completed daily Sudoku problems. Results Analyses show a significant improvement of olfactory function for participants in the OT group and improved verbal function and subjective well-being. In addition, results indicated a decrease of depressive symptoms. Conclusion Based on the present results, OT may constitute an inexpensive, simple way to improve quality of life in older people. Copyright © 2017 John Wiley & Sons, Ltd.

Abstract: Survival of marine fishes that are exposed to elevated near-future CO2 levels is threatened by their altered responses to sensory cues Here we demonstrate a physiological and molecular mechanism in the olfactory system that helps to explain altered behaviour under elevated CO2 We combine electrophysiology measurements and transcriptomics with behavioural experiments to investigate how elevated CO2 affects the olfactory system of European sea bass (Dicentrarchus labrax) When exposed to elevated CO2 (approximately 1,000 µatm), fish must be up to 42% closer to an odour source for detection, compared with current CO2 levels (around 400 µatm), decreasing their chances of detecting food or predators Compromised olfaction correlated with the suppression of the transcription of genes involved in synaptic strength, cell excitability and wiring of the olfactory system in response to sustained exposure to elevated CO2 levels Our findings complement the previously proposed impairment of γ-aminobutyric acid receptors, and indicate that both the olfactory system and central brain function are compromised by elevated CO2 levels Marine fishes exposed to elevated CO2 levels can have altered responses to sensory cues Research now reveals a physiological and molecular mechanism in the olfactory system that helps to explain this altered behaviour under elevated CO2

Abstract: Disorders causing a loss of the sense of smell remain a therapeutic challenge. Basic research has, however, greatly expanded our knowledge of the organization and function of the olfactory system. This review describes advances in our understanding of the cellular components of the peripheral olfactory system, specifically the olfactory epithelium in the nose. The article discusses recent findings regarding the mechanisms involved in regeneration and cellular renewal from basal stem cells in the adult olfactory epithelium, considering the strategies involved in embryonic olfactory development and insights from research on other stem cell niches. In the context of clinical conditions causing anosmia, the current view of adult olfactory neurogenesis, tissue homeostasis, and failures in these processes is considered, along with current and future treatment strategies. Level of evidence NA.

Abstract: The impact of health, management, and microbiota on olfactory function in canines has not been examined in review. The most important characteristic of the detection canine is its sense of smell. Olfactory receptors are primarily located on the ethmoturbinates of the nasal cavity. The vomeronasal organ is an additional site of odor detection that detects chemical signals that stimulate behavioral and/or physiological changes. Recent advances in the genetics of olfaction suggest that genetic changes, along with the unique anatomy and airflow of the canine nose, are responsible for the macrosmia of the species. Inflammation, alterations in blood flow and hydration, and systemic diseases alter olfaction and may impact working efficiency of detection canines. The scientific literature contains abundant information on the potential impact of pharmaceuticals on olfaction in humans, but only steroids, antibiotics, and anesthetic agents have been studied in the canine. Physical stressors including exercise, lack of conditioning, and high ambient temperature impact olfaction directly or indirectly in the canine. Dietary fat content, amount of food per meal, and timing of meals have been demonstrated to impact olfaction in mice and dogs. Gastrointestinal (GI) microbiota likely impacts olfaction via bidirectional communication between the GI tract and brain, and the microbiota is impacted by exercise, diet, and stress. The objective of this literature review is to discuss the specific effects of health, management, and microbiota shifts on olfactory performance in working canines.

Abstract: Olfactory dysfunction has been well studied in depression. Common brain areas are involved in depression and in the olfactory process, suggesting that olfactory impairments may constitute potential markers of this disorder. Olfactory markers of depression can be either state (present only in symptomatic phases) or trait (persistent after symptomatic remission) markers. This study presents the etiology of depression, the anatomical links between olfaction and depression, and a literature review of different olfactory markers of depression. Several studies have also shown that olfactory impairment affects the quality of life and that olfactory disorders can affect daily life and may be lead to depression. Thus, this study discusses the links between olfactory processing, depression, and quality of life. Finally, olfaction is an innovative research field that may constitute a new therapeutic tool for the treatment of depression.

Abstract: Olfactory function is a key sense for human well-being and health, with olfactory dysfunction having been linked to serious diseases. As the microbiome is involved in normal olfactory epithelium development, we explored the relationship between olfactory function (odor threshold, discrimination, identification) and nasal microbiome in 67 healthy volunteers. Twenty-eight subjects were found to have normal olfactory function, 29 had a particularly good sense of smell ("good normosmics") and 10 were hyposmic. Microbial community composition differed significantly between the three olfactory groups. In particular, butyric acid-producing microorganisms were found to be associated with impaired olfactory function. We describe the first insights of the potential interplay between the olfactory epithelium microbial community and olfactory function, and suggest that the microbiome composition is able to mirror and potentially shape olfactory function by producing strong odor compounds.

Abstract: The evolution of mammalian olfaction is manifested in a remarkable diversity of gene repertoires, neuroanatomy and skull morphology across living species. Olfactory receptor genes (ORGs), which initiate the conversion of odorant molecules into odour perceptions and help an animal resolve the olfactory world, range in number from a mere handful to several thousand genes across species. Within the snout, each of these ORGs is exclusively expressed by a discrete population of olfactory sensory neurons (OSNs), suggesting that newly evolved ORGs may be coupled with new OSN populations in the nasal epithelium. Because OSN axon bundles leave high-fidelity perforations (foramina) in the bone as they traverse the cribriform plate (CP) to reach the brain, we predicted that taxa with larger ORG repertoires would have proportionately expanded footprints in the CP foramina. Previous work found a correlation between ORG number and absolute CP size that disappeared after accounting for body size. Using updated, digital measurement data from high-resolution CT scans and re-examining the relationship between CP and body size, we report a striking linear correlation between relative CP area and number of functional ORGs across species from all mammalian superorders. This correlation suggests strong developmental links in the olfactory pathway between genes, neurons and skull morphology. Furthermore, because ORG number is linked to olfactory discriminatory function, this correlation supports relative CP size as a viable metric for inferring olfactory capacity across modern and extinct species. By quantifying CP area from a fossil sabertooth cat (Smilodon fatalis), we predicted a likely ORG repertoire for this extinct felid.

Abstract: Pheromones are chemicals that serve intraspecific communication. In animals, the ability to detect and discriminate pheromones in a complex chemical environment substantially contributes to the survival of the species. Insects widely use pheromones to attract mating partners, to alarm conspecifics or to mark paths to rich food sources. The various functional roles of pheromones for insects are reflected by the chemical diversity of pheromonal compounds. The precise detection of the relevant intraspecific signals is accomplished by specialized chemosensory neurons housed in hair-like sensilla located on the surface of body appendages. Current data indicate that the extraordinary sensitivity and selectivity of the pheromone-responsive neurons (PRNs) is largely based on specific pheromone receptors (PRs) residing in their ciliary membrane. Besides these key elements, proper ligand-induced responses of PR-expressing neurons appear to generally require a putative co-receptor, the so-called "sensory neuron membrane protein 1" (SNMP1). Regarding the PR-mediated chemo-electrical signal transduction processes in insect PRNs, ionotropic as well as metabotropic mechanisms may be involved. In this review, we summarize and discuss current knowledge on the peripheral detection of pheromones in the olfactory system of insects with a focus on PRs and their specific role in the recognition and transduction of volatile intraspecific chemical signals.

Abstract: In many species, survival depends on olfaction, yet the mechanisms that underlie olfactory sensitivity are not well understood. Here we examine how a conserved subset of olfactory receptors, the trace amine-associated receptors (TAARs), determine odor detection thresholds of mice to amines. We find that deleting all TAARs, or even single TAARs, results in significant odor detection deficits. This finding is not limited to TAARs, as the deletion of a canonical odorant receptor reduced behavioral sensitivity to its preferred ligand. Remarkably, behavioral threshold is set solely by the most sensitive receptor, with no contribution from other highly sensitive receptors. In addition, increasing the number of sensory neurons (and glomeruli) expressing a threshold-determining TAAR does not improve detection, indicating that sensitivity is not limited by the typical complement of sensory neurons. Our findings demonstrate that olfactory thresholds are set by the single highest affinity receptor and suggest that TAARs are evolutionarily conserved because they determine the sensitivity to a class of biologically relevant chemicals.

Abstract: It was recently proposed that olfaction evolved to aid navigation. Consistent with this hypothesis, olfactory identification and spatial memory are linked to overlapping brain areas which include the orbitofrontal cortex and hippocampus. However, the relationship between these two processes has never been specifically investigated. Here, we show that olfactory identification covaries with spatial memory in humans. We also found that the cortical thickness of the left medial orbitofrontal cortex, and the volume of the right hippocampus, predict both olfactory identification and spatial memory. Finally, we demonstrate deficits in both olfactory identification and spatial memory in patients with lesions of the medial orbitofrontal cortex. Our findings reveal an intrinsic relationship between olfaction and spatial memory that is supported by a shared reliance on the hippocampus and medial orbitofrontal cortex. This relationship may find its roots in the parallel evolution of the olfactory and hippocampal systems.

Abstract: Background Olfactory training (OT) helps many patients with olfactory loss, but unfortunately it is ineffective for a significant number of patients. Budesonide irrigations are widely used to help patients with paranasal sinus inflammation, but have never been tested as a treatment for olfactory loss. We sought to examine the effect of adding budesonide irrigation to olfactory training on patients with olfactory loss without any visible sign of sinonasal inflammation. Methods In this randomized, controlled trial, 138 patients with olfactory loss and without any visible sign of sinonasal inflammation were randomized to either OT with saline irrigations or OT with budesonide irrigations. The University of Pennsylvania Smell Identification Test (UPSIT) was administered at the beginning of the study and at 6 months. Results A total of 133 patients completed the study. Forty-seven patients (35.3%) had a clinically significant change in UPSIT score. Among those in the budesonide irrigation + olfactory therapy group, 43.9% improved, compared with 26.9% in the saline irrigation + olfactory therapy group (p = 0.039); this corresponds to an odds ratio of 3.93 (95% confidence interval, 1.20-12.88) in a fully adjusted model (p = 0.024). Younger age and shorter duration of olfactory loss were also significant predictors of improvement. Conclusion Adding budesonide irrigation to olfactory training significantly improved olfactory ability compared with olfactory training plus saline irrigation.

Abstract: Most insect species rely on the detection of olfactory cues for critical behaviors for the survival of the species, e.g., finding food, suitable mates and appropriate egg-laying sites. Although insects show a diverse array of molecular receptors dedicated to the detection of sensory cues, two main types of molecular receptors have been described as responsible for olfactory reception in Drosophila, the odorant receptors (ORs) and the ionotropic receptors (IRs). Although both receptor families share the role of being the first chemosensors in the insect olfactory system, they show distinct evolutionary origins and several distinct structural and functional characteristics. While ORs are seven-transmembrane-domain receptor proteins, IRs are related to the ionotropic glutamate receptor (iGluR) family. Both types of receptors are expressed on the olfactory sensory neurons (OSNs) of the main olfactory organ, the antenna, but they are housed in different types of sensilla, IRs in coeloconic sensilla and ORs in basiconic and trichoid sensilla. More importantly, from the functional point of view, they display different odorant specificity profiles. Research advances in the last decade have improved our understanding of the molecular basis, evolution and functional roles of these two families, but there are still controversies and unsolved key questions that remain to be answered. Here, we present an updated review on the advances of the genetic basis, evolution, structure, functional response and regulation of both types of chemosensory receptors. We use a comparative approach to highlight the similarities and differences among them. Moreover, we will discuss major open questions in the field of olfactory reception in insects. A comprehensive analysis of the structural and functional convergence and divergence of both types of receptors will help in elucidating the molecular basis of the function and regulation of chemoreception in insects.

Abstract: Flowers attract pollinating insects like honeybees by sophisticated compositions of olfactory and visual cues. Using honeybees as a model to study olfactory–visual integration at the neuronal level, we focused on mushroom body (MB) output neurons (MBON). From a neuronal circuit perspective, MBONs represent a prominent level of sensory-modality convergence in the insect brain. We established an experimental design allowing electrophysiological characterization of olfactory, visual, as well as olfactory–visual induced activation of individual MBONs. Despite the obvious convergence of olfactory and visual pathways in the MB, we found numerous unimodal MBONs. However, a substantial proportion of MBONs (32%) responded to both modalities and thus integrated olfactory–visual information across MB input layers. In these neurons, representation of the olfactory–visual compound was significantly increased compared with that of single components, suggesting an additive, but nonlinear integration. Population analyses of olfactory–visual MBONs revealed three categories: (i) olfactory, (ii) visual and (iii) olfactory–visual compound stimuli. Interestingly, no significant differentiation was apparent regarding different stimulus qualities within these categories. We conclude that encoding of stimulus quality within a modality is largely completed at the level of MB input, and information at the MB output is integrated across modalities to efficiently categorize sensory information for downstream behavioural decision processing.

Abstract: Alzheimer’s disease (AD), a neurodegenerative condition, is one of the most prevalent kinds of dementia, whose frequency doubles for every 5 years of age in elderly. Objective: To determine the correlation between AD and olfactory alterations, identifying the most affected domains and exploring the utility of olfactory tests for complementing early diagnosis. Methods: Databases were searched using the terms “olfactory OR smell OR olfaction AND alzheimer” for articles related to the proposed theme. The selected studies were categorized and evaluated separately depending on the method of analysis of the olfactory tests: identification of odors, discrimination and recognition, and a meta-analysis was carried out. Results: Fifty-one articles were selected for analysis. The effect size for most studies was large, as were the summary values for each category of individualized olfactory analysis. Conclusion: Among the olfactory domains, except memory, identification appears to be the most altered in AD. The possibility of including tests that specifically evaluate the identification of odors as an item in early diagnostic evaluation should be explored. PROSPERO registration: CRD42018089076.

Abstract: Nasal inhalation is the basis of olfactory perception and drives neural activity in olfactory and limbic brain regions Therefore, our ability to investigate the neural underpinnings of olfaction and respiration can only be as good as our ability to characterize features of respiratory behavior However, recordings of natural breathing are inherently nonstationary, nonsinusoidal, and idiosyncratic making feature extraction difficult to automate The absence of a freely available computational tool for characterizing respiratory behavior is a hindrance to many facets of olfactory and respiratory neuroscience To solve this problem, we developed BreathMetrics, an open-source tool that automatically extracts the full set of features embedded in human nasal airflow recordings Here, we rigorously validate BreathMetrics' feature estimation accuracy on multiple nasal airflow datasets, intracranial electrophysiological recordings of human olfactory cortex, and computational simulations of breathing signals We hope this tool will allow researchers to ask new questions about how respiration relates to body, brain, and behavior

Abstract: Background Olfactory training (OT) has been shown to increase olfactory performance in healthy subjects and patients with post-traumatic or post-infectious olfactory loss. Morphological correlates such as olfactory bulb volume increase and gray matter changes suggest central changes in olfactory brain areas following olfactory exposure. Some evidence from animal studies indicates peripheral changes upon OT whereas no such data exist in humans. This study explores the question whether changes in olfaction following OT are associated with alterations of the electro-olfactogram (EOG) derived from the olfactory epithelium. Methodology We compared electrophysiological EOG responses to a pleasant, rose-like odor (phenylethyl alcohol, PEA) and to an unpleasant odor (rotten eggs, H2S) in patients and controls. EOG were recorded in smell impaired patients before and after OT for a period of 4-6 months. Results EOG recordings following PEA and H2S stimulation were significantly more often obtained in controls than in patients. OT was associated with a significantly higher number of EOG recordings. Conclusions OT is associated with an increase in EOG responses implicating stimulus-induced plasticity to start at the level of the olfactory epithelium.

Abstract: Among the insect olfactory receptors the odorant receptors (ORs) evolved in parallel to the onset of insect flight. A special property of this receptor type is the capability to adjust sensitivity of odor detection according to previous odor contacts. This article presents a current view on regulatory processes affecting the performance of ORs and proposes a model of mechanisms contributing to OR sensitization.

Abstract: Background Though olfactory deficits are well-documented in schizophrenia, fewer studies have examined olfactory performance profiles across the psychosis spectrum. The current study examined odor identification, discrimination, and detection threshold performance in first-episode psychosis (FEP) patients diagnosed with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, major depression with psychotic features, and other psychotic conditions. Method FEP patients (n = 97) and healthy adults (n = 98) completed birhinal assessments of odor identification, discrimination, and detection threshold sensitivity for lyral and citralva. Participants also completed measures of anticipatory pleasure, anhedonia, and empathy. Differences in olfactory performances were assessed between FEP patients and controls and within FEP subgroups. Sex-stratified post hoc analyses were employed for a complete analysis of sex differences. Relationships between self-report measures and olfactory scores were also examined. Results Individuals with psychosis had poorer scores across all olfactory measures when compared to the control group. Within the psychosis cohort, patients with schizophrenia-associated psychosis had poorer odor identification, discrimination, and citralva detection threshold scores relative to controls. In schizophrenia patients, greater olfactory disturbance was associated with increased negative symptomatology, greater self-reported anhedonia, and lower self-reported anticipatory pleasure. Patients with mood-associated psychosis performed comparable to controls though men and women in this cohort showed differential olfactory profiles. Conclusions These findings indicate that olfactory deficits extend beyond measures of odor identification in FEP with greater deficits observed in schizophrenia-related subgroups of psychosis. Studies examining whether greater olfactory dysfunction confers greater risk for developing schizophrenia relative to other forms of psychosis are warranted.

Abstract: Neuromodulation is a ubiquitous feature of neural systems, allowing flexible, context specific control over network dynamics. Neuromodulation was first described in invertebrate motor systems and early work established a basic dichotomy for neuromodulation as having either an intrinsic origin (i.e., neurons that participate in network coding) or an extrinsic origin (i.e., neurons from independent networks). In this conceptual dichotomy, intrinsic sources of neuromodulation provide a "memory" by adjusting network dynamics based upon previous and ongoing activation of the network itself, while extrinsic neuromodulators provide the context of ongoing activity of other neural networks. Although this dichotomy has been thoroughly considered in motor systems, it has received far less attention in sensory systems. In this review, we discuss intrinsic and extrinsic modulation in the context of olfactory processing in invertebrate and vertebrate model systems. We begin by discussing presynaptic modulation of olfactory sensory neurons by local interneurons (LNs) as a mechanism for gain control based on ongoing network activation. We then discuss the cell-class specific effects of serotonergic centrifugal neurons on olfactory processing. Finally, we briefly discuss the integration of intrinsic and extrinsic neuromodulation (metamodulation) as an effective mechanism for exerting global control over olfactory network dynamics. The heterogeneous nature of neuromodulation is a recurring theme throughout this review as the effects of both intrinsic and extrinsic modulation are generally non-uniform.

Abstract: The field of chemical senses has made major progress in understanding the cellular mechanisms of olfaction and taste in the past 2 decades. However, the molecular understanding of odor and taste recognition is still lagging far behind and will require solving multiple structures of the relevant full-length receptors in complex with native ligands to achieve this goal. However, the development of multiple complimentary strategies for the structure determination of G protein-coupled receptors (GPCRs) makes this goal realistic. The common conundrum of how multi-specific receptors that recognize a large number of different ligands results in a sensory perception in the brain will only be fully understood by a combination of high-resolution receptor structures and functional studies. This review discusses the first steps on this pathway, including biochemical and physiological assays, forward genetics approaches, molecular modeling, and the first steps towards the structural biology of olfactory and taste receptors.