Abstract: Although referred to in passing in several places, there have been few attempts to specify the functions of the human olfactory system. This article presents an initial effort at identifying and categorizing these functions, using 3 sources of information as a guide: 1) losses experienced by anosmic participants; 2) olfactory function in other mammals; and 3) capacity, namely, whether the human olfactory system can support the suggested function and whether there is evidence that it does. Three major classes of function were identified, relating to Ingestion (Detection/identification prior to ingestion; Detection of expectancy violations; Appetite regulation; Breast orientation and feeding), Avoiding environmental hazards (Fear related; Disgust related), and Social communication (Reproductive [inbreeding avoidance, fitness detection in prospective mates]; Emotional contagion [fear contagion, stress buffering]). These suggested functions were then examined with respect to 1) issues of ecological validity in human olfactory research; 2) their impact on olfactory loss; and 3) their general and specific implications for the study of human olfaction.

Abstract: The stimulus complexity of naturally occurring odours presents unique challenges for central nervous systems that are aiming to internalize the external olfactory landscape. One mechanism by which the brain encodes perceptual representations of behaviourally relevant smells is through the synthesis of different olfactory inputs into a unified perceptual experience--an odour object. Recent evidence indicates that the identification, categorization and discrimination of olfactory stimuli rely on the formation and modulation of odour objects in the piriform cortex. Convergent findings from human and rodent models suggest that distributed piriform ensemble patterns of olfactory qualities and categories are crucial for maintaining the perceptual constancy of ecologically inconstant stimuli.

Abstract: A striking commonality across insects and vertebrates is the recurring presence of parallel olfactory subsystems, suggesting that such an organization has a highly adaptive value. Conceptually, two different categories of parallel systems must be distinguished. In one, specific sensory organs or processing streams analyze different chemical stimuli (segregate parallel systems). In the other, similar odor stimuli are processed but analyzed with respect to different features (dual parallel systems). Insects offer many examples for both categories. For example, segregate parallel systems for different chemical stimuli are realized in specialized neuronal streams for processing sex pheromones and CO2. Dual parallel streams related to similar or overlapping odor stimuli are prominent in Hymenoptera. Here, a clear separation of sensory tracts to higher-order brain centers is present despite no apparent differences regarding the classes or categories of olfactory stimuli being processed. In this paper, we review...

Abstract: Alzheimer's disease often results in impaired olfactory perceptual acuity—a potential biomarker of the disorder. However, the usefulness of olfactory screens to serve as informative indicators of Alzheimer's is precluded by a lack of knowledge regarding why the disease impacts olfaction. We addressed this question by assaying olfactory perception and amyloid-β (Aβ) deposition throughout the olfactory system in mice that overexpress a mutated form of the human amyloid-β precursor protein. Such mice displayed progressive olfactory deficits that mimic those observed clinically—some evident at 3 months of age. Also, at 3 months of age, we observed nonfibrillar Aβ deposition within the olfactory bulb—earlier than deposition within any other brain region. There was also a correlation between olfactory deficits and the spatial-temporal pattern of Aβ deposition. Therefore, nonfibrillar, versus fibrillar, Aβ-related mechanisms likely contribute to early olfactory perceptual loss in Alzheimer's disease. Furthermore, these results present the odor cross-habituation test as a powerful behavioral assay, which reflects Aβ deposition and thus may serve to monitor the efficacy of therapies aimed at reducing Aβ.

Abstract: The canine nasal cavity contains hundreds of millions of sensory neurons, located in the olfactory epithelium that lines convoluted nasal turbinates recessed in the rear of the nose. Traditional explanations for canine olfactory acuity, which include large sensory organ size and receptor gene repertoire, overlook the fluid dynamics of odorant transport during sniffing. But odorant transport to the sensory part of the nose is the first critical step in olfaction. Here we report new experimental data on canine sniffing and demonstrate allometric scaling of sniff frequency, inspiratory airflow rate and tidal volume with body mass. Next, a computational fluid dynamics simulation of airflow in an anatomically accurate three-dimensional model of the canine nasal cavity, reconstructed from high-resolution magnetic resonance imaging scans, reveals that, during sniffing, spatially separate odour samples are acquired by each nostril that may be used for bilateral stimulus intensity comparison and odour source localization. Inside the nose, the computation shows that a unique nasal airflow pattern develops during sniffing, which is optimized for odorant transport to the olfactory part of the nose. These results contrast sharply with nasal airflow in the human. We propose that mammalian olfactory function and acuity may largely depend on odorant transport by nasal airflow patterns resulting from either the presence of a highly developed olfactory recess (in macrosmats such as the canine) or the lack of one (in microsmats including humans).

Abstract: Many neurons release classical transmitters together with neuropeptide co-transmitters whose functions are incompletely understood. Here we define the relationship between two transmitters in the olfactory system of C. elegans, showing that a neuropeptide-to-neuropeptide feedback loop alters sensory dynamics in primary olfactory neurons. The AWC olfactory neuron is glutamatergic and also expresses the peptide NLP-1. Worms with nlp-1 mutations show increased AWC-dependent behaviors, suggesting that NLP-1 limits the normal response. The receptor for NLP-1 is the G protein-coupled receptor NPR-11, which acts in postsynaptic AIA interneurons. Feedback from AIA interneurons modulates odor-evoked calcium dynamics in AWC olfactory neurons and requires INS-1, a neuropeptide released from AIA. The neuropeptide feedback loop dampens behavioral responses to odors on short and long timescales. Our results point to neuronal dynamics as a site of behavioral regulation and reveal the ability of neuropeptide feedback to remodel sensory networks on multiple timescales.

Abstract: Within glomeruli, the initial sites of synaptic integration in the olfactory pathway, olfactory sensory axons terminate on dendrites of projection and juxtaglomerular (JG) neurons. JG cells form at least two major circuits: the classic intraglomerular circuit consisting of external tufted (ET) and periglomerular (PG) cells and an interglomerular circuit comprised of the long-range connections of short axon (SA) cells. We examined the projections and the synaptic inputs of identified JG cell chemotypes using mice expressing green fluorescent protein (GFP) driven by the promoter for glutamic acid decarboxylase (GAD) 65 kDa, 67 kDa, or tyrosine hydroxylase (TH). Virtually all (97%) TH+ cells are also GAD67+ and are thus DAergic–GABAergic neurons. Using a combination of retrograde tracing, whole-cell patch-clamp recording, and single-cell three-dimensional reconstruction, we show that different JG cell chemotypes contribute to distinct microcircuits within or between glomeruli. GAD65+ GABAergic PG cells ramify principally within one glomerulus and participate in uniglomerular circuits. DAergic–GABAergic cells have extensive interglomerular projections. DAergic–GABAergic SA cells comprise two subgroups. One subpopulation contacts 5–12 glomeruli and is referred to as “oligoglomerular.” Approximately one-third of these oligoglomerular DAergic SA cells receive direct olfactory nerve (ON) synaptic input, and the remaining two-thirds receive input via a disynaptic ON→ET→SA circuit. The second population of DAergic–GABAergic SA cells also disynaptic ON input and connect tens to hundreds of glomeruli in an extensive “polyglomerular” network. Although DAergic JG cells have traditionally been considered PG cells, their interglomerular connections argue that they are more appropriately classified as SA cells.

Abstract: Paradoxically, although humans have a superb sense of smell, they don’t trust their nose. Furthermore, although human odorant detection thresholds are very low, only unusually high odorant concentrations spontaneously shift our attention to olfaction. Here we suggest that this lack of olfactory awareness reflects the nature of olfactory attention that is shaped by the spatial and temporal envelopes of olfaction. Regarding the spatial envelope, selective attention is allocated in space. Humans direct an attentional spotlight within spatial coordinates in both vision and audition. Human olfactory spatial abilities are minimal. Thus, with no olfactory space, there is no arena for olfactory selective attention. Regarding the temporal envelope, whereas vision and audition consist of nearly continuous input, olfactory input is discreet, made of sniffs widely separated in time. If similar temporal breaks are artificially introduced to vision and audition, they induce “change blindness”, a loss of attentional capture that results in a lack of awareness to change. Whereas “change blindness” is an aberration of vision and audition, the long inter-sniff-interval renders “change anosmia” the norm in human olfaction. Therefore, attentional capture in olfaction is minimal, as is human olfactory awareness. All this, however, does not diminish the role of olfaction through sub-attentive mechanisms allowing subliminal smells a profound influence on human behavior and perception.

Abstract: The categorial nature of sensory, cognitive and behavioural acts indicates that the brain classifies neuronal activity patterns into discrete representations. Pattern classification may be achieved by abrupt switching between discrete activity states of neuronal circuits, but few experimental studies have directly tested this. We gradually varied the concentration or molecular identity of odours and optically measured responses across output neurons of the olfactory bulb in zebrafish. Whereas population activity patterns were largely insensitive to changes in odour concentration, morphing of one odour into another resulted in abrupt transitions between odour representations. These transitions were mediated by coordinated response changes among small neuronal ensembles rather than by shifts in the global network state. The olfactory bulb therefore classifies odour-evoked input patterns into many discrete and defined output patterns, as proposed by attractor models. This computation is consistent with perceptual phenomena and may represent a general information processing strategy in the brain.

Abstract: In the past decade, much has been elucidated regarding the functional organization of the axonal connection of olfactory sensory neurons to olfactory bulb (OB) glomeruli. However, the manner in which projection neurons of the OB process odorant input and send this information to higher brain centers remains unclear. Here, we report long-range, large-scale tracing of the axonal projection patterns of OB neurons using two-photon microscopy. Tracer injection into a single glomerulus demonstrated widely distributed mitral/tufted cell axonal projections on the lateroventral surface of the mouse brain, including the anterior/posterior piriform cortex (PC) and olfactory tubercle (OT). We noted two distinct groups of labeled axons: PC-orienting axons and OT-orienting axons. Each group occupied distinct parts of the lateral olfactory tract. PC-orienting axons projected axon collaterals to a wide area of the PC but only a few collaterals to the OT. OT-orienting axons densely projected axon collaterals primarily to the anterolateral OT (alOT). Different colored dye injections into the superficial and deep portions of the OB external plexiform layer revealed that the PC-orienting axon populations originated in presumed mitral cells and the OT-orienting axons in presumed tufted cells. These data suggest that although mitral and tufted cells receive similar odor signals from a shared glomerulus, they process the odor information in different ways and send their output to different higher brain centers via the PC and alOT.

Abstract: The olfactory system detects and discriminates myriad chemical structures across a wide range of concentrations. To meet this task, the system utilizes a large family of G protein–coupled receptors—the odorant receptors—which are the chemical sensors underlying the perception of smell. Interestingly, the odorant receptors are also involved in a number of developmental decisions, including the regulation of their own expression and the patterning of the olfactory sensory neurons' synaptic connections in the brain. This review will focus on the diverse roles of the odorant receptor in the function and development of the olfactory system.

Abstract: We investigated associations between olfactory function and gray matter thickness in 46 healthy young subjects by means of an automated technique for measuring cortical thickness. We used an extended version of the Sniffin’ Sticks test to assess olfactory function, including odor threshold, concentration discrimination, quality discrimination, and odor identification. We observed a correlation between olfactory performance and cortical thickness of structures involved in earlier and later stages of chemosensory processing such as right medial orbitofrontal cortex, right insula, and adjacent cortex. Furthermore, we found significant bilateral correlations of olfactory performance with cortical thickness of areas around the central sulcus bilaterally, structures responsible for voluntary respiration and sniffing. In addition to expected general sex effects on cortical thickness, we observed areas, such as the entorhinal cortex, occipital cortex, intraparietal sulcus and insula (all in the right hemisphere), where the correlation between higher order olfactory functions and cortical thickness differed between women and men. These data demonstrate, for some neuroanatomical structures, a link between cortical thickness and olfactory function, in that thicker cortex is usually associated with better performance, but not always. This association between anatomy and olfactory performance suggests a possible biological explanation for the high degree of individual differences and sex effects observed in higher order olfactory tasks.

Abstract: Clinical experience shows that the individual significance of olfactory function varies between subjects. In order to estimate these individual differences we developed a questionnaire to study the subjective importance of the sense of smell. Questions were arranged within three subscales: association with olfactory sensations, application of the sense of smell, and the readiness to draw consequences from the olfactory perception. The questionnaire was shown to be time efficient, suitable for normosmic subjects and patients with hyposmia or anosmia. It exhibited a good internal reliability (Cronbach’s Alpha = 0.77). First results in 123 subjects indicate that the subjective importance of the sense of smell stays at the same level throughout life-span despite of a decreased olfactory sensitivity. Furthermore, women reported a higher importance of olfaction. It is hoped that this questionnaire will contribute to clarify, for example, cross-cultural differences in the perception of odours.

Abstract: Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson’s disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Abstract: The mammalian olfactory system is well established for its remarkable capability of undergoing experience-dependent plasticity. Although this process involves changes at multiple stages throughout the central olfactory pathway, even the early stages of processing, such as the olfactory bulb and piriform cortex, can display a high degree of plasticity. As in other sensory systems, this plasticity can be controlled by centrifugal inputs from brain regions known to be involved in attention and learning processes. Specifically, both the bulb and cortex receive heavy inputs from cholinergic, noradrenergic, and serotonergic modulatory systems. These neuromodulators are shown to have profound effects on both odor processing and odor memory by acting on both inhibitory local interneurons and output neurons in both regions.

Abstract: Olfaction, taste and trigeminal function are three distinct modalities. However, in daily life they are often activated concomitantly. In health and disease, it has been shown that in two of these senses, the trigeminal and olfactory senses, modification of one sense leads to changes in the other sense and vice versa. The objective of the study was to investigate whether and (if so) how, the third modality, taste, is influenced by olfactory impairment. We tested 210 subjects with normal (n = 107) or impaired (n = 103) olfactory function for their taste identification capacities. Validated tests were used for olfactory and gustatory testing (Sniffin' Sticks, Taste Strips). In an additional experiment, healthy volunteers underwent reversible olfactory cleft obstruction to investigate short-time changes of gustatory function after olfactory alteration. Mean gustatory identification (taste strip score) for the subjects with impaired olfaction was 19.4 +/- 0.6 points and 22.9 +/- 0.5 points for those with normal olfactory function (t = 4.6, p < 0.001). The frequencies of both, smell and taste impairments interacted significantly (Chi(2), F = 16.4, p < 0.001), and olfactory and gustatory function correlated (r (210) = 0.30, p < 0.001). Neither age nor olfactory impairment cause effects interfered with this olfactory-gustatory interaction. In contrast, after short-lasting induced olfactory decrease, gustatory function remained unchanged. The present study suggests that longstanding impaired olfactory function is associated with decreased gustatory function. These findings seem to extend previously described mutual chemosensory interactions also to smell and taste. It further raises the question whether chemical senses in general decrease mutually after acquired damage.

Abstract: Olfactory dysfunction is known to occur before the appearance of the classical motor signs in Parkinson's disease (PD) and diffusion tensor imaging (DTI) studies in PD have reported fractional anisotropy (FA) reductions in the early disease stages. We aimed to investigate the relationship between olfactory dysfunction and white matter (WM) FA of central olfactory areas in early PD. Twenty-four patients at Hoehn and Yahr stages I and II and 24 healthy controls matched by age, gender and years of education participated in this study. DTI was acquired at a 3 Tesla scanner and odor identification was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). We performed FA voxelwise group comparisons in the central olfactory structures using tract-based spatial statistics (TBSS) and correlation analyses between FA values in these central olfactory areas and UPSIT scores. Patients with severe microsmia (UPSIT between 19 and 25) and anosmia (UPSIT lower or equal to 18) had lower FA values than PD patients with mild/moderate or no olfactory dysfunction (UPSIT between 26 and 40) and healthy controls in the WM adjacent to gyrus rectus. In addition, patients with anosmia had reduced FA in the WM surrounding primary olfactory areas in comparison with healthy controls. FA values in the WM adjacent to primary olfactory cortex and right gyrus rectus correlated with UPSIT scores in the PD group. This study demonstrates, for the first time, that microstructural WM reductions are present in the central olfactory system of early stage PD patients and that these reductions are associated with reduced ability to smell.

Abstract: The mammalian olfactory system detects an unlimited variety of odorants with a limited set of odorant receptors. To cope with the complexity of the odor world, each odorant receptor must detect many different odorants. The demand for low odor selectivity creates problems for the transduction process: the initial transduction step, the synthesis of the second messenger cAMP, operates with low efficiency, mainly because odorants bind only briefly to their receptors. Sensory cilia of olfactory receptor neurons have developed an unusual solution to this problem. They accumulate chloride ions at rest and discharge a chloride current upon odor detection. This chloride current amplifies the receptor potential and promotes electrical excitation. We have studied this amplification process by examining identity, subcellular localization, and regulation of its molecular components. We found that the Na+/K+/2Cl− cotransporter NKCC1 is expressed in the ciliary membrane, where it mediates chloride accumulation into the ciliary lumen. Gene silencing experiments revealed that the activity of this transporter depends on the kinases SPAK and OSR1, which are enriched in the cilia together with their own activating kinases, WNK1 and WNK4. A second Cl− transporter, the Cl−/HCO3− exchanger SLC4A1, is expressed in the cilia and may support Cl− accumulation. The calcium-dependent chloride channel TMEM16B (ANO2) provides a ciliary pathway for the excitatory chloride current. These findings describe a specific set of ciliary proteins involved in anion-based signal amplification. They provide a molecular concept for the unique strategy that allows olfactory sensory neurons to operate as efficient transducers of weak sensory stimuli.

Abstract: Insect mushroom bodies are required for diverse behavioral functions, including odor learning and memory. Using the numerically simple olfactory pathway of the Drosophila melanogaster larva, we provide evidence that the formation of appetitive olfactory associations relies on embryonic-born intrinsic mushroom body neurons (Kenyon cells). The participation of larval-born Kenyon cells, i.e., neurons that become gradually integrated in the developing mushroom body during larval life, in this task is unlikely. These data provide important insights into how a small set of identified Kenyon cells can store and integrate olfactory information in a developing brain. To investigate possible functional subdivisions of the larval mushroom body, we anatomically disentangle its input and output neurons at the single-cell level. Based on this approach, we define 10 subdomains of the larval mushroom body that may be implicated in mediating specific interactions between the olfactory pathway, modulatory neurons, and neuronal output.

Abstract: In mice, nonvolatile social cues are detected and analyzed by the accessory olfactory system (AOS). Here we provide a first view of information processing in the AOS with respect to individual chemical cues. 12 sulfated steroids, recently discovered mouse AOS ligands, caused widespread activity among vomeronasal sensory neurons (VSNs), yet VSN responses clustered into a small number of repeated functional patterns or processing streams. Downstream neurons in the accessory olfactory bulb (AOB) responded to these ligands with enhanced signal/noise compared to VSNs. Although the dendritic connectivity of AOB mitral cells suggests the capacity for broad integration, most sulfated steroid responses were well-modeled by linear excitatory drive from just one VSN processing stream. However, a substantial minority demonstrated multi-stream integration. Most VSN excitation patterns were also observed in the AOB, but excitation by estradiol sulfate processing streams was rare, suggesting AOB circuit organization is specific to the biological relevance of sensed cues.

Abstract: Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence that Apaf-1/caspase-9–mediated caspase signaling regulates the development of olfactory sensory neurons (OSNs), which includes axonal projection, synapse formation, and maturation of these neurons. This caspase signaling leads to a cleavage of Semaphorin 7A, a membrane-anchored semaphorin that is required for the proper axonal projection. Mutant mice deficient for apaf-1 or caspase-9 exhibit misrouted axons, impaired synaptic formation, and defects in the maturation of OSNs without affecting the number of these cells. Our findings suggest that Apaf-1/caspase-9–mediated nonapoptotic caspase signaling is required for the proper neural network formation during olfactory development.

Abstract: Several lineages within the Crustacea conquered land independently during evolution, thereby requiring physiological adaptations for a semi-terrestrial or even a fully terrestrial lifestyle. Birgus latro Linnaeus, 1767, the giant robber crab or coconut crab (Anomura, Coenobitidae), is the largest land-living arthropod and inhabits Indo-Pacific islands such as Christmas Island. B. latro has served as a model in numerous studies of physiological aspects related to the conquest of land by crustaceans. From an olfactory point of view, a transition from sea to land means that molecules need to be detected in gas phase instead of in water solution. Previous studies have provided physiological evidence that terrestrial hermit crabs (Coenobitidae) such as B. latro have a sensitive and well differentiated sense of smell. Here we analyze the brain, in particular the olfactory processing areas of B. latro, by morphological analysis followed by 3 D reconstruction and immunocytochemical studies of synaptic proteins and a neuropeptide. The primary and secondary olfactory centers dominate the brain of B. latro and together account for ca. 40% of the neuropil volume in its brain. The paired olfactory neuropils are tripartite and composed of more than 1,000 columnar olfactory glomeruli, which are radially arranged around the periphery of the olfactory neuropils. The glomeruli are innervated ca. 90,000 local interneurons and ca. 160,000 projection neurons per side. The secondary olfactory centers, the paired hemiellipsoid neuropils, are targeted by the axons of these olfactory projection neurons. The projection neuron axonal branches make contact to ca. 250.000 interneurons (per side) associated with the hemiellipsoid neuropils. The hemiellipsoid body neuropil is organized into parallel neuropil lamellae, a design that is quite unusual for decapod crustaceans. The architecture of the optic neuropils and areas associated with antenna two suggest that B. latro has visual and mechanosensory skills that are comparable to those of marine Crustacea. In parallel to previous behavioral findings that B. latro has aerial olfaction, our results indicate that their central olfactory pathway is indeed most prominent. Similar findings from the closely related terrestrial hermit crab Coenobita clypeatus suggest that in Coenobitidae, olfaction is a major sensory modality processed by the brain, and that for these animals, exploring the olfactory landscape is vital for survival in their terrestrial habitat. Future studies on terrestrial members of other crustacean taxa such as Isopoda, Amphipoda, Astacida, and Brachyura will shed light on how frequently the establishment of an aerial sense of olfaction evolved in Crustacea during the transition from sea to land. Amounting to ca. 1,000,000, the numbers of interneurons that analyse the olfactory input in B. latro brains surpasses that in other terrestrial arthropods, as e.g. the honeybee Apis mellifera or the moth Manduca sexta, by two orders of magnitude suggesting that B. latro in fact is a land-living arthropod that has devoted a substantial amount of nervous tissue to the sense of smell.