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Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome1-3. How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense.

Diverse sensory organs, including mammalian taste buds and insect chemosensory sensilla, show a marked compartmentalization of receptor cells; however, the functional impact of this organization remains unclear. Here we show that compartmentalized Drosophila olfactory receptor neurons (ORNs) communicate with each other directly. The sustained response of one ORN is inhibited by the transient activation of a neighbouring ORN. Mechanistically, such lateral inhibition does not depend on synapses and is probably mediated by ephaptic coupling. Moreover, lateral inhibition in the periphery can modulate olfactory behaviour. Together, the results show that integration of olfactory information can occur via lateral interactions between ORNs. Inhibition of a sustained response by a transient response may provide a means of encoding salience. Finally, a CO(2)-sensitive ORN in the malaria mosquito Anopheles can also be inhibited by excitation of an adjacent ORN, suggesting a broad occurrence of lateral inhibition in insects and possible applications in insect control.

Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established, the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline. [ABSTRACT FROM AUTHOR]

Many species are critically dependent on olfaction for survival. In the main olfactory system of mammals, odours are detected by sensory neurons that express a large repertoire of canonical odorant receptors and a much smaller repertoire of trace amine-associated receptors (TAARs). Odours are encoded in a combinatorial fashion across glomeruli in the main olfactory bulb, with each glomerulus corresponding to a specific receptor. The degree to which individual receptor genes contribute to odour perception is unclear. Here we show that genetic deletion of the olfactory Taar gene family, or even a single Taar gene (Taar4), eliminates the aversion that mice display to low concentrations of volatile amines and to the odour of predator urine. Our findings identify a role for the TAARs in olfaction, namely, in the high-sensitivity detection of innately aversive odours. In addition, our data reveal that aversive amines are represented in a non-redundant fashion, and that individual main olfactory receptor genes can contribute substantially to odour perception. [ABSTRACT FROM AUTHOR]

Mushroom bodies are a well-known site for associative learning in insects. Yet the precise mechanisms that underlie plasticity there and ensure their specificity remain elusive. In locusts, the synapses between the intrinsic mushroom body neurons and their postsynaptic targets obey a Hebbian spike-timing-dependent plasticity (STDP) rule. Although this property homeostatically regulates the timing of mushroom body output, its potential role in associative learning is unknown. Here we show in vivo that pre-post pairing causing STDP can, when followed by the local delivery of a reinforcement-mediating neuromodulator, specify the synapses that will undergo an associative change. At these synapses, and there only, the change is a transformation of the STDP rule itself. These results illustrate the multiple actions of STDP, including a role in associative learning, despite potential temporal dissociation between the pairings that specify synaptic modification and the delivery of reinforcement-mediating neuromodulator signals. [ABSTRACT FROM AUTHOR]

Olfactory systems encode odours by which neurons respond and by when they respond. In mammals, every sniff evokes a precise, odour-specific sequence of activity across olfactory neurons. Likewise, in a variety of neural systems, ranging from sensory periphery to cognitive centres, neuronal activity is timed relative to sampling behaviour and/or internally generated oscillations. As in these neural systems, relative timing of activity may represent information in the olfactory system. However, there is no evidence that mammalian olfactory systems read such cues. To test whether mice perceive the timing of olfactory activation relative to the sniff cycle ('sniff phase'), we used optogenetics in gene-targeted mice to generate spatially constant, temporally controllable olfactory input. Here we show that mice can behaviourally report the sniff phase of optogenetically driven activation of olfactory sensory neurons. Furthermore, mice can discriminate between light-evoked inputs that are shifted in the sniff cycle by as little as 10 milliseconds, which is similar to the temporal precision of olfactory bulb odour responses. Electrophysiological recordings in the olfactory bulb of awake mice show that individual cells encode the timing of photoactivation in relation to the sniff in both the timing and the amplitude of their responses. Our work provides evidence that the mammalian olfactory system can read temporal patterns, and suggests that timing of activity relative to sampling behaviour is a potent cue that may enable accurate olfactory percepts to form quickly. [ABSTRACT FROM AUTHOR]

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Nav1.7, causes a congenital inability to experience pain in humans. Here we show that Nav1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Nav1.7 in odour perception, we generated conditional null mice in which Nav1.7 was removed from all olfactory sensory neurons. In the absence of Nav1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. [ABSTRACT FROM AUTHOR]

Chemotactic bacteria rely on local concentration gradients to guide them towards the source of a nutrient. Such local cues pointing towards the location of the source are not always available at macroscopic scales because mixing in a flowing medium breaks up regions of high concentration into random and disconnected patches. Thus, animals sensing odours in air or water detect them only intermittently as patches sweep by on the wind or currents. A macroscopic searcher must devise a strategy of movement based on sporadic cues and partial information. Here we propose a search algorithm, which we call ‘infotaxis’, designed to work under such conditions. Any search process can be thought of as acquisition of information on source location; for infotaxis, information plays a role similar to concentration in chemotaxis. The infotaxis strategy locally maximizes the expected rate of information gain. We demonstrate its efficiency using a computational model of odour plume propagation and experimental data on mixing flows. Infotactic trajectories feature ‘zigzagging’ and ‘casting’ paths similar to those observed in the flight of moths. The proposed search algorithm is relevant to the design of olfactory robots, but the general idea of infotaxis can be applied more broadly in the context of searching with sparse information. [ABSTRACT FROM AUTHOR]

Centre-surround inhibition-the suppression of activity of neighbouring cells by a central group of neurons-is a fundamental mechanism that increases contrast in patterned sensory processing. The initial stage of neural processing in olfaction occurs in olfactory bulb glomeruli, but evidence for functional interactions between glomeruli is fragmentary. Here we show that the so-called ‘short axon’ cells, contrary to their name, send interglomerular axons over long distances to form excitatory synapses with inhibitory periglomerular neurons up to 20-30 glomeruli away. Interglomerular excitation of these periglomerular cells potently inhibits mitral cells and forms an on-centre, off-surround circuit. This interglomerular centre-surround inhibitory network, along with the well-established mitral-granule-mitral inhibitory circuit, forms a serial, two-stage inhibitory circuit that could enhance spatiotemporal responses to odours. [ABSTRACT FROM AUTHOR]

Determines whether or not V1r gene receptors are involved in the behavioral and electrophysiological responses to pheromones by deleting a cluster of V1r genes in the germ line of mice. Deficits in a subset of vomeronasal organ (VNO)-dependent behaviors that are exhibited by the mutant mice; Failure of the epithelium of the VNO of the mutant mice to respond detectably to specific pheromonal ligands.

Presents a study on the olfactory functions of the tiger salamander. Translation of olfactory stimuli to perception; Discussions on the aspects of olfactory coding; Relationship between odorants and action potential firing patterns from individual neurons.

Examines the mechanisms involved in olfaction. Anatomical organization of the olfactory system; Odor receptors in vertebrates and mammals; Tuning curves in primary sensory cells; Olfactory thresholds measured behaviorally in animals and humans and in single cell recordings; Description of accessory organs involved in the olfactory system.

Shows that with naturally intermittent odor stimulation, spike patterns recorded from moth antennal-lobe output neurons varied predictably with the fine-scale temporal dynamics and intensity of the odor. How this finding supports the hypothesis the olfactory circuits compensate for contextual variations in the stimulus pattern with high temporal precision; Observation that the timing of output neuron activity is constantly modulated to reflect ongoing changes in stimulus intensity and dynamics that occur on a millisecond timescale.

There is strong evidence of brain-related abnormalities in COVID-19 1-13 . However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up., (© 2022. The Author(s).)

Presents research which sought to determine whether sniffing can induce activation in the piriform of humans. Role of sniffing in smell, or olfaction; Sniffing inducing an oscillation of activity in the olfactory bulb; Use of functional magnetic resonance imaging (fMRI); Findings; Source of sniff-induced activation; Distinction in brain organization depending on smelling or sniffing.

Presents research which used honeybees to show that odor encoding involves the oscillatory synchronization of assemblies of projection neurons and that this synchronization is selectively abolished by picotoxin. Description of stimulus-evoked oscillatory synchronization of neural assemblies in olfactory and visual systems; Use of behavioral learning paradigm; Relevance of oscillatory synchronization; Implications.

Reports the results of a study which investigated neuronal population responses to odorants delivered naturally to the honeybee. The use of optical recordings n the honeybee brain; The ability of odors to evoke specific spatio-temporal excitation patterns in the antennal lobe; The antennal lobe being the structural and functional analogue of the olfactory bulb; The potential for the formation of singular codes for complex odor blends.

Shows that the transduction current in rat olfactory receptor cells is initiated by cyclic-nucleotide-gated channels. Olfactory function in mammals and amphibians; Absence of chloride- (Cl) channels in mammals; Nonlinear amplifications of the transduction signal as a function of the Cl-channel.

States that odorant stimulation leads to a depolarization of olfactory receptor neurons. Mechanism underlying this transduction; Adenyl cyclase activity; Another mechanism that is not as well established; Additional information.

Reports the identification of new members of the gene family encoding putative odorant receptors and demonstrates that they are indeed transcribed in olfactory receptor neurons. Second messenger levels in receptor-expressing Sf9 cells; Polymerase chain reaction (PCR); Hybridization of S-labelled OR5 antisense RNA to mRNAs in coronal sections of rat olfactory epithelium; Further details.

Presents the molecular cloning and expression of an olfactory-specific UGT. Suggests a role for olfactory UGT in terminating diverse odorant signals.

Reports an odorant-induced, transient accumulation of cyclic AMP in isolated olfactory cilia from rats, and the generation of inositol trisphosphate in antennal preparations from insects. Both show subsecond time courses that are sufficiently rapid to mediate the odorant-regulated permeability of olfactory receptor cells. Research methods; Discussion.

The article profiles Jacek Koziel, an analytical chemist in the Department of Agriculture & Biosystems Engineering. Koziel specializes in finding and identifying trace volatile organic compounds responsible for odor. On a pig farm in Iowa, he shows some of the peaks and troughs of life as a human detector. Koziel uses a gas chromatography mass spectometry olfactometer to catalog manure's most offensive components. The article details how Koziel conducts simultaneous chemical and nose "detection" analyses of air samples.