Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases. Diet is one of the most powerful determinants of gut microbiome community structure, and dietary habits are associated with brain health and disease. Recently, the metaorganismal (i.e., diet-microbe-host) trimethylamine N-oxide (TMAO) pathway has been linked to the development of several brain diseases including Alzheimer's, Parkinson's, and ischemic stroke. However, it is poorly understood how metaorganismal TMAO production influences brain function under normal physiological conditions. To address this, here we have reduced TMAO levels by inhibiting gut microbe-driven choline conversion to trimethylamine (TMA), and then performed comprehensive behavioral phenotyping in mice. Unexpectedly, we find that TMAO is particularly enriched in the murine olfactory bulb, and when TMAO production is blunted at the level of bacterial choline TMA lyase (CutC/D), olfactory perception is altered. Taken together, our studies demonstrate a previously underappreciated role for the TMAO pathway in olfactory-related behaviors.

Understanding the relationship between a stimulus and how it is perceived reveals fundamental principles about the mechanisms of sensory perception. While this stimulus-percept problem is mostly understood for color vision and tone perception, it is not currently possible to predict how a given molecule smells. While there has been some progress in predicting the pleasantness and intensity of an odorant, perceptual data for a larger number of diverse molecules are needed to improve current predictions. Towards this goal, we tested the olfactory perception of 480 structurally and perceptually diverse molecules at two concentrations using a panel of 55 healthy human subjects.

Inhibitory response occurs throughout the nervous system, including the peripheral olfactory system. While odor-evoked excitation in peripheral olfactory cells is known to encode odor information, the molecular mechanism and functional roles of odor-evoked inhibition remain largely unknown. Here, we examined Drosophila olfactory sensory neurons and found that inhibitory odors triggered outward receptor currents by reducing the constitutive activities of odorant receptors, inhibiting the basal spike firing in olfactory sensory neurons. Remarkably, this odor-evoked inhibition of olfactory sensory neurons elicited by itself a full range of olfactory behaviors from attraction to avoidance, as did odor-evoked olfactory sensory neuron excitation. These results indicated that peripheral inhibition is comparable to excitation in encoding sensory signals rather than merely regulating excitation. Furthermore, we demonstrated that a bidirectional code with both odor-evoked inhibition and excitation in single olfactory sensory neurons increases the odor-coding capacity, providing a means of efficient sensory encoding.

Sensory perception depends on interactions between external inputs transduced by peripheral sensory organs and internal network dynamics generated by central neuronal circuits. In the sensory cortex, desynchronized network states associate with high signal-to-noise ratio stimulus-evoked responses and heightened perception. Cannabinoid-type-1-receptors (CB1Rs) - which influence network coordination in the hippocampus - are present in anterior piriform cortex (aPC), a sensory paleocortex supporting olfactory perception. Yet, how CB1Rs shape aPC network activity and affect odor perception is unknown. Using pharmacological manipulations coupled with multi-electrode recordings or fiber photometry in the aPC of freely moving male mice, we show that systemic CB1R blockade as well as local drug infusion increases the amplitude of gamma oscillations in aPC, while simultaneously reducing the occurrence of synchronized population events involving aPC excitatory neurons. In animals exposed to odor sources, blockade of CB1Rs reduces correlation among aPC excitatory units and lowers behavioral olfactory detection thresholds. These results suggest that endogenous endocannabinoid signaling promotes synchronized population events and dampen gamma oscillations in the aPC which results in a reduced sensitivity to external sensory inputs.

A fast growing literature of multisensory emotion integration notwithstanding, the chemical senses, intimately associated with emotion, have been largely overlooked. Moreover, an ecologically highly relevant principle of "inverse effectiveness", rendering maximal integration efficacy with impoverished sensory input, remains to be assessed in emotion integration. Presenting minute, subthreshold negative (vs. neutral) cues in faces and odors, we demonstrated olfactory-visual emotion integration in improved emotion detection (especially among individuals with weaker perception of unimodal negative cues) and response enhancement in the amygdala. Moreover, while perceptual gain for visual negative emotion involved the posterior superior temporal sulcus/pSTS, perceptual gain for olfactory negative emotion engaged both the associative olfactory (orbitofrontal) cortex and amygdala. Dynamic causal modeling (DCM) analysis of fMRI timeseries further revealed connectivity strengthening among these areas during crossmodal emotion integration. That multisensory (but not low-level unisensory) areas exhibited both enhanced response and region-to-region coupling favors a top-down (vs. bottom-up) account for olfactory-visual emotion integration. Current findings thus confirm the involvement of multisensory convergence areas, while highlighting unique characteristics of olfaction-related integration. Furthermore, successful crossmodal binding of subthreshold aversive cues not only supports the principle of "inverse effectiveness" in emotion integration but also accentuates the automatic, unconscious quality of crossmodal emotion synthesis.

A growing body of research aims at solving what is often referred to as the stimulus-percept problem in olfactory perception. Although computational efforts have made it possible to predict perceptual impressions from the physicochemical space of odors, studies with large psychophysical datasets from non-experts remain scarce. Following previous approaches, we developed a physicochemical odor space using 4094 molecular descriptors of 1389 odor molecules. For 20 of these odors, we examined associations with perceived pleasantness, intensity, odor quality and detection threshold, obtained from a dataset of 2000 naïve participants. Our results show significant differences in perceptual ratings, and we were able to replicate previous findings on the association between perceptual ratings and the first dimensions of the physicochemical odor space. However, the present analyses also revealed striking interindividual variations in perceived pleasantness and intensity. Additionally, interactions between pleasantness, intensity, and olfactory and trigeminal qualitative dimensions were found. To conclude, our results support previous findings on the relation between structure and perception on the group level in our sample of non-expert raters. In the challenging task to relate olfactory stimulus and percept, the physicochemical odor space can serve as a reliable and helpful tool to structure the high-dimensional space of olfactory stimuli. Nevertheless, human olfactory perception in the individual is not an analytic process of molecule detection alone, but is part of a holistic integration of multisensory inputs, context and experience.

Olfaction and gustation contribute both to the appreciation of food flavours. Although acquired loss of smell has profound consequences on the pleasure of eating, food habits and body weight, less is known about the impact of congenital olfactory impairment on gustatory processing. Here we examined taste identification accuracy and its neural correlates using functional magnetic resonance imaging (fMRI) in 12 congenitally olfactory impaired individuals and 8 normosmic controls. Results showed that taste identification was worse in congenitally olfactory impaired compared to control subjects. The fMRI results demonstrated that olfactory impaired individuals had reduced activation in medial orbitofrontal cortex (mOFC) relative to normosmic subjects while tasting. In addition, olfactory performance as measured with the Sniffin' Sticks correlated positively with taste-induced blood-oxygen-level dependent (BOLD) signal increases in bilateral mOFC and anterior insula. Our data provide a neurological underpinning for the reduced taste perception in congenitally olfactory impaired individuals.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Understanding how smell or taste translates into behavior remains challenging. We have developed a behavioral paradigm in Drosophila larvae to investigate reception and processing of appetitive olfactory inputs in higher-order olfactory centers. We found that the brief presentation of appetitive odors caused fed larvae to display impulsive feeding of sugar-rich food. Deficiencies in the signaling of neuropeptide F (NPF), the fly counterpart of neuropeptide Y (NPY), blocked appetitive odor-induced feeding by disrupting dopamine (DA)-mediated higher-order olfactory processing. We have identified a small number of appetitive odor-responsive dopaminergic neurons (DL2) whose activation mimics the behavioral effect of appetitive odor stimulation. Both NPF and DL2 neurons project to the secondary olfactory processing center; NPF and its receptor NPFR1 mediate a gating mechanism for reception of olfactory inputs in DL2 neurons. Our findings suggest that eating for reward value is an ancient behavior and that fly larvae are useful for studying neurobiology and the evolution of olfactory reward-driven behavior.

Anecdotal reports suggest that blind people might develop supra-normal olfactory abilities. However, scientific evidence shows a mixed pattern of findings. Inconsistent observations are reported for both sensory-driven olfactory tasks (e.g., odor threshold) and higher-order olfactory functions (e.g., odor identification). To quantify the evidence systematically, we conducted a review and meta-analysis. Studies were included if they examined olfactory function (i.e., odor threshold, odor discrimination, free odor identification, or cued odor identification) in blind compared with a sighted control group. Articles were identified through computerized literature search. A total of 18 studies focused on olfactory threshold (n = 1227: 590 blind and 637 sighted individuals), 14 studies targeted discrimination (n = 940: 455 blind and 485 sighted), 14 studies measured cued identification (n = 968: 468 blind and 500 sighted), and 7 studies (n = 443: 224 blind and 219 sighted individuals) assessed free identification. Overall, there were no differences in effect sizes between the blind and sighted individuals after correcting the results for publication bias. We additionally conducted an exploratory analysis targeting the role played by three moderators of interests: participants' age, the proportion of women versus men in each of the studies included into meta-analysis and onset of blindness (early blind vs. late-blind). However, none of the moderators affected the observed results. To conclude, blindness seems not to affect cued/free odor identification, odor discrimination or odor thresholds.

Nitric oxide (NO) modulates the dynamics of central olfactory networks and has been implicated in olfactory processing including learning. Land mollusks have a specialized olfactory lobe in the brain called the procerebral (PC) lobe. The PC lobe produces ongoing local field potential (LFP) oscillation, which is modulated by olfactory stimulation. We hypothesized that NO should be released in the PC lobe in response to olfactory stimulation, and to prove this, we applied an NO electrode to the PC lobe of the land slug Limax in an isolated tentacle-brain preparation. Olfactory stimulation applied to the olfactory epithelium transiently increased the NO concentration in the PC lobe, and this was blocked by the NO synthase inhibitor L-NAME at 3.7 mM. L-NAME at this concentration did not block the ongoing LFP oscillation, but did block the frequency increase during olfactory stimulation. Olfactory stimulation also enhanced spatial synchronicity of activity, and this response was also blocked by L-NAME. Single electrical stimulation of the superior tentacle nerve (STN) mimicked the effects of olfactory stimulation on LFP frequency and synchronicity, and both of these effects were blocked by L-NAME. L-NAME did not block synaptic transmission from the STN to the nonbursting (NB)-type PC lobe neurons, which presumably produce NO in an activity-dependent manner. Previous behavioral experiments have revealed impairment of olfactory discrimination after L-NAME injection. The recording conditions in the present work likely reproduce the in vivo brain state in those behavioral experiments. We speculate that the dynamical effects of NO released during olfactory perception underlie precise odor representation and memory formation in the brain, presumably through regulation of NB neuron activity.

The consequences of sub-lethal levels of ambient air pollution are underestimated for insects, for example, the accumulation of particulate matter on sensory receptors located on their antennae may have detrimental effects to their function. Here we show that the density of particulate matter on the antennae of houseflies (Musca domestica) collected from an urban environment increases with the severity of air pollution. A combination of behavioural assays, electroantennograms and transcriptomic analysis provide consistent evidence that a brief exposure to particulate matter pollution compromises olfactory perception of reproductive and food odours in both male and female houseflies. Since particulate matter can be transported thousands of kilometres from its origin, these effects may represent an additional factor responsible for global declines in insect numbers, even in pristine and remote areas.

While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics-independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates.

Previous research has shown that odorants consistently evoke associations with textures and their tactile properties like smoothness and roughness. Also, it has been observed that olfaction can modulate tactile perception. We therefore hypothesized that tactile roughness perception may be biased towards the somatosensory connotation of an ambient odorant. We performed two experiments to test this hypothesis. In the first experiment, we investigated the influence of ambient chemosensory stimuli with different roughness connotations on tactile roughness perception. In addition to a pleasant odor with a connotation of softness (PEA), we also included a trigeminal stimulant with a rough, sharp or prickly connotation (Ethanol). We expected that-compared to a No-odorant control condition-tactile texture perception would be biased towards smoothness in the presence of PEA and towards roughness in the presence of Ethanol. However, our results show no significant interaction between chemosensory stimulation and perceived tactile surface roughness. It could be argued that ambient odors may be less effective in stimulating crossmodal associations, since they are by definition extraneous to the tactile stimuli. In an attempt to optimize the conditions for sensory integration, we therefore performed a second experiment in which the olfactory and tactile stimuli were presented in synchrony and in close spatial proximity. In addition, we included pleasant (Lemon) and unpleasant (Indole) odorants that are known to have the ability to affect tactile perception. We expected that tactile stimuli would be perceived as less rough when simultaneously presented with Lemon or PEA (both associated with softness) than when presented with Ethanol or Indole (odors that can be associated with roughness). Again, we found no significant main effect of chemosensory condition on perceived tactile roughness. We discuss the limitations of this study and we present suggestions for future research.

In blood-feeding dipterans, olfaction plays a role in finding hosts and, hence, in spreading pathogens. Several pathogens are known to alter olfactory responses and behavior in vectors. As a mosquito-borne pathogen, Rift Valley Fever Virus (RVFV) can affect humans and cause great losses in livestock. We test the influence of RVFV infection on sensory perception, olfactory choice behavior and activity on a non-biting insect, Drosophila melanogaster, using electroantennograms (EAG), Y-maze, and locomotor activity monitor. Flies were injected with RVFV MP12 strain. Replication of RVFV and its persistence for at least seven days was confirmed by quantitative reverse transcription-PCR (RT-qPCR). One day post injection, infected flies showed weaker EAG responses towards 1-hexanol, vinegar, and ethyl acetate. In the Y-maze, infected flies showed a significantly lower response for 1-hexanol compared to uninfected flies. At days six or seven post infection, no significant difference between infected and control flies could be found in EAG or Y-maze anymore. Activity of infected flies was reduced at both time points. We found an upregulation of the immune-response gene, nitric oxide synthase, in infected flies. An infection with RVFV is able to transiently reduce olfactory perception and attraction towards food-related odors in Drosophila, while effects on activity and immune effector gene expression persist. A similar effect in blood-feeding insects could affect vector competence in RVFV transmitting dipterans.

The right orbitofrontal cortex (rOFC) has been proposed as the region where conscious olfactory perception arises; however, evidence supporting this hypothesis has all been collected from neuroimaging and lesion studies in which only correlation and not a temporal pattern can be established. Continuous theta burst stimulation (cTBS) causes a reversible disruption of cortical activity and has been used successfully to disrupt orbitofrontal activity. To overcome intrinsic limitations of current experimental research, a crossover, double-blind, prospective and longitudinal study was carried out in which cTBS was applied over the rOFC to evaluate its effect on odorant stimuli detection. All subjects received real and sham cTBS. Experimental procedures were done in two different sessions with a separation of at least one week between them to avoid carryover and learning effects. A total of 15 subjects completed the experiment, and their data were included in the final analysis (10 women, 5 men, mean age 22.40 ± 3.41). Every session consisted of two different measures of the conscious olfactory perception task: A baseline measure and one 5 min after cTBS/sham. Compared to baseline, marks in the olfactory task during the sham cTBS session increased (p = 0.010), while marks during the real cTBS session decreased (p = 0.017). Our results support the hypothesis that rOFC is an important node of a complex network required for conscious olfactory perception to arise. However, the exact mechanism that explains our results is unclear and could be explained by the disruption of other cognitive functions related to the rOFC.

In olfaction, to preserve the sensitivity of the response, the bioavailability of odor molecules is under the control of odorant-metabolizing enzymes (OMEs) expressed in the olfactory neuroepithelium. Although this enzymatic regulation has been shown to be involved in olfactory receptor activation and perceptual responses, it remains widely underestimated in vertebrates. In particular, the possible activity of OMEs in the nasal mucus, i.e. the aqueous layer that lined the nasal epithelium and forms the interface for airborne odorants to reach the olfactory sensory neurons, is poorly known. Here, we used the well-described model of the mammary pheromone (MP) and behavioral response in rabbit neonates to challenge the function of nasal mucus metabolism in an unprecedented way. First, we showed, in the olfactory epithelium, a rapid glutathione transferase activity toward the MP by ex vivo real-time mass spectrometry (PTR-MS) which supported an activity in the closest vicinity of both the odorants and olfactory receptors. Indeed and second, both the presence and activity of glutathione transferases were evidenced in the nasal mucus of neonates using proteomic and HPLC analysis respectively. Finally, we strikingly demonstrated that the deregulation of the MP metabolism by in vivo mucus washing modulates the newborn rabbit behavioral responsiveness to the MP. This is a step forward in the demonstration of the critical function of OMEs especially in the mucus, which is at the nasal front line of interaction with odorants and potentially subjected to physiopathological changes.

In the nasal olfactory epithelium, olfactory metabolic enzymes ensure odorant clearance from the olfactory receptor environment. This biotransformation of odorants into deactivated polar metabolites is critical to maintaining peripheral sensitivity and perception. Olfactory stimuli consist of complex mixtures of odorants, so binding interactions likely occur at the enzyme level and may impact odor processing. Here, we used the well-described model of mammary pheromone-induced sucking-related behavior in rabbit neonates. It allowed to demonstrate how the presence of different aldehydic odorants efficiently affects the olfactory metabolism of this pheromone (an aldehyde too: 2-methylbut-2-enal). Indeed, according to in vitro and ex vivo measures, this metabolic interaction enhances the pheromone availability in the epithelium. Furthermore, in vivo presentation of the mammary pheromone at subthreshold concentrations efficiently triggers behavioral responsiveness in neonates when the pheromone is in mixture with a metabolic challenger odorant. These findings reveal that the periphery of the olfactory system is the place of metabolic interaction between odorants that may lead, in the context of odor mixture processing, to pertinent signal detection and corresponding behavioral effect.

Some types of glia play an active role in neuronal signaling by modifying their activity although little is known about their role in sensory information signaling at the receptor level. In this research, we report a functional role for the glia that surround the soma of the olfactory receptor neurons (OSNs) in adult Drosophila. Specific genetic modifications have been targeted to this cell type to obtain live individuals who are tested for olfactory preference and display changes both increasing and reducing sensitivity. A closer look at the antenna by Ca2+ imaging shows that odor activates the OSNs, which subsequently produce an opposite and smaller effect in the glia that partially counterbalances neuronal activation. Therefore, these glia may play a dual role in preventing excessive activation of the OSNs at high odorant concentrations and tuning the chemosensory window for the individual according to the network structure in the receptor organ.

The olfactory response of the vinegar fly Drosophila melanogaster to food odor is modulated by starvation. Here we show that this modulation is not restricted to food odors and their detecting sensory neurons but rather increases the behavioral response to odors as different as food odors, repellents and pheromones. The increased behavioral responsiveness is paralleled by an increased physiological sensitivity of sensory neurons regardless whether they express olfactory or ionotropic receptors and regardless whether they are housed in basiconic, coeloconic, or trichoid sensilla. Silencing several genes that become up-regulated under starvation confirmed the involvement of the short neuropeptide f receptor in the starvation effect. In addition it revealed that the CCHamide-1 receptor is another important factor governing starvation-induced olfactory modifications.