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: Respiration and airflow through the nasal cavity are known to be correlated with rhythmic neural activity in the central nervous system. Here we show in rodents that during conditioned fear-induced freezing behavior, mice breathe at a steady rate (~4 Hz), which is correlated with a predominant 4-Hz oscillation in the prelimbic prefrontal cortex (plPFC), a structure critical for expression of conditioned fear behaviors. We demonstrate anatomical and functional connections between the olfactory pathway and plPFC via circuit tracing and optogenetics. Disruption of olfactory inputs significantly reduces the 4-Hz oscillation in the plPFC, but leads to prolonged freezing periods. Our results indicate that olfactory inputs can modulate rhythmic activity in plPFC and freezing behavior.

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: Primates have traditionally been regarded as vision-oriented animals with low olfactory ability, though this "microsmatic primates" view has been challenged recently. To clarify when and how degeneration of the olfactory system occurred and to specify the relevant factors during primate evolution, we here examined the olfactory receptor (OR) genes from 24 phylogenetically and ecologically diverse primate species. The results revealed that strepsirrhines with curved noses had functional OR gene repertoires that were nearly twice as large as those for haplorhines with simple noses. Neither activity pattern (nocturnal/diurnal) nor color vision system showed significant correlation with the number of functional OR genes while phylogeny and nose structure (haplorhine/strepsirrhine) are statistically controlled, but extent of folivory did. We traced the evolutionary fates of individual OR genes by identifying orthologous gene groups, demonstrating that the rates of OR gene losses were accelerated at the ancestral branch of haplorhines, which coincided with the acquisition of acute vision. The highest rate of OR gene loss was observed at the ancestral branch of leaf-eating colobines; this reduction is possibly linked with the dietary transition from frugivory to folivory because odor information is essential for fruit foraging but less so for leaf foraging. Intriguingly, we found accelerations of OR gene losses in an external branch to every hominoid species examined. These findings suggest that the current OR gene repertoire in each species has been shaped by a complex interplay of phylogeny, anatomy, and habitat; therefore, multiple factors may contribute to the olfactory degeneration in primates.

Abstract: In many mammalian species, the accessory olfactory system plays a central role in guiding behavioral and physiological responses to social and reproductive interactions. Because of its relatively compact structure and its direct access to amygdalar and hypothalamic nuclei, the accessory olfactory pathway provides an ideal system to study sensory control of complex mammalian behavior. During the last several years, many studies employing molecular, behavioral, and physiological approaches have significantly expanded and enhanced our understanding of this system. The purpose of the current review is to integrate older and newer studies to present an updated and comprehensive picture of vomeronasal signaling and coding with an emphasis on early accessory olfactory system processing stages. These include vomeronasal sensory neurons in the vomeronasal organ, and the circuitry of the accessory olfactory bulb. Because the overwhelming majority of studies on accessory olfactory system function employ rodents, this review is largely focused on this phylogenetic order, and on mice in particular. Taken together, the emerging view from both older literature and more recent studies is that the molecular, cellular, and circuit properties of chemosensory signaling along the accessory olfactory pathway are in many ways unique. Yet, it has also become evident that, like the main olfactory system, the accessory olfactory system also has the capacity for adaptive learning, experience, and state-dependent plasticity. In addition to describing what is currently known about accessory olfactory system function and physiology, we highlight what we believe are important gaps in our knowledge, which thus define exciting directions for future investigation.

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 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 hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. Here we selectively inhibit hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually cued odour recall. We find that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory.

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: 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: 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: Upper respiratory tract infection (URI) is one of the most common etiology of olfactory loss. Previous studies demonstrated that both olfactory bulb (OB) volume and sulcus (OS) depth decreased in patients with post-infectious olfactory loss (PIOL) compared to normal controls. The aim of our study was to observe alterations of central olfactory pathways in patients with PIOL. T1 weighted magnetic resonance images were acquired in 19 PIOL patients and 19 age- and sex-matched control subjects on a 3 T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. We also analyzed OB volume in coronal T2-weighted images. Whole-brain analysis revealed a significant gray matter volume loss in the right orbitofrontal cortex (OFC) in patients group. Further analysis with region of interest exhibited a significant negative correlation between gray matter volume in right OFC as well as OB volume and the duration of olfactory loss in these patients (r = -0.566 and r = -0.535 both P < 0.05, respectively). In conclusion, the morphological alterations in the right OFC and OB might contribute to the pathogenic mechanism of olfactory dysfunction after upper respiratory tract infection.

Abstract: Objective Although the effectiveness of olfactory training (OT) had already been documented, the optimal regimen for such training remains unexplored. We examined whether the complexity of OT, namely alteration of odor quantity and quality, increases its effectiveness. Design One-hundred eight patients (Mage = 60.1 ± 1) with postinfectious (n = 57) or idiopathic (n = 51) olfactory dysfunction underwent OT preceded and followed by examination of olfactory function. Methods Subjects were randomly assigned to one of the three experimental conditions: 1) simple training comprising four basic, single-molecule substances; 2) complex training involving four odor mixtures; and 3) odor-altering training in which patients changed sets of mixtures every 2 months. Results The analysis of variance revealed that the benefit seen in this sample was not affected by the complexity of OT with regard to odor mixtures or alteration of odor type. The highest increase of the Sniffin' Sticks (Burghardt GmbH; Wedel, Germany) threshold, discrimination, and identification (and overall TDI) score was observed in postinfectious patients. Conclusion We conclude that the outcomes of OT are not strongly influenced by the training regimen. However, further investigation of OT regimens is required, particularly with regard to training duration. Level of evidence 2b. Laryngoscope, 128:1518-1522, 2018.

Abstract: Different regions of the mammalian nose smell different odors. In the mouse olfactory system, spatially regulated expression of >1000 olfactory receptors (ORs) along the dorsomedial-ventrolateral (DV) axis forms a topological map in the main olfactory epithelium (MOE). However, the locations of most ORs along the DV axis are currently unknown. By sequencing mRNA of 12 isolated MOE pieces, we mapped out the DV locations-as quantified by "zone indices" on a scale of 1-5-of 1033 OR genes with an estimated error of 0.3 zone indices. Our map covered 81% of all intact OR genes and 99.4% of the total OR mRNA abundance. Spatial regulation tended to vary gradually along chromosomes. We further identified putative non-OR genes that may exhibit spatial expression along the DV axis.

Abstract: In mammals, neural circuits are formed based on a genetic program and further refined by neuronal activity during the neonatal period. We report that in the mouse olfactory system, the glomerular map is not merely refined but newly connected to second-order neurons by odorant-receptor-derived neuronal activity. Here, we analyzed a pair of molecules, Sema7A, expressed in olfactory sensory neurons (OSNs) in an activity-dependent manner, and PlxnC1, localized to dendrites of mitral/tufted (M/T) cells in the first week after birth. In Sema7A or PlxnC1 knockout (KO) mice, initiation of synapse formation and dendrite selection of M/T cells were perturbed. Reconstitution and rescue experiments demonstrated that Sema7A-PlxnC1 interaction is essential to form the post-synaptic assembly. Pharmacological blocking experiments indicated that synaptic transmission triggers primary dendrite selection by synaptic competition. We conclude that Sema7A signaling is key to inducing activity-dependent post-synapse events and dendrite selection in M/T-cells during the neonatal period.

Abstract: Autism Spectrum Disorders (ASDs) are characterized by atypical sensory functioning in the visual, tactile, and auditory systems. Although less explored, olfactory changes have been reported in ASD patients. To explore these changes on a neural level, 18 adults with ASD and 18 healthy neurotypical controls were examined in a 2-phase study. Participants were first tested for odor threshold and odor identification. Then, (i) structural magnetic resonance (MR) images of the olfactory bulb were acquired, and (ii) a functional MR imaging olfaction study was conducted. ASD patients exhibited decreased function for odor thresholds and odor identification; this was accompanied by a relatively decreased activation in the piriform cortex. In conclusion, these findings suggest, that the known alterations in olfaction in ASD are rooted in the primary olfactory cortex.

Abstract: The ability to track odor plumes to their source (food, mate, etc.) is key to the survival of many insects. During this odor-guided navigation, flapping wings could actively draw odorants to the antennae to enhance olfactory sensitivity, but it is unclear if improving olfactory function comes at a cost to aerodynamic performance. Here, we computationally quantify the odor plume features around a fruit fly in forward flight and confirm that the antenna is well positioned to receive a significant increase of odor mass flux (peak 1.8 times), induced by wing flapping, vertically from below the body but not horizontally. This anisotropic odor spatial sampling may have important implications for behavior and the algorithm during plume tracking. Further analysis also suggests that, because both aerodynamic and olfactory functions are indispensable during odor-guided navigation, the wing shape and size may be a balance between the two functions.

Abstract: This review covers the field of olfaction and chemosensation of odorants and puts this information into the context of interactions between microbes and behaviour; the microbiome-gut-brain axis (MGBA). Recent emphasis has also been placed on the concept of the holobiome which states that no single aspect of an organism should be viewed separately and thus must include examination of their associated microbial populations and their influence. While it is known that the microbiome may be involved in the modulation of animal behaviour, there has been little systematized effort to incorporate into such studies the rapidly developing knowledge of the wide range of olfactory systems. The classical olfactory system is evolutionarily conserved in multiple taxa from insects through to fish, reptiles and mammals, and is represented by the largest gene families in vertebrates. Mice have over 1000 different olfactory receptors and humans about 400. They are distributed throughout the body and are even found in spermatozoa where they function in chemotaxis. Each olfactory receptor has the unique functional capability of high-affinity binding to several different molecular ligands. These and other properties render the cataloguing of odorants (odorome) with specific actions a difficult task. Some ectopic olfactory receptors have been shown to have functional effects in the gut and kidney, highlighting the complexity of the systems engaged by odorants. However, there are, in addition to classical olfactory receptors, at least two other families of receptors involved in olfaction that are also widely found expressed on tissues in many different organs in addition to the nervous system and brain: the trace-amine associated and formyl peptide receptors. Bacteria can make many if not most odorants and are responsible for recognition of species and relative relatedness, as well as predator presence, among many other examples. Activation of different combinations of olfactory receptors by bacterial products such as β-phenylethylamine have been shown even to control expression of emotions such as fear and aggression. The number of examples of bacterial products and volatile odorants influencing brain function and behaviour is expanding rapidly. Since it is recognized that many different bacterial products and metabolites also function as social cues, and may themselves be directly or indirectly causative of behavioural change, it becomes ever more important to include olfaction into studies of the MGBA. Clearly there are broader implications for the involvement of olfaction in this rapidly evolving field. These include improvement in our understanding of the pathways engaged in various behaviours, and the identification of novel approaches and new targets in efforts to modulate behavioural changes.

Abstract: A bioelectronic nose, an intelligent chemical sensor array system coupled with bio-receptors to identify gases and vapours, resembles mammalian olfaction by which many vertebrates can sniff out volatile organic compounds (VOCs) sensitively and specifically even at very low concentrations. Olfaction is undertaken by the olfactory system, which detects odorants that are inhaled through the nose where they come into contact with the olfactory epithelium containing olfactory receptors (ORs). Because of its ability to mimic biological olfaction, a bio-inspired electronic nose has been used to detect a variety of important compounds in complex environments. Recently, biosensor systems have been introduced that combine nanoelectronic technology and olfactory receptors themselves as a source of capturing elements for biosensing. In this article, we will present the latest advances in bioelectronic nose technology mimicking the olfactory system, including biological recognition elements, emerging detection systems, production and immobilization of sensing elements on sensor surface, and applications of bioelectronic noses. Furthermore, current research trends and future challenges in this field will be discussed.

Abstract: Olfactory limbic structures, like the amygdala, the entorhinal, and the piriform cortices, are closely involved in cognitive processes. Thus, besides olfactory dysfunctions, it is conceivable that the compromise of these structures can lead to cognitive impairment. The olfactory bulb is affected by alpha-synuclein pathology in almost all cases of both Parkinson's disease and dementia with Lewy bodies. The clinical distinction between these disorders relies on the timing in the appearance of dementia in relationship to motor symptoms. Typically, it occurs late in the course of Parkinson's disease, and within the first year in dementia with Lewy bodies. The close anatomical proximity of the olfactory bulb with limbic regions, together with the early occurrence of cognitive impairment that is observed in dementia with Lewy bodies, raise the question whether the propagation of alpha-synuclein pathology in this condition might originate in the olfactory bulb, spreading from there to other limbic structures, and thereby reaching the associative neocortex. This review will describe the anatomical basis of the olfactory system and discuss the evidence of potential spreading pathways from the olfactory bulb that could support the presence of early dementia in the setting of Lewy body disorders.

Abstract: Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional mTOR knockout mouse model to address this question. Using the Cre-LoxP system, the mTOR gene was specifically knocked out in cells expressing Vip (vasoactive intestinal peptide), which represent a major population of interneurons widely distributed in the neocortex, suprachiasmatic nucleus (SCN), olfactory bulb (OB), and other brain regions. Using a combination of biochemical, behavioral, and imaging approaches, we found that mice lacking mTOR in VIP neurons displayed erratic circadian behavior and weakened synchronization among cells in the SCN, the master circadian pacemaker in mammals. Furthermore, we have discovered a critical role for mTOR signaling in mediating olfaction. Odor stimulated mTOR activation in the OB, anterior olfactory nucleus, as well as piriform cortex. Odor-evoked c-Fos responses along the olfactory pathway were abolished in mice lacking mTOR in VIP neurons, which is consistent with reduced olfactory sensitivity in these animals. Together, these results demonstrate that mTOR is a key regulator of SCN circadian clock synchrony and olfaction.