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... 44,45 Only five (VN1R1-5) have been reported to be expressed in humans, notably not in the VNO but in the MOE, and to respond in a similar way to other olfactory receptors in cell cultures. [46][47][48] One of the genes necessary for the signal transduction pathway downstream of the vomeronasal receptors in rodents (Trpc2) is also a pseudogene in humans, further indicating a different mechanistic function for these receptors in humans compared with rodents. 49 The natural monoterpene myrtenal and the synthetic agonist Hedione have both been found to activate the human vomeronasal type-1 receptor 1 (VN1R1). ...
... 49 The natural monoterpene myrtenal and the synthetic agonist Hedione have both been found to activate the human vomeronasal type-1 receptor 1 (VN1R1). 48,50 The latter has sex-differentiated effects on hypothalamus activity, increasing it significantly more in females than males. 48 The gene VN1R1 contains two nonsynonymous single-nucleotide polymorphisms (rs61744949; rs28649880), in complete linkage disequilibrium with each other. ...
... 48,50 The latter has sex-differentiated effects on hypothalamus activity, increasing it significantly more in females than males. 48 The gene VN1R1 contains two nonsynonymous single-nucleotide polymorphisms (rs61744949; rs28649880), in complete linkage disequilibrium with each other. ...
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Pheromones regulate social and reproductive behavior in most mammalian species. These effects are mediated by the vomeronasal and main olfactory systems. Effects of putative pheromones on human neuroendocrine activity, brain activity and attractiveness ratings suggest that humans may communicate via similar chemosignaling. Here we studied two samples of younger and older individuals, respectively, with respect to one nonsynonymous polymorphism in the gene encoding the human vomeronasal type-1 receptor 1, VN1R1, and one nonsynonymous polymorphism in the gene encoding the olfactory receptor OR7D4. Participants in both samples had self-reported their sociosexual behavior using the sociosexual orientation inventory, including questions regarding lifetime number of one-night stands, number of partners last year and expected number of partners the coming 5 years. In women, there was a significant association between the VN1R1 polymorphism and sociosexual behavior in both samples, driven specifically by the question regarding one-night stands. Our results support the hypothesis that human social interaction is modulated by communication via chemosignaling.
... Thus, whereas it is largely accepted that reciprocal behavior facilitates cooperation, the bio-chemical mechanisms that underlie and moderate this behavior remain largely unknown. The present research suggests chemosensation (i.e., chemical communication) to contribute to the explanation of human reciprocal impulses by combining research methods from neuroscience, physiology (Wallrabenstein et al., 2015), and experimental economics. Whereas many animals use airborne chemicals to communicate, it remains a largely open and highly controversial research question whether humans may use chemosignals for social communication. ...
... But up to today, there is limited, if any, evidence that links another defining characteristic of human behavior-our ability to successfully cooperate with strangers-to chemosensory perception. Our research aims to fill that gap by investigating if a subtle application of an odorant that has been shown to affect chemosensory systems in humans (Wallrabenstein et al., 2015) may alter subsequent reciprocity in terms of costly reciprocal punishments and rewards in laboratory games. ...
... The perception of mammalian chemosignals is mainly achieved in the main olfactory epithel (MOE) and the vomeronasal organ (VNO). Partly, the controversy about humans' ability to rely on chemosignals may result from the knowledge that humans lack a functional VNO and have silenced most of the VNO receptor genes [i.e., only five genes (V1N1-5) are still functional; Wallrabenstein et al., 2015]. This does, however, not necessarily lead to the conclusion that chemosensory communication is entirely disabled (Witt and Hummel, 2006). ...
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Cooperation among unrelated humans is frequently regarded as a defining feature in the evolutionary success of our species. Whereas, much research has addressed the strategic and cognitive mechanisms that underlie cooperation, investigations into chemosensory processes have received very limited research attention. To bridge that gap, we build on recent research that has identified the chemically synthesized odorant Hedione (HED) as a ligand for the putative human pheromone receptor (VN1R1) expressed in the olfactory mucosa, and hypothesize that exposure to HED may increase reciprocity. Applying behavioral economics paradigms, the present research shows that exposure to the ligand causes differentiated behavioral effects in reciprocal punishments (Study 1) as well as rewards (Study 2), two types of behaviors that are frequently regarded as essential for the development and maintenance of cooperation.
... Additionally, women are believed to perform better than men in olfaction tests that required odor identification or odor detection thresholds (Doty et al. 1985) and in odor memory tasks (Larsson et al. 2004). Despite efforts to observe the neural network that underlies these gender effects (Evans et al. 1995;Lundström and Hummel 2006;Lundström et al. 2005), and although several fMRI studies have explored this question in the context of intersubject variability in olfaction (Morrot et al. 2013), hedonic valence of odors (Royet et al. 2003), and pheromone receptor stimulation (Wallrabenstein et al. 2015), results have not been conclusive yet (Seubert et al. 2013;Yousem et al. 1999). Thus, new fMRI studies are needed in order to obtain concluding results that can guide clinical practice. ...
... Finally, in order to provide a positive control for sex effects in our experiment, differences in the activity of the hypothalamus were explored. This structure was chosen due to its sexually dimorphic characteristics (Swaab et al. 1993;Goldstein et al. 2001), its strong connections with the olfactory system (Price et al. 1991), and its sex-differentiated differential response to specific odors (e.g., hedione: Wallrabenstein et al. 2015). The MNI coordinates of the hypothalamic nuclei provided by Baroncini et al. (2012) were used to perform SVC (3 mm radius). ...
... Likewise, these results are coherent with the reported sex-related differences in the olfactory system of other mammals (Price 2004) and reinforce previous micro and macroanatomical findings in humans. For example, the differential activity observed in the hypothalamus (men > women) is consistent with the anatomical differences described in humans (Swaab et al. 1993;Goldstein et al. 2001) and provides new data about the sex-differentiated participation of this structure in human olfaction (Wallrabenstein et al. 2015). The most prominent sex differences appeared in the right middle/superior temporal lobe, areas that participate in olfaction (Gottfried 2015), especially when trigeminal odors are delivered (Boyle et al. 2007;Hummel et al. 2005). ...
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Introduction Olfactory dysfunction is an early marker of neurological disease and a common symptom in psychotic disorders. Previous anatomical and functional research suggests that sex effects may be crucial in the assessment of the olfactory system. Nonetheless, the neural mechanisms through which the factor sex impacts olfactory perception are still not well understood. In this context, we use fMRI to investigate sex differences in the passive processing of chemical stimuli, in order to obtain new neuroscientific data that may help improve the assessment of odor perception. Methods Thirty healthy subjects (17 women) were stimulated with mint and butanol (event-related design) in a 3.0-T MRI scanner. A one-sample t test analysis was performed in order to observe olfactory-related activations. Intergroup differences (women vs. men) and the influence of each aroma were analyzed using a 2 × 2 ANOVA and post hoc contrasts. Results Men and women showed differential activity (males > females) in right superior/middle temporal areas, the right inferior frontal cortex, and the hypothalamus. Both groups showed a predominance of the right hemisphere for the processing of odors. Conclusion Functional differences between women and men in olfaction are not restricted to specific sensory areas and reflect a more general sex-dependent effect in multisensory integration processes. Implications Considering sex differences is essential in order to develop more specific and efficient strategies for the assessment and rehabilitation of the olfactory system and for the interpretation of the olfactory loss as an early biomarker of neurological and psychiatric diseases.
... Even though it is not released by humans, it seems to mimic the natural (unknown) molecules at the receptor site. Hedione is the first identified ligand of the human VN1R1 receptor (Wallrabenstein et al., 2015). This receptor is structurally homologous to a pheromone receptor in the rodent vomeronasal system (Boschat et al., 2002). ...
... This receptor is structurally homologous to a pheromone receptor in the rodent vomeronasal system (Boschat et al., 2002). Although there is a consensus that humans lack a functional vomeronasal organ (VNO; Smith et al., 2014), the VN1R1 receptor is one of five VNO receptor types that are still expressed in the human nasal mucosa (Rodriguez et al., 2000;Wallrabenstein et al., 2015). To what extent it is involved in human chemosignal detection is currently subject to investigation. ...
... To what extent it is involved in human chemosignal detection is currently subject to investigation. Evidence from an fMRI study using Hedione to activate the VN1R1 receptor suggests stronger activations in limbic brain regions (amygdala, hippocampus) and the hypothalamus in contrast to a common floral odor (phenylethyl alcohol; Wallrabenstein et al., 2015). The hypothalamic activation, being ten times larger in females than in male participants, led the authors to consider a modulation of hormonal secretion by Hedione. ...
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Observing another person in a stressful situation can cause a full-blown physiological stress response in the observer, which is referred to as empathic stress. One under through which stress-related information might be transmitted between individuals in conditions of empathic stress is chemosensory communication. In the present study, we investigated whether the odorant Hedione, as a potential chemosignal, affects the empathic stress response at a physiological and psychological level. For this purpose, two experiments were designed, each testing one group of participants in an odor-free room and a second group in a room scented with Hedione. In Experiment 1, 60 participants (25 males) watched a video of an unknown female participant in the Trier Social Stress Test (TSST). In Experiment 2, 37 free-cycling females watched a live video of a male participant in the TSST. Observers’ psychological and physiological stress response was captured via repeated measurements of salivary cortisol, alpha-amylase, and self-report ratings. Empathy with the stressed participants was assessed on the dimensions of personal distress and empathic concern of the Emotional Response Scale (ERS). Our results show no substantial physiological stress response in the observers and no effect of Hedione on physiological stress measures. Further, in Experiment 1, there was no subjective stress elicited by the video and no effect of Hedione. In Experiment 2, the observation was perceived as stressful and Hedione reduced subjective vicarious stress. The subjective stress response was associated with the Observers’ direct personal distress, but not with their empathic concern for the target in both experiments. Based on the findings presented above, we conclude that under conditions of empathic stress, Hedione alleviates subjectively perceived stress felt when observing another person being stressed, while leaving empathic concern for the target unaffected. In this regard, future research is warranted to clarify the underlying mechanisms of this effect.
... The presentation of hedione (floral smell), a putative agonist for vomeronasal receptors, resulted in bilateral amygdala activation (Wallrabenstein et al., 2015). ...
... Unilateral ROI response (yellow) was found by: Burke et al. (2012) and Mujica-Parodi et al. (2009). Bilateral ROI response (blue) was found by Wallrabenstein et al. (2015). No studies found whole brain bilateral responses. ...
Article
This review serves as a comprehensive discussion of chemosensory stimulation of the amygdala in healthy humans. Following an introduction of the neuroanatomy of chemosensory processing in primary and secondary olfactory structures, functional resonance magnetic imaging and positron imaging tomography studies are systematically categorized based on valence of stimuli, stimulus concentration, and paradigm-dependent amygdala activation. The amygdala shows patterns of lateralization due to stimulus valence. Main findings include pleasant odors being associated with bilateral or left amygdala activation, and unpleasant odors being associated with activation of the right amygdala, suggesting a crucial role of the right amygdala in evolutionary preservation. Potentially threatening social stimuli, however, might be processed apart from the olfactory system and tend to activate the left amygdala. Amygdala response to chemosensory stimuli correlated with simultaneous activation in the orbitofrontal cortex (OFC), piriform cortex (PC), and insula, suggesting a close-knit network of these areas during stimulus processing.
... As we were looking for a possible oxytocin release, it was specifically checked whether the odors would be related to enhanced hypothalamic activation. For this purpose, a region-of-interest (ROI) sphere of 6 mm 3 was created around the hypothalamic peak activation observed in a previous odor study (3 0 -8; MNI space, Wallrabenstein et al. 2015) and a threshold of p < 0.01 (uncorrected) was applied. The more liberal threshold was used, as the ROI analysis minimizes the possibility of false-positive responses; however, interpretation should nevertheless be considered with respect to this level. ...
... Gender-specific effects were observed for the hypothalamus, with enhanced activation in men for Oriental and an enhanced activation in women for Deep Sleep. The result of gender-differentiated hypothalamic activation of odors is in line with previous findings of sex differences in the hypothalamus associated with putative pheromone inhalation (Wallrabenstein et al. 2015), but given the a priori search and activation probability threshold, it would be preferable to conduct further studies into this. ...
... As we were looking for a possible oxytocin release, it was specifically checked whether the odors would be related to enhanced hypothalamic activation. For this purpose, a region-of-interest (ROI) sphere of 6 mm 3 was created around the hypothalamic peak activation observed in a previous odor study (3 0 -8; MNI space, Wallrabenstein et al. 2015) and a threshold of p < 0.01 (uncorrected) was applied. The more liberal threshold was used, as the ROI analysis minimizes the possibility of false-positive responses; however, interpretation should nevertheless be considered with respect to this level. ...
... Gender-specific effects were observed for the hypothalamus, with enhanced activation in men for Oriental and an enhanced activation in women for Deep Sleep. The result of gender-differentiated hypothalamic activation of odors is in line with previous findings of sex differences in the hypothalamus associated with putative pheromone inhalation (Wallrabenstein et al. 2015), but given the a priori search and activation probability threshold, it would be preferable to conduct further studies into this. ...
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Introduction Olfaction has an important role in physiological and affective processes, as well as the potential to have profound effects on activities such as sleep and learning. We investigated two commercially manufactured odors (“Deep Sleep” and “Oriental,” from This Works) purported to promote sleep, compared with control odor, where we aimed to explore whether neural and behavioral differences existed after odor inhalation. Methods In a neuroimaging study, 30 healthy participants were exposed to the odors via an olfactometer during functional magnetic resonance imaging (fMRI). In a further behavioral study using 12 chronic insomniacs, we investigated whether the commercial odors showed effects on sleep during a double-blind, randomized home evaluation. Results In the neuroimaging, the odors were related to activation of olfactory-relevant areas, such as the orbitofrontal cortex, and we found positive connectivity between the piriform cortex and the hippocampus, amygdala, insula, and middle cingulate cortex. Deep Sleep specifically activated the superior temporal gyrus, whereas Oriental activated the caudate. Further, these commercial odors showed some beneficial impact on sleep. Conclusions The perceptual and neural impacts of the commercial odors showed that olfactory stimulation can potentially aid sleep and modify affective processes in a number of ways. Implications The present work opens up opportunities for further investigations into how different odors may lead to specific behavioral and physiological modifications, such as their impact on sleep and well-being, which may provide non-pharmacological alternative approaches.
... Adding to this notion is the fact that the human genome harbors approximately 200 VN1R pseudogenes but only five remnant, putative functional genes of this family [99][100][101]. Functional VN1R supposedly recognize small volatiles such as key food odorants, compounds from axillary sweat, or sulfated steroids [102][103][104]. Despite their many similarities to OR, the expression of VN1R in leukocytes has not been demonstrated yet. ...
Chapter
Chemosensory taste and smell perceptions are induced by adequate stimuli from our chemical environment interacting with their ca. 400 different odorant receptor types or 25 bitter taste receptor types, and sweet and umami receptor dimers in the sensory cells of the olfactory or gustatory epithelia, respectively. Beyond an expression in their canonical chemosensory epithelia, there is increasing evidence for an ectopic expression of at least some 90 olfactory and taste G protein-coupled receptors in a variety of non-chemosensory epithelia and cells, including our cellular immune system. Here we review the evidence for the expression of chemosensory receptors in different types of blood cells, and discuss their putative immunological functions and roles as targets for receptor- and immune cell-specific bioactives, such as foodborne flavor chemicals, or allelochemicals in general.
... The neuroprotective properties of sex steroids against various brain diseases, such as PD, together with a modulation of dopaminergic brain transmission by sex steroids, are well known. Recently, a greater striatal dopamine-transporter (DAT) activity in women than in men was demonstrated, but a more rapid decline of this activity with aging was exhibited in women, implying that DAT activity and then dopamine uptake in neurons are sustained by sex steroids [31]. This work suggested that the effect of sex steroids in women can protect dopaminergic neurons against age-related processes during fertile life, but the drop of sex hormones as a result of menopause makes women vulnerable to PD as well as men. ...
Article
Several olfactory receptors (ORs) have been characterized outside the olfactory neuroepithelium in neuronal and non-neuronal tissues, where they were implicated in the recognition of diverse chemical signals. ORs have been found to regulate melanogenesis in skin melanocytes, and OR expression has been found in the human brain nigrostriatal dopaminergic neurons, where production of melanin occurs as neuromelanin and can change with age; OR expression is downregulated in Parkinson's disease. Therefore, we propose several odorants as new functional ligands to ORs expressed in non-olfactory pigmented cells as dopaminergic neurons and melanocytes, where, by acting on cAMP-induced melanin production, they could help to counteract melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson's disease.
... The odorous molecule methyl dihydrojasmonate, also known as hedione (Figure 1), is considered as a reference ligand to the receptor VN1R1, ectopically expressed in limbic areas (amygdala, hippocampus) of human brain, where it has been proposed to modulate a gender-specific secretion of sex hormones (Wallrabenstein et al., 2015). In our opinion, a noteworthy challenge would be to enquire if the enhanced activation of the VN1R1 in limbic areas by hedione might mimic a more sustained estrogen release in the female brain during aging, thus helping to counteract its susceptibility to PD in quiescent life. ...
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The expression of ectopic olfactory receptors (ORs) in melanized cells, such as the human brain nigrostriatal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson's disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through α-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pigmentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson's disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VN1R1 is proposed, helping to counteract female susceptibility to Parkinson's disease in quiescent life.
... Hedione (methyl dihydrojasmonate), a constituent in perfumery Figure 2. SPME-GC-MS representative chromatogram of headspace volatiles collected from apple, green grape, guava, melon, watermelon, unflavored "Kas" hookah Egyptian (EG) specimens and cigarette after brought hot with charcoal at 50 °C for 10 minutes. The corresponding compound names for volatile peaks follow that listed in Supplementary Table S1 that act as a human pheromone leading to sex-differentiated hypothalamic activation and has potential aphrodisiac properties 35,36 was detected in Rothmans tobacco cigarette at 5%. Cinnamyl isobutyrate was found exclusively in watermelon (EG) flavored hookah tobacco at 9% and is routinely detected as a fragrance in cosmetic products for its characteristic fruity, slightly floral odor 37 . ...
Article
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Abstract Flavors profiling in flavored hookah tobacco is an issue of increasing scrutiny for the health sector owing to its adverse effects on humans, especially being heated to produce smoke. This study aims at tackling the components involved in the flavored hookah tobacco from a chemical and biological point of view. Detecting individual flavor compounds, within a complex hookah tobacco matrix was accomplished using headspace solid phase microextraction (SPME). A total of 114 volatiles were identified in 13 flavored hookah tobacco products, with esters amounting for the major component up to 40%. Whereas oxygenated monoterpenes presented another major volatile class, contributing up to 23%, including (E)-anethole. Superheating flavored hookah tobacco at 190 °C resulted in the release of a mixture of phenol derivatives and polycyclic aromatic compounds that are indicative of coal tar, a major component produced during hookah tobacco usage with potential health hazards. This study provides the first comprehensive volatile profile of hookah tobacco products from different origins identifying chemical components involved in flavors. It is expected to serve as informative grounds for the better understanding of hookah tobacco production and usage. The information presented is also expected to raise awareness on the health risks of hookah tobacco smoking.
... These findings indicate that TRPC2 loss specifically, rather than loss of pheromonal signaling overall or the entire VNO, increases SSSB in the KO mice. Indeed, while modern humans have no neural tissue in their vestigial VNO (Smith et al., 2002), there is growing evidence that humans can still detect and process some pheromonal information through the MOE (Berglund, Lindström, & Savic, 2006;Savic, Berglund, & Lindström, 2005;Tan & Goldman, 2017;Wallrabenstein et al., 2015), including detection of the MHC (Milinski, Croy, Hummel, & Boehm, 2013). Loss of TRPC2 in our catarrhine ancestor may have disabled systems enforcing opposite-sex sex behavior despite the retention of some pheromonal signaling via the MOE. ...
Article
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Primate same-sex sexual behavior (SSSB) is rarely observed in strepsirrhine species, and only somewhat more common in platyrrhines, but is observed in nearly all catarrhine species, including humans, suggesting the common catarrhine ancestor as the origin of routine SSSB. In mice, disruption of the transient receptor potential cation channel 2 (TRPC2) gene, which is crucial for transducing chemosensory signals from pheromones in the vomeronasal organ, greatly increased the likelihood of SSSB. We note that catarrhine primates share a common deleterious mutation in this gene, indicating that the protein was dysfunctional in the common catarrhine ancestral primate approximately 25 mya (million years ago). We hypothesize that the loss of this protein for processing pheromonal signals in males and females made SSSB more likely in a primate ancestral species by effectively lifting a pheromonally mediated barrier to SSSB and that this was an important precursor to the evolution of such behavior in humans. Additional comparisons between SSSB and the functional status of the TRPC2 gene or related proteins across primate species could lend support to or falsify this hypothesis. Our current research indicates that loss of TRPC2 function in developing mice leads to the loss or attenuation of sexually dimorphisms in the adult brain, which may help us to understand the biological underpinnings of SSSB. Our hypothesis offers an ultimate evolutionary explanation for SSSB in humans.
... Additionally, further studies are needed to compare ortho versus retronasal stimulations or to examine the impact of the odorant qualities. For instance, the impact of trigeminal component of odorants (Brand, 2006) has never been explored, except in the study of Wallrabenstein et al. (2015) suggesting that the activation of VN1R1 by hedione might play a role in sex-specific modulation of hormonal secretion in humans. More specifically, because of the importance of pleasantness in food consumption, research should explore the role of food composition in sensory attributes evaluation. ...
Article
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Odor hedonic evaluation (pleasant/unpleasant) is considered as the first and one of the most prominent dimension in odor perception. While sex differences in human olfaction have been extensively explored, gender effect in hedonic perception appears to be less considered. However, a number of studies have included comparisons between men and women, using different types of measurements (psychophysical, psychophysiological,…). This overview presents experimental works with non-specific and body odors separately presented as well as experimental studies comparing healthy participants vs patients with psychiatric disorders. Contrary to sensitivity, identification or discrimination, the overall literature tends to prove that no so clear differences occur in odor hedonic judgment between men and women. On the whole, gender effect appears more marked for body than non-specific odors and is almost never reported in psychiatric diseases. These findings are discussed in relation to the processes classically implied in pleasantness rating and emotional processes.
... Tables 7-10). Excluding from the analysis transcripts with low relative expression (Extended Data Fig. 7a), our data included one mature neuron expressing the vomeronasal type-1 receptor 1 (VN1R1), whose ligand Hedione has been shown to elicit sex-specific human brain activity 17 (Fig. 3a). Olfactory neuron identity was distinguished by coexpression of known olfactory transduction genes (see Fig. 2a); in the UMAP cell cluster labeled as 'mature neurons' , 96% of cells express RTP1, 94% express GFY, 99% express GNAL and 96% express GNG13 (Fig. 2a and Supplementary Tables 3 and 5). ...
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The presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying input to the olfactory bulbs of the brain. Using single-cell RNA sequencing analyzing 28,726 cells, we identified neural stem cell and neural progenitor cell pools and neurons. Additionally, we detailed the expression of 140 olfactory receptors. These data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans. Durante et al. report the presence of active neurogenic niches in adult humans using single-cell RNA sequencing of the human olfactory neuroepithelium. Data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans.
... Healthy volunteers were analyzed by functional magnetic resonance imaging (fMRI) to evaluate the effects of hedione, a synthetic ester ligand for VN1R1 with a jasmine-like smell, on the human brain. They found that hedione induces enhanced activation of limbic areas (amygdala, hippocampus) and elicits a sex-differentiated response in the hypothalamic region that is associated with hormone release 37 . Finally, ex-posure to hedione causes differentiated behavioral effects in reciprocal punishments and rewards, two types of behavior necessary for the development and maintenance of cooperation 38 . ...
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Pheromones are ectohormones that play an important role in communication and behavior. Pheromones and pheromone receptor genes are important in mice and other mammals that rely heavily on pheromone cues to survive. Although there is controversy about whether pheromones and pheromone receptor genes have the same importance or are even active in humans, there are some hints that they might have roles in sociosexual behavior and mental disorders. The aim of this qualitative review was to provide an overview of the state of the art regarding pheromones and pheromone receptors in humans and their possible implications in human physiology and pathology. An electronic search was conducted in MED-LINE, PubMed and Scopus databases for articles published in English up to December 2018. The search concerned a possible role of pher-omones and pheromone receptors in humans with implications for sociosexual behavior, mental disorders, the menstrual cycle and nutrition. Pheromone communication in humans has not been definitively demonstrated. However, the potential ability of putative pheromones to activate the hypothalamus, which controls the release of many hormones, suggests they could have a role in systemic functions in humans. Future confirmation of the effects of pheromones and pheromone receptors in humans could be useful in the prevention and treatment of various human disorders.
... To verify these responses, the same participants attended a second session with identical set-up. Moreover, we aimed to compare the touch responses to those elicited by smelling an odorant, previously reported as mildly pleasant (Wallrabenstein et al., 2015). This served as "Part 2" of the experiment and was included to control for modality specific effects and effects related to the mere passage of time. ...
Article
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Subjective reports and physiological responses provide different appraisals of sensory input. The coherence between subjective and physiological responses to repeated pleasant stimuli remains largely unexplored, and is particularly important in situations where subjective responses are prone to cognitive or contextual bias. Here, we investigate how subjective and physiological responses to repeated gentle touch correspond at two separate sessions and compare these to responses obtained when smelling an odorant. Forty-eight participants underwent 60 trials of skin-to-skin slow stroking touch directed to the forearm. We collected subjective pleasantness reports, recorded facial electromyography (EMG) of the corrugator and zygomaticus muscles and heart-rate variability (HRV). With increasing touch repetitions, mean ratings of pleasantness decreased and corrugator muscle activity increased during session 1, whereas zygomaticus activity remained largely unchanged during both sessions. HRV was significantly higher during the first session, but did not increase from baseline during either sessions. Touch was rated as more pleasant than odor, and demonstrated greater resilience to satiety than the odor responses. Facial EMG recordings of the corrugator muscle appear to be a relevant measure for capturing satiety effects in skin-to-skin touch. Zygomaticus and HRV responses were independent of the subjective appraisal of the gentle touch. Rather than being blueprints of the subjective reports, physiological responses appear to reflect different parts of the subjective experience. As such, an improved understanding of the subjective and physiological responses to pleasant stimuli may improve our understanding of the dynamic interactions that take place in shaping complex emotional phenomena, such as aversion and pleasantness.
... Before the fMRI test, participants took part in a training session where they practiced the velopharyngeal closure which enables breathing only through the mouth (Kobal, 1981), and were instructed to use this technique during the fMRI scanning. This technique can effectively eliminate the influences of the nasal breathing cycle (inhalation and exhalation) on brain activations, and had been used in multiple previous fMRI studies with a similar setup (Kareken et al., 2004;Croy et al., 2014;Wallrabenstein et al., 2015;Han et al., 2020). ...
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The understanding of food cue associated neural activations that predict future weight variability may guide the design of effective prevention programs and treatments for overeating and obesity. The current study investigated the association between brain response to different food odors with varied energy density and individual changes of body mass index (BMI) over 2 years. Twenty-five participants received high-fat (chocolate and peanut), low-fat (bread and peach) food odors, and a nonfood odor (rose) while the brain activation was measured using functional magnetic resonance imaging (fMRI). BMIs were calculated with participant's self-reported body weight and height collected at the time of the fMRI scan and again at 2 years later. Regression analyses revealed significant negative correlations between BMI increase over 2 years and brain activation of the bilateral precuneus and the right posterior cingulate cortex (PCC) in response to high-fat vs. low-fat food odors. Also, brain activation of the right supplementary motor area (SMA) in response to food vs. non-food odor was negatively correlated to subsequent BMI increase over 2 years. Taken together, the current findings suggest that individual differences in neural responsivity to (high calorie) food odors in brain regions of the default mode and motor control network serve as a neural marker for future BMI change.
... Before the scan, participants were trained to use the velopharyngeal closure technique (breathing only through the mouth by lifting the soft palate) during the scan (Kobal, 1981). This technique enables olfactory stimulation to be unaffected by patterns of inhalation and exhalation, and have been applied in previous fMRI studies with odor stimulation (Croy et al., 2014;Kareken et al., 2004;Wallrabenstein et al., 2015). ...
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Taste sensitivity relates to food preferences and macronutrients intake. The current study investigated whether the neural responses to food odors varied in sensory quality (sweet or non-sweet) and their associations with macronutrient content (high- or low-fat) in young healthy participants varied in sweet taste sensitivity. Thirty-eight participants were assessed for their sensitivity to sucrose solutions using a modified "taste strip" test. They were divided into high sweetness sensitive (HS, n = 15) and low sweetness sensitive (LS, n = 15) groups using the median split approach. Brain responses to four food-related odors (chocolate, peach, peanut, and bread) and one non-food odor (rose) were assessed using functional magnetic resonance imaging (fMRI). Preferences for tastes and macronutrients were measured using a computer-based task. Behavioral results showed that HS group, compared to LS group, had a higher preference for carbohydrate-dominated foods and liking for sweet foods, but a lower liking for protein-dominated foods. The food odors, in comparison to non-food odors, produced greater brain-activations in the gustatory and reward regions. Compared to LS group, the HS group showed a higher level of activation in the frontal inferior operculum in response to sweet vs. savory food odors, and stronger insular activations to high-fat vs. low-fat food odors. In addition, individual sweetness sensitivity was positively associated with activation of the insula in response to chocolate odor, suggesting an overlap of neural responses to food odor with high sugar and fat content. Our findings highlight that high sensitivity to sweetness can be associated with increased preference for carbohydrate-dominated or sweet foods, and elevated brain activations to sweet or high-fat food odors in the areas related to food reward processing.
Article
Olfactory cues can affect subjective and autonomic manifestations of the human stress response, but evidence of altered endocrine stress reactivity is inconclusive. In the present study, we investigated effects of the odorant Hedione on the human stress response. We exposed 56 women in their follicular phases to a stressor in a room scented with Hedione or no odor. Subjective stress was captured via repeated self-report measurements and the assessment of anticipatory appraisal. As physiological markers of stress, we assessed blood pressure, salivary cortisol and alpha-amylase. The odorant enhanced the cortisol and cardiovascular stress response while leaving subjective stress unaffected. Our results provide evidence for a modulation of the human response to acute psychosocial stress by Hedione. A potential mechanism underlying this effect is Hedione targeting the hypothalamus via binding to the VN1R1 receptor, which is expressed on the human nasal mucosa.
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We summarize literature from animal as well as human studies assessing sex differences in the ability of the main olfactory system to detect and process sex‐specific olfactory signals (‘pheromones’) that control the expression of psychosexual functions in males and females. A case is made in non primate mammals for an obligatory role of pheromonal signaling via the main olfactory system (in addition to the vomeronasal‐accessory olfactory system) in mate recognition and sexual arousal, with male‐specific as well as female‐specific pheromones subserving these functions in the opposite sex. Although the case for an obligatory role of pheromones in mate recognition and mating among old world primates, including humans, is weaker, we review the current literature assessing the role of putative human pheromones (e.g., AND; EST; ‘copulin’), detected by the main olfactory system, in promoting mate choice and mating in men and women. Based on animal studies, we hypothesize that sexually dimorphic effects of putative human pheromones are mediated via main olfactory inputs to the medial amygdala which, in turn, transmits olfactory information to sites in the hypothalamus that regulate reproduction. This article is protected by copyright. All rights reserved. This review discusses the role of main olfactory pathways in the processing of chemosignals involved in mammalian reproduction
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The vomeronasal system (VNS) provides regulation of a wide range of autonomic and affective functions, behavioral reactions in response to the specific chemical stimuli pheromones secreted by mammals, including humans. The results of experimental studies confirming the existence of VNS and explaining the basic mechanisms of its functioning are presented. The results of studies of healthy volunteers, explaining the effect of pheromones on a number of functions of the human body, are considered.
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Synopsis Mammals detect odors and pheromones by receptors expressed in the olfactory epithelium and vomeronasal organ. The receptors are encoded by several multigene families including olfactory receptors, vomeronasal receptors, and trace amine-associated receptors. Each species has its own repertoire of these gene families that are adapted to its living environment. Recent progress on the evolution and function of these multigene families in mammals is summarized.
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The existence of pheromones in humans is controversial, partly because of definitional difficulties and partly because of the question of possible chemical substances. The synthetic compound Methyl dihydrojasmonate (Hedione) is potent to bind to vomeronasal-type 1 receptors (VN1R1s) and activate limbic areas of the brain in a sex-specific manner. However, one of the most important definitional points for a human pheromone effect has not yet been investigated, i.e., whether smelling Hedione, a model of pheromone, has a behavioral effect. We tested in females whether Hedione leads to altered perception of male social stimuli. Each of the included women were sensitive to Hedione and were tested around the time of ovulation in three consecutive sessions, during each they were exposed to either Hedione or Phenylethyl alcohol or Odorless air. We measured the speed of male face recognition (implicit priming task) and collected ratings of facial attractiveness and likeability of men (explicit task). Only about half of the women tested were sensitive to Hedione. Those women did not show any effect of Hedione exposure in the implicit priming task and moderate, but non-significant effects in the explicit task. We therefore assume that Hedione is not a potent model of pheromone in humans and this observation may be due to the fact that the artificially produced substance is not suited for signaling the proximity of other humans. Furthermore, the high rate of Hedione-specific anosmia leads to the hypothesis that a substantial proportion of individuals has a poor V1NR1 receptor expression.
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Cisplatin resistance is a major therapeutic challenge in advanced head and neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the key signaling pathway for cisplatin resistance in HNSCC cells. Vomeronasal type-1 receptor 5 (VN1R5) was identified as a cisplatin resistance-related protein and was highly expressed in cisplatin-resistant HNSCC cells and tissues. The long noncoding RNA (lncRNA) lnc-POP1-1 was confirmed to be a downstream target induced by VN1R5. VN1R5 transcriptionally regulated lnc-POP1-1 expression by activating the specificity protein 1 (Sp1) transcription factor via the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. VN1R5 promoted cisplatin resistance in HNSCC cells in a lnc-POP1-1-dependent manner. Mechanistically, lnc-POP1-1 bound to the Minichromosome Maintenance Deficient 5 (MCM5) protein directly and decelerated MCM5 degradation by inhibiting ubiquitination of the MCM5 protein, which facilitated the repair of DNA damage caused by cisplatin. In summary, we identified the cisplatin resistance-related protein VN1R5 and its downstream target lnc-POP1-1. Upon upregulation by VN1R5, lnc-POP1-1 promotes DNA repair in HNSCC cells through interaction with MCM5 and deceleration of its degradation.
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Odours constitute effective context cues, facilitating memory retrieval. Identifying factors which modulate the effectiveness of olfactory context cues can advance the understanding of processes underlying this effect. We hypothesized that the interplay of subjective stress and semantic relatedness between the odour and the learning material would modulate the effectiveness of an olfactory context cue. We further explored the effect of the odorant Hedione, which is a ligand for a putative human pheromone receptor (VN1R1). To this end, 120 participants watched a video of a stressful episode in which visual objects were present, that were either manipulated in the video (central objects) or not (peripheral objects). Participants rated their subjective stress afterwards. After 24 h, recognition and spatial memory of the objects in the video were tested. Ambient during encoding and recall was an odour related to the episode, an unrelated odour, Hedione or no odour. As a result, we observed a narrowing of recognition memory with increased subjective stress elicited by the video - but only if a semantically related odour was ambient. Moreover, higher subjective stress predicted enhanced spatial memory in the no odour condition, but not in presence of a semantically related or unrelated odour. When exposed to Hedione, higher subjective stress predicted impaired recognition and spatial memory of peripheral objects. Our findings stress the importance of considering semantic relatedness between the olfactory context and the encoded episode when applying odours as context cues for emotional or stressful memories.
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Olfactory system of organisms serves as a genetically and anatomically model for studying how sensory input can be translated into behavior output. Some neurologic diseases are considered to be related to olfactory disturbance, especially Alzheimer's disease, Parkinson's disease, multiple sclerosis, and etc. However, it is still unclear that how olfactory system affects diseases' generation processes and olfaction's delivery processes. Molecular imaging, a modern multi-disciplinary technology, can provide valid tool for the early detection and characterization of diseases, evaluation of treatment, and study of biological processes in living subjects, since molecular imaging applies specific molecular probes as a novel approach to produce special data to study biological processes in cellular and subcellular levels. Recently, molecular imaging plays a key role in studying the activation of olfactory system, thus it could help to prevent or delay some diseases. Herein, we present a comprehensive review on the research progress of the imaging probes for visualizing olfactory system, which is classified on different imaging modalities, including PET, MRI and optical imaging. Additionally, the probes' design, sensing mechanism and biological application are discussed. Finally, we provide an outlook for future studies in this field.
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The ability of animals to sense and differentiate among thousands of odorants relies on a large set of olfactory receptors (OR) and a multitude of accessory proteins within the olfacto-ry epithelium (OE). ORs and related signaling mechanisms have been the subject of inten-sive studies over the past years, but our knowledge regarding olfactory processing remains limited. The recent development of next generation sequencing (NGS) techniques encour-aged us to assess the transcriptome of the murine OE. We analyzed RNA from OEs of fe-male and male adult mice and from fluorescence-activated cell sorting (FACS)-sorted olfactory receptor neurons (ORNs) obtained from transgenic OMP-GFP mice. The Illumina RNA-Seq protocol was utilized to generate up to 86 million reads per transcriptome. In OE samples, nearly all OR and trace amine-associated receptor (TAAR) genes involved in the perception of volatile amines were detectably expressed. Other genes known to participate in olfactory signaling pathways were among the 200 genes with the highest expression lev-els in the OE. To identify OE-specific genes, we compared olfactory neuron expression pro-files with RNA-Seq transcriptome data from different murine tissues. By analyzing different transcript classes, we detected the expression of non-olfactory GPCRs in ORNs and established an expression ranking for GPCRs detected in the OE. We also identified other previously undescribed membrane proteins as potential new players in olfaction. The quantitative and comprehensive transcriptome data provide a virtually complete cata-logue of genes expressed in the OE and present a useful tool to uncover candidate genes involved in, for example, olfactory signaling, OR trafficking and recycling, and proliferation.
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The olfactory (OR) and vomeronasal receptor (VR) repertoires are collectively encoded by 1700 genes and pseudogenes in the mouse genome. Most OR and VR genes were identified by comparative genomic techniques and therefore, in many of those cases, only their protein coding sequences are defined. Some also lack experimental support, due in part to the similarity between them and their monogenic, cell-specific expression in olfactory tissues. Here we use deep RNA sequencing, expression microarray and quantitative RT-PCR in both the vomeronasal organ and whole olfactory mucosa to quantify their full transcriptomes in multiple male and female mice. We find evidence of expression for all VR, and almost all OR genes that are annotated as functional in the reference genome, and use the data to generate over 1100 new, multi-exonic, significantly extended receptor gene annotations. We find that OR and VR genes are neither equally nor randomly expressed, but have reproducible distributions of abundance in both tissues. The olfactory transcriptomes are only minimally different between males and females, suggesting altered gene expression at the periphery is unlikely to underpin the striking sexual dimorphism in olfactory-mediated behavior. Finally, we present evidence that hundreds of novel, putatively protein-coding genes are expressed in these highly specialized olfactory tissues, and carry out a proof-of-principle validation. Taken together, these data provide a comprehensive, quantitative catalog of the genes that mediate olfactory perception and pheromone-evoked behavior at the periphery.
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As the outermost barrier of the body, the skin is exposed to multiple environmental factors, including temperature, humidity, mechanical stress, and chemical stimuli, such as odorants that are often used in cosmetic articles. Keratinocytes, the major cell type of the epidermal layer, express a variety of different sensory receptors that enable them to react to various environmental stimuli and process information in the skin. Here, we report the identification of a novel type of chemoreceptors in human keratinocytes, the olfactory receptors (ORs). We cloned and functionally expressed the cutaneous olfactory receptor, OR2AT4, and identified Sandalore, a synthetic sandalwood odorant, as an agonist of this receptor. Sandalore induces strong Ca(2+) signals in cultured human keratinocytes, which are mediated by OR2AT4, as demonstrated by receptor knockdown experiments using RNA interference. The activation of OR2AT4 induces a cAMP-dependent pathway and phosphorylation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Moreover, the long-term stimulation of keratinocytes with Sandalore positively affected cell proliferation and migration, and regeneration of keratinocyte monolayers in an in vitro wound scratch assay. These findings combined with our studies on human skin organ cultures strongly indicate that the olfactory receptor 2AT4 is involved in human keratinocyte reepithelialization during wound healing processes.Journal of Investigative Dermatology accepted article preview online, 07 July 2014; doi:10.1038/jid.2014.273.
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Growing evidence suggests that the main olfactory epithelium contains a subset of olfactory sensory neurons (OSNs) responding to pheromones. One candidate subpopulation expresses the calcium activated cation channel TRPM5 (transient receptor potential channel M5). Using GFP driven by the TRPM5 promoter in mice, we show that this subpopulation responds to putative pheromones, urine, and major histocompatibility complex peptides, but not to regular odors or a pheromone detected by other species. In addition, this subpopulation of TRPM5-GFP(+) OSNs uses novel transduction. In regular OSNs, odorants elicit activation of the cyclic nucleotide-gated (CNG) channel, leading to Ca(2+) gating of Cl(-) channels; in TRPM5-GFP(+) OSNs, the Ca(2+)-activated Cl(-) ANO2 (anoctamin 2) channel is not expressed, and pheromones elicit activation of the CNG channel leading to Ca(2+) gating of TRPM5. In conclusion, we show that OSNs expressing TRPM5 respond to pheromones, but not to regular odors through the opening of CNG channels leading to Ca(2+) gating of TRPM5.
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Olfactory receptors (ORs) provide the molecular basis for the detection of volatile odorant molecules by olfactory sensory neurons. The OR supergene family encodes G-protein coupled proteins that belong to the seven-transmembrane-domain receptor family. It was initially postulated that ORs are exclusively expressed in the olfactory epithelium. However, recent studies have demonstrated ectopic expression of some ORs in a variety of other tissues. In the present study, we conducted a comprehensive expression analysis of ORs using an extended panel of human tissues. This analysis made use of recent dramatic technical developments of the so-called Next Generation Sequencing (NGS) technique, which encouraged us to use open access data for the first comprehensive RNA-Seq expression analysis of ectopically expressed ORs in multiple human tissues. We analyzed mRNA-Seq data obtained by Illumina sequencing of 16 human tissues available from Illumina Body Map project 2.0 and from an additional study of OR expression in testis. At least some ORs were expressed in all the tissues analyzed. In several tissues, we could detect broadly expressed ORs such as OR2W3 and OR51E1. We also identified ORs that showed exclusive expression in one investigated tissue, such as OR4N4 in testis. For some ORs, the coding exon was found to be part of a transcript of upstream genes. In total, 111 of 400 OR genes were expressed with an FPKM (fragments per kilobase of exon per million fragments mapped) higher than 0.1 in at least one tissue. For several ORs, mRNA expression was verified by RT-PCR. Our results support the idea that ORs are broadly expressed in a variety of tissues and provide the basis for further functional studies.
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Background Recent evidence indicates that methyl jasmonate (MJ), a plant stress hormone, exhibits anti-cancer activity on human cancer cells. The aim of this study is to determine whether sub-cytotoxic MJ can abolish the migration, invasion and angiogenesis gastric cancer cells. Methods Human gastric cancer cell lines SGC-7901 and MKN-45 were treated with diverse concentrations of MJ. Cell viability, proliferation, migration, invasion and angiogenesis capabilities of cancer cells were measured by MTT colorimetry, EdU incorporation, scratch assay, matrigel invasion assay, and tube formation assay. Gene expression was detected by western blot and real-time quantitative RT-PCR. Binding of transcription factor on gene promoter was detected by chromatin immunoprecipitation. Results Sub-cytotoxic (0.05 to 0.2 mM) MJ attenuated the migration, invasion and angiogenesis, but not the cell viability or proliferation, of gastric cancer cells in a time- and dose-dependent manner, with down-regulation of matrix metalloproteinase 14 (MMP-14) and its downstream gene vascular endothelial growth factor. Restoration of MMP-14 expression rescued the SGC-7901 and MKN-45 cells from sub-cytotoxic MJ-inhibited migration, invasion and angiogenesis. In addition, sub-cytotoxic MJ decreased the specificity protein 1 (Sp1) expression and binding on MMP-14 promoter, while restoration of Sp1 expression rescued the cancer cells from sub-cytotoxic MJ-mediated defects in MMP-14 expression, migration, invasion and angiogenesis. Conclusions Sub-cytotoxic MJ attenuates the MMP-14 expression via decreasing the Sp1 expression and binding on MMP-14 promoter, thus inhibiting the migration, invasion and angiogenesis of gastric cancer cells.
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In addition to the canonical olfactory receptors, TAARs were currently suggested to be a second class of chemosensory receptors in the olfactory epithelium of vertebrates. In contrast to several deorphanized murine TAARs, agonists for the intact human TAAR genes 2, 5, 6, 8 and 9 that are potentially expressed in the human olfactory epithelium have not been determined so far. Moreover, the physiological relevance of TAARs still remains elusive. We present the first successful functional expression of a human TAAR and agonists of human TAAR5. We performed a ligand screening using recombinantly expressed human TAAR5 in HANA3A cells and Xenopus laevis oocytes. In order to measure receptor activity, we used a cAMP-dependent reporter gene assay and two-electrode voltage clamp technique. As a result, human TAAR5 can be activated in a concentration-dependent manner by trimethylamine and with less efficacy by dimethylethylamine. It could neither be activated by any other of the tested single amines with a related chemical structure (42 in total), nor by any of the tested odorant mixtures. The hypothesis that Single Nucleotide Polymorphisms (SNP) within the reading frame of an olfactory receptor gene can cause a specific anosmia, formed the basis for clarifying the question, if anosmia for trimethylamine is caused by a SNP in a TAAR coding sequence. All functional human TAAR gene reading frames of subjects with specific anosmia for trimethylamine were amplified and products analyzed regarding SNP distribution. We demonstrated that the observed specific anosmia for trimethylamine is not correlated with a SNP in the coding sequence of one of the putatively functional human TAAR genes.
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The odorous steroid compound 4,16-androstadien-3-one (androstadienone), found in axillary sweat, was previously reported to evoke hypothalamic activation in heterosexual women, but not in heterosexual men. However, subjects were exposed to the pure crystalline form of androstadienone, which raised the question whether the observed hypothalamic response is physiologically relevant. Therefore, in the present study, we asked whether sexually dimorphic hypothalamic responses could be measured when subjects were exposed to lower, more physiologically relevant concentrations of androstadienone. A total of 21 women and 16 men, all heterosexual, participated in our functional magnetic resonance imaging study (fMRI). Three different concentrations of androstadienone diluted in propylene glycol (10 mM "high," 0.1 mM "medium" and 0.001 mM "low") were delivered to the subjects' nostrils using a computer-controlled stimulator. When exposed to the "high" androstadienone concentration, women showed stronger hypothalamic activation than men. By contrast, men showed more hypothalamic activation when exposed to the "medium" androstadienone concentrations in comparison to women. Thus, we replicated that smelling the chemo-signal androstadienone elicits a hypothalamic activation. However, this effect does not seem to be gender-specific, because androstadienone activated the hypothalamus in both men and women, suggesting that androstadienone exerts specific effects in heterosexual individuals of both sexes.
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Trace amine-associated receptors (TAARs) have recently been identified in mouse olfactory epithelium (OE) and may be implicated in the detection of volatile amines, including pheromones. We investigated TAAR expression in human nasal mucosa, evaluating 32 nasal mucosa biopsies obtained from 16 patients with normal olfactory function undergoing routine nasal surgery. OE was identified on the basis of olfactory marker protein gene expression, and it was included in 11 samples out of 32. With the exception of TAAR1, which was detected at trace levels in a few samples of both groups, TAAR expression was limited to OE. TAAR5 was expressed in all OE samples at levels ranging from 15 to 1,480 copies/50ng cDNA; TAAR8 was detected in 5 OE samples at trace levels and in another 5 OE samples at levels ranging from 11 to 33 cDNA copies/50ng RNA; TAAR9, TAAR2, and TAAR5 were expressed at trace levels in 5, 3, and 3 OE samples, respectively. In conclusion, most TAARs, and particularly TAAR5, are selectively expressed in human OE. TAAR5 might play a significant functional role since it is known to be activated by trimethylamine, which is present in human secretions and has been implicated in behavioral responses. KeywordsHuman Olfactory Epithelium-Olfactory Receptors-Quantitative PCR-TAARs-Trace Amines-Trimethylamine
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The vomeronasal system is one of several fine-tuned scent-detecting signaling systems in mammals. However, despite significant efforts, how these receptors detect scent remains an enigma. One reason is the lack of sufficient purified receptors to perform detailed biochemical, biophysical and structural analyses. Here we report the ability to express and purify milligrams of purified, functional human vomeronasal receptor hVN1R1. Circular dichroism showed that purified hVN1R1 had an alpha-helical structure, similar to that of other GPCRs. Microscale thermophoresis showed that hVN1R1 bound its known ligand myrtenal with an EC50 ∼1 µM. This expression system can enable structural and functional analyses towards understanding how mammalian scent detection works.
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Emotional tearing is a poorly understood behavior that is considered uniquely human. In mice, tears serve as a chemosignal. We therefore hypothesized that human tears may similarly serve a chemosignaling function. We found that merely sniffing negative-emotion-related odorless tears obtained from women donors induced reductions in sexual appeal attributed by men to pictures of women's faces. Moreover, after sniffing such tears, men experienced reduced self-rated sexual arousal, reduced physiological measures of arousal, and reduced levels of testosterone. Finally, functional magnetic resonance imaging revealed that sniffing women's tears selectively reduced activity in brain substrates of sexual arousal in men.
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Chemosensory-based communication is a vital signaling tool in most species, and evidence has recently emerged in support of the notion that humans also use social chemosignals (so-called pheromones) to communicate. An ongoing controversy does exist, however, concerning the receptor organ through which these chemicals are processed. There is a widespread belief that the vomeronasal organ (VNO) is responsible for processing social chemosignals in humans. Here we demonstrate that functional occlusion of the VNO does not change the percept of, sensitivity toward, or functional neuronal processing of a putative human pheromone. Perithreshold and suprathreshold perception of the endogenous chemical androstadienone (AND) were compared, as were positron emission tomography brain activations evoked by AND when the VNO was either occluded or left open. In addition, we compared sensitivity to AND in subjects with an identifiable VNO to those in whom no VNO could be detected. Thus we could examine the effects of the VNO at several different levels of processing. Occlusion or absence of the VNO did not affect either the perceptual measurements or the functional processing of the putative human pheromone, AND. These results provide strong evidence that the human VNO has no obvious function. Pheromonal communication in humans may be conveyed via the main olfactory system.
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Whether pheromone signaling exists in humans is still a matter of intense discussion. In the present study we tested if smelling of Androstenol, a steroid produced by the human body and reported to affect human behavior, may elicit cerebral activation. A further issue was to evaluate whether the pattern of activation resembles the pattern of common odors. PET measurements of regional cerebral blood flow (rCBF) were conducted in 16 healthy heterosexual women during passive smelling of Androstenol, four ordinary odors (OO), and odorless air (the base line condition). Smelling Androstenol caused activation of a portion of the hypothalamus, which according to animal data mediates the pheromone triggered mating behavior. Smelling of OO, on the other hand, engaged only the classical olfactory regions (the piriform cortex, lateral amygdala, anterior insular and anterior cingulate cortex). The observed pattern of activation is very similar to the pattern previously detected with 4,16-androstadien-3-one in heterosexual females. It suggests that several compounds released by human body may activate cerebral networks involved in human reproduction.
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We report an evolutionary analysis of the V1R gene family across 37 mammalian genomes. V1Rs comprise one of three chemosensory receptor families expressed in the vomeronasal organ, and contribute to pheromone detection. We first demonstrate that Trace Archive data can be used effectively to determine V1R family sizes and to obtain sequences of most V1R family members. Analyses of V1R sequences from trace data and genome assemblies show that species-specific expansions previously observed in only eight species were prevalent throughout mammalian evolution, resulting in "semi-private" V1R repertoires for most mammals. The largest families are found in mouse and platypus, whose V1R repertoires have been published previously, followed by mouse lemur and rabbit (approximately 215 and approximately 160 intact V1Rs, respectively). In contrast, two bat species and dolphin possess no functional V1Rs, only pseudogenes, and suffered inactivating mutations in the vomeronasal signal transduction gene Trpc2. We show that primate V1R decline happened prior to acquisition of trichromatic vision, earlier during evolution than was previously thought. We also show that it is extremely unlikely that decline of the dog V1R repertoire occurred in response to selective pressures imposed by humans during domestication. Functional repertoire sizes in each species correlate roughly with anatomical observations of vomeronasal organ size and quality; however, no single ecological correlate explains the very diverse fates of this gene family in different mammalian genomes. V1Rs provide one of the most extreme examples observed to date of massive gene duplication in some genomes, with loss of all functional genes in other species.
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Alarm substances are airborne chemical signals, released by an individual into the environment, which communicate emotional stress between conspecifics. Here we tested whether humans, like other mammals, are able to detect emotional stress in others by chemosensory cues. Sweat samples collected from individuals undergoing an acute emotional stressor, with exercise as a control, were pooled and presented to a separate group of participants (blind to condition) during four experiments. In an fMRI experiment and its replication, we showed that scanned participants showed amygdala activation in response to samples obtained from donors undergoing an emotional, but not physical, stressor. An odor-discrimination experiment suggested the effect was primarily due to emotional, and not odor, differences between the two stimuli. A fourth experiment investigated behavioral effects, demonstrating that stress samples sharpened emotion-perception of ambiguous facial stimuli. Together, our findings suggest human chemosensory signaling of emotional stress, with neurobiological and behavioral effects.
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A fundamental question in olfaction is which odorant receptors (ORs) are activated by a given odorant. A major roadblock to investigating odorant-OR relationships in mammals has been the inability to express ORs in heterologous cells suitable for screening active ligands for ORs. The discovery of the receptor-transporting protein family has facilitated the effective cell-surface expression of ORs in heterologous cells. The establishment of a robust heterologous expression system for mammalian ORs facilitates the high-throughput 'deorphanization' of these receptors by matching them to their cognate ligands. This protocol details the method used for evaluating the cell-surface expression and measuring the functional activation of ORs of transiently expressed mammalian ORs in HEK293T cells. The stages of OR cell-surface expression include cell culture preparation, transfer of cells, transfection, immunocytochemistry or flow cytometry, odorant stimulation and luciferase assay. This protocol can be completed in a period of 3 d from the transfer of cells to cell-surface expression detection and/or measurement of functional activation.
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In mammals, olfactory sensory perception is mediated by two anatomically and functionally distinct sensory organs: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Pheromones activate the VNO and elicit a characteristic array of innate reproductive and social behaviors, along with dramatic neuroendocrine responses. Differential screening of cDNA libraries constructed from single sensory neurons from the rat VNO has led to the isolation of a family of about 30 putative receptor genes. Sequence analysis indicates that these genes comprise a novel family of seven transmembrane domain proteins unrelated to the receptors expressed in the MOE. Moreover, the expression of each member of the gene family is restricted to a small subpopulation of VNO neurons. These genes are likely to encode mammalian pheromone receptors.
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Here, we provide the first evidence for functional expression of a human olfactory receptor protein (OR17-40) and show that recombinant olfactory receptors can be functionally expressed in heterologous systems. A mixture of 100 different odorants (Henkel 100) elicited a transient increase in intracellular [Ca(2+)] in human embryonic kidney 293 (HEK293) cells stably or transiently transfected with the plasmid pOR17-40. By subdividing the odorant mixture into progressively smaller groups, we identified a single component that represented the only effective substance: helional. Only the structurally closely related molecule heliotroplyacetone also activated the receptor. Other compounds, including piperonal, safrole, and vanillin, were completely ineffective. Mock-transfected cells and cells transfected with other receptors showed no change in intracellular [Ca(2+)] in response to odor stimulation. We were also able to functionally express OR17-40 in Xenopus laevis oocytes. Coexpression of a "reporter" channel allowed measurement of the response of oocytes injected with the cRNA of the human receptor to the odor mixture Henkel 100. The effective substances were the same (helional, heliotropylacetone) as those identified by functionally expressing the receptor in HEK293 cells and were active at the same, lower micromolar concentration. These findings open the possibility of now characterizing the sensitivity and specificity of many, if not all, of the hundreds of different human olfactory receptors.
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We examined the effects of 5alpha-androst-16-en-3alpha-ol (3alpha-androstenol) on pulsatile luteinizing hormone (LH) secretion in human females. The frequency of the LH pulse in the follicular phase was decreased by exposing the women to 3alpha-androstenol.
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Pheromones elicit specific behavioural responses and physiological alterations in recipients of the same species. In mammals, these chemical signals are recognized within the nasal cavity by sensory neurons that express pheromone receptors. In rodents, these receptors are thought to be represented by two large multigene families, comprising the V1r and V2r genes, which encode seven-transmembrane proteins. Although pheromonal effects have been demonstrated in humans, V1R or V2R counterparts of the rodent genes have yet to be characterized.
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In most mammals, intraspecies communication relies heavily on the vomeronasal system and its ability to detect pheromones1. Vomeronasal sensory neurons (VSNs) express G protein−coupled, seven-transmembrane receptors from either the V1r or V2r superfamilies2, 3, 4, 5, which represent the only candidate pheromone receptors in mammals. Here, we show at the single-cell level that V1r receptors are involved in chemodetection and identify a specific receptor−agonist pair in the vomeronasal system.
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The vomeronasal organ (VNO) detects pheromones in many vertebrate species but is likely to be vestigial in humans. TRPC2(TRP2), a gene that is essential for VNO function in the mouse, is a pseudogene in humans. Because TRPC2 is expressed only in the VNO, the loss of selective pressure on this gene can serve as a molecular marker for the time at which the VNO became vestigial. By analyzing sequence data from the TRPC2 gene of 15 extant primate species, we provide evidence that the VNO was most likely functional in the common ancestor of New World monkeys and Old World monkeys and apes, but then became vestigial in the common ancestor of Old World monkeys and apes. We propose that, at this point in evolution, other modalities, notably the development of color vision, may have largely replaced signaling by pheromones.
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The mammalian vomeronasal organ detects social information about gender, status, and individuality. The molecular cues carrying this information remain largely unknown. Here, we show that small peptides that serve as ligands for major histocompatibility complex (MHC) class I molecules function also as sensory stimuli for a subset of vomeronasal sensory neurons located in the basal Gao- and V2R receptor-expressing zone of the vomeronasal epithelium. In behaving mice, the same peptides function as individuality signals underlying mate recognition in the context of pregnancy block. MHC peptides constitute a previously unknown family of chemosensory stimuli by which MHC genotypic diversity can influence social behavior.
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Central to the concept of attention is the fact that identical stimuli can be processed in different ways. In olfaction, attention may designate the identical flow of air through the nose as either respiration or olfactory exploration. Here we have used functional magnetic resonance imaging (fMRI) to probe this attentional mechanism in primary olfactory cortex (POC). We report a dissociation in POC that revealed attention-dependent and attention-independent subregions. Whereas a temporal subregion comprising temporal piriform cortex (PirT) responded equally across conditions, a frontal subregion comprising frontal piriform cortex (PirF) and the olfactory tubercle responded preferentially to attended sniffs as opposed to unattended sniffs. In addition, a task-specific anticipatory response occurred in the attention-dependent region only. This dissociation was consistent across two experimental designs: one focusing on sniffs of clean air, the other focusing on odor-laden sniffs. Our findings highlight the role of attention at the earliest cortical levels of olfactory processing.
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Mammalian urine releases complex mixtures of volatile compounds that are used in reproduction, territoriality and conspecific recognition. To understand how such complex mixtures are represented in the main olfactory bulb, we analysed the electrophysiological responses of individual mitral cells to volatile compounds in mouse urine. In both males and females, urine volatile compounds evoke robust responses in a small subset of mitral cells. Fractionation of the volatile compounds using gas chromatography showed that out of the hundreds of compounds present, mitral cells are activated by single compounds. One cohort of mitral cells responded exclusively to male urine; these neurons were activated by (methylthio)methanethiol, a potent, previously unknown semiochemical present only in male urine. When added to urine, synthetic (methylthio)methanethiol significantly enhances urine attractiveness to female mice. We conclude that mitral cells represent natural odorant stimuli by acting as selective feature detectors, and that their activation is largely independent of the presence of other components in the olfactory stimulus.
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Recent studies have suggested the existence of human sex pheromones, with particular interest in two human steroids: androstadienone (androsta-4,16,-dien-3-one) and estratetraenol (estra-1,3,5(10),16-tetraen-3-ol). The current study takes a critical step to test the qualification of the two steroids as sex pheromones by examining whether they communicate gender information in a sex-specific manner. By using dynamic point-light displays that portray the gaits of walkers whose gender is digitally morphed from male to female [1 • Troje N.F. Decomposing biological motion: a framework for analysis and synthesis of human gait patterns.J. Vis. 2002; 2: 371-387 • Crossref • PubMed • Scopus (567) • Google Scholar , 2 • Troje N.F. Retrieving information from human movement patterns.in: Shipley T.F. Zacks J.M. Understanding Events: How Humans See, Represent, and Act on Events. Oxford University Press, New York2008: 308-334 • Crossref • Scopus (54) • Google Scholar ], we show that smelling androstadienone systematically biases heterosexual females, but not males, toward perceiving the walkers as more masculine. By contrast, smelling estratetraenol systematically biases heterosexual males, but not females, toward perceiving the walkers as more feminine. Homosexual males exhibit a response pattern akin to that of heterosexual females, whereas bisexual or homosexual females fall in between heterosexual males and females. These effects are obtained despite that the olfactory stimuli are not explicitly discriminable. The results provide the first direct evidence that the two human steroids communicate opposite gender information that is differentially effective to the two sex groups based on their sexual orientation. Moreover, they demonstrate that human visual gender perception draws on subconscious chemosensory biological cues, an effect that has been hitherto unsuspected.
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Trace amine-associated receptors (TAARs) are vertebrate olfactory receptors. However, ligand recognition properties of TAARs remain poorly understood, as most are "orphan receptors" without known agonists. Here, we identify the first ligands for many rodent TAARs and classify these receptors into two subfamilies based on the phylogeny and binding preference for primary or tertiary amines. Some mouse and rat orthologs have similar response profiles, although independent Taar7 gene expansions led to highly related receptors with altered ligand specificities. Using chimeric TAAR7 receptors, we identified an odor contact site in transmembrane helix III that functions as a selectivity filter. Homology models based on the β(2) adrenergic receptor structure indicate spatial proximity of this site to the ligand. Gain-of-function mutations at this site created olfactory receptors with radically altered odor recognition properties. These studies provide new TAAR ligands, valuable tools for studying receptor function, and general insights into the molecular pharmacology of G protein-coupled receptors.
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The physiological significance of the human vomeronasal duct (VND) is still unclear. The aim of the present study was to investigate the question whether mucosal responses obtained from the VND are different from those obtained from the respiratory epithelium. There were 15 healthy subjects (8 male, 7 female; age range 19-45 years; 14 normosmic subjects, 1 anosmic subject). All subjects participated in two sessions whereby the first session was used to acquaint them with the experimental conditions. For chemical stimulation, an olfactometer was used which delivered chemical stimulants without altering mechanical or thermal conditions at the stimulated nasal mucosa. For stimulation we used substances previously reported to produce vomeronasal activation ("estra"=estra-1,3,5(10),16-tetraen-3ol and "andro"=androsta-4,16-dien-3-on); in addition, gaseous CO(2) was used as a non-odorous, relatively specific stimulant of the trigeminal nerve. Placement of electrodes either in the VND or on the respiratory epithelium was performed under endoscopical guidance. Subjects rated the overall intensity of the stimuli, the strength of trigeminally mediated sensations, and the hedonic tone of the stimulants. Responses could not be recorded from all subjects. For the remaining 7 subjects, intensity was strongest for CO(2) stimuli (p<0.001), whereas no significant difference was observed between "andro" and "estra" (p=0.33). All three stimulants produced responses at the respiratory epithelium with largest responses obtained after stimulation with CO(2). Similar findings were made for recordings inside the VND. Due to the small sample size sexual dimorphisms could not be addressed. In summary, these results seem to indicate that the presently used stimulants produce similar responses at the respiratory epithelium and in the VND which argues against a specific responsiveness of the VND epithelium to chemosensory stimuli although it has to be kept in mind that the effective sample size was small.
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Jasmonates act as signal transduction intermediates when plants are subjected to environmental stresses such as UV radiation, osmotic shock and heat. In the past few years several groups have reported that jasmonates exhibit anti-cancer activity in vitro and in vivo and induce growth inhibition in cancer cells, while leaving the non-transformed cells intact. Recently, jasmonates were also discovered to have cytotoxic effects towards metastatic melanoma both in vitro and in vivo. Three mechanisms of action have been proposed to explain this anti-cancer activity. The bio-energetic mechanism - jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation. Furthermore, methyl jasmonate (MJ) has the ability to detach hexokinase from the mitochondria. Second, jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity and were found to act similar to the cytokinin isopentenyladenine (IPA). Third, jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Combination of MJ with the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and with four conventional chemotherapeutic drugs resulted in super-additive cytotoxic effects on several types of cancer cells. Finally, jasmonates have the ability to induce death in spite of drug-resistance conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonates are anti-cancer agents that exhibit selective cytotoxicity towards cancer cells, and thus present hope for the development of cancer therapeutics.
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The mammalian olfactory system can recognize and discriminate a large number of different odorant molecules. The detection of chemically distinct odorants presumably results from the association of odorous ligands with specific receptors on olfactory sensory neurons. To address the problem of olfactory perception at a molecular level, we have cloned and characterized 18 different members of an extremely large multigene family that encodes seven transmembrane domain proteins whose expression is restricted to the olfactory epithelium. The members of this novel gene family are likely to encode a diverse family of odorant receptors.
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Student volunteers (38 of each sex) were exposed unknowingly overnight to the vapour of pheromonally active substances and compared with controls. The substances were either 5 alpha-16-androsten-3 alpha-ol (androstenol, occurring in human underarm sweat, and known to be pheromonally active in pig and man), or a mixture of short-chain fatty acids (occurring in human vaginal fluid, and known to be sexually attractive to the male rhesus monkey). The following morning, the subjects provided information about their social exchanges since rising, by recording on a standardized test diagram the number, depth, duration and direction of initiation, of all verbal exchanges with other individuals. Irrespective of treatment, males returned significantly higher scores than did females for all exchanges and also for some exchanges initiated by other males. Neither exposure to androstenol nor to the fatty acids had any significant effects on any of the scores of males interacting with either sex, nor on any scores of females with other females. However, exposure of females to androstenol, but not to the fatty acids, resulted in significantly higher scores of exchanges with males, in terms of all parameters for all exchanges. Findings are considered in relation to the origin and maintenance across species of pheromonal communication: evolutionary conservation is seen in terms of the utilization of substances that have provided the means of controlling the social milieu.
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Our electrophysiological experiments in female mice have provided evidence that electrical stimulation of the accessory olfactory bulb orthodromically excites a subpopulation of tuberoinfundibular arcuate neurons by way of the amygdala. The present study shows that half of such neurons are identified as dopaminergic by examining the effectiveness of infusing 6-hydroxydopamine and 5,7-dihydroxytryptamine locally into the median eminence in blocking their antidromic response. Further attention is focused on excitatory amino acid receptors within the amygdala and the amygdaloid pathway that mediate the accessory bulb-induced excitation of tuberoinfundibular arcuate neurons. The excitatory transmission was reversibly blocked by intra-amygdala infusion (3 nmol) of the excitatory amino acid antagonists kynurenic acid, D,L-2-amino-5-phosphonovalerate, gamma-D-glutamylaminomethylsulphonate and D,L-2-amino-4-phosphonobutyrate. Intra-amygdala infusions (3 nmol) of N-methyl-D-aspartate and kainate markedly enhanced the firing activity of tuberoinfundibular arcuate neurons with excitatory inputs from the accessory bulb, whereas similar infusions of quisqualate were without effect Intra-stria terminalis infusions of the local anaesthetic lignocaine completely abolished the excitatory transmission in all the cells tested. Furthermore, tuberoinfundibular arcuate neurons stimulated from the accessory bulb were also orthodromically stimulated from the stria terminalis with a shorter latency. These studies demonstrate that the projections of the accessory olfactory bulb activate excitatory amino acid receptors within the amygdala and subsequently the stria terminalis route, thereby causing excitation of tuberoinfundibular dopaminergic arcuate neurons. This functional pathway can account for the reproductive effects so far described as a consequence of vomeronasal chemoreception.
A stimulation method was employed by which chemosensory evoked potentials were recorded without tactile somatosensory contamination. The purpose of the study was to determine whether potential components evoked by stimulation of the chemoreceptors of the trigeminal nerve can be distinguished from those of the olfactory nerve. The stimulants (vanillin, phenylethyl alcohol, limonene, menthol, anethol, benzaldehyde, carbon dioxide and a mixture of vanillin and carbon dioxide) were presented in a randomized order to 13 volunteers. Chemosensory evoked potentials to substances which anosmics are unable to perceive (vanillin, phenylethyl alcohol) were termed olfactory evoked potentials; potentials to CO2, which effected no olfactory sensations were termed chemo-somatosensory potentials. Analysis of variance revealed that the different substances resulted in statistically significant changes in the amplitudes and latencies of the evoked potentials, and also in the subjective estimates of intensity. An increased excitation of the somatosensory system resulted in reduced latencies and enhanced amplitudes of the evoked potentials. Responses to the mixture of carbon dioxide and vanillin appeared significantly earlier (50-150 msec) than responses to either substance alone.
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By performing uni- and bilateral olfactory bulb lesions and uni- and bilateral transsections of the infraorbital branches of the trigeminal nerves in 2-day-old rabbits, it could be shown that: Both the olfactory and tactile modalities are essential for the successful performance of nipple-search behaviour. While bilateral bulbectomy completely eliminates searching, and hence suckling, unilateral bulbectomy has relatively little effect. Bilateral denervation of the muzzle does not eliminate searching, but pups are unable to suckle as they fail to show the mouth-opening component necessary for nipple attachment. In contrast to unilateral bulbectomy, unilateral denervation of the muzzle results in a lateralization of head movements during searching, nipple grasping and nipple release.
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A radioimmunoassay for the boar pheromone, 5α-androst-16-en-3-one, in human axillae has been validated by studies on pooled axillary collections. Oleic acid, diolein and triolein were shown to interfere in the assay but these effects were eliminated by the extensive extraction and separation stages employed. Levels of 5α-androst-16-en-3-one were 12-1134 pmol/24 h, n = 14 in men and 13–39 pmol/24 h, n = 14 in women, with the exception of one normal female subject (551 pmol). The significance of these results, in relation to the possibility of 5α-androst-16-en-3-one being a human pheromone, is discussed.
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Based largely on results of studies of laboratory rodents, the vomeronasal or accessory olfactory system is believed to function mainly in social communication, mediating the effects of stimuli such as urine or glandular secretions on the behavior or endocrine response of conspecifics. In the domestic pig (Sus scrofa), the steroid androstenone has been identified as a pheromone that facilitates expression of both attraction to the male and a receptive mating stance in estrous females. Though the domestic pig is one of the few vertebrate species in which the identity of a compound that functions as a pheromone is known, the role of the vomeronasal system in domestic pigs has never been investigated. We have examined the role of the vomeronasal organ in mediating the pheromonal effects of androstenone in pigs. In addition, we have examined the structure of the vomeronasal organ at the gross and light-microscopic levels. The vomeronasal organ appears functional, with sensory epithelium lining the medial wall, and has access to stimuli from both the oral and nasal cavities. To determine whether the vomeronasal organ is necessary for androstenone detection or attraction or receptive behavior in female pigs, access to the vomeronasal organ was blocked with surgical cement, and androstenone detection threshold and sexual behavior were measured. Experimental animals did not differ significantly in androstenone sensitivity, measured behaviorally, from untreated controls. Vomeronasal organ-blocked animals also did not differ from untreated controls in either androstenone-mediated receptive standing behavior or attraction to the odor of androstenone. We conclude that in the domestic pig, the vomeronasal organ is not necessary for androstenone detection or androstenone-mediated sexual behavior in estrous females.
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Mammals have retained two functionally and anatomically independent collections of olfactory neurons located in the main olfactory epithelium and in the vomeronasal organ (VNO). Pheromones activate the VNO in order to elicit fixed action behaviors and neuroendocrine changes involved in animal reproduction and aggression. Differential screening of cDNA libraries constructed from individual rat VNO neurons has led to the isolation of a novel family of approximately 100 genes encoding seven transmembrane receptors with sequence similarity with Ca2+-sensing and metabotropic glutamate receptors. These genes are likely to encode a novel family of pheromone receptors. Patterns of receptor gene expression suggest that the VNO is organized into discrete and sexually dimorphic functional units that may permit segregation of pheromone signals leading to specific arrays of behaviors and neuroendocrine responses.
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Androstadienone is the most prominent androstene present on male human axillary hair and on the male axillary skin surface. We have previously shown that this volatile steroid is able to stimulate [corrected] the human female vomeronasal organ in picogram (pg) quantities, resulting in changes in autonomic activity. These effects are gender-specific. The purpose of the present study was to ascertain whether androstadienone could be considered a human pheromone by altering behavior as well as autonomic function. Forty normal female subjects were randomized in a double-blind manner to receive either control or 100 pg of androstadienone directly to the vomeronasal organ. We report that administration of this steroid under these conditions results in a significant reduction of nervousness, tension and other negative feeling states. Concordant changes were observed in autonomic physiology.
Article
The vomeronasal organ (VNO) is a chemoreceptive organ that is thought to transduce pheromones into electrical responses that regulate sexual, hormonal and reproductive function in mammals. The characteristics of pheromone signal detection by vomeronasal neurons remain unclear. Here we use a mouse VNO slice preparation to show that six putative pheromones evoke excitatory responses in single vomeronasal neurons, leading to action potential generation and elevated calcium entry. The detection threshold for some of these chemicals is remarkably low, near 10(-11) M, placing these neurons among the most sensitive chemodetectors in mammals. Using confocal calcium imaging, we map the epithelial representation of the pheromones to show that each of the ligands activates a unique, nonoverlapping subset of vomeronasal neurons located in apical zones of the epithelium. These neurons show highly selective tuning properties and their tuning curves do not broaden with increasing concentrations of ligand, unlike those of receptor neurons in the main olfactory epithelium. These findings provide a basis for understanding chemical signals that regulate mammalian communication and sexual behaviour.
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The anatomical pathways for processing of odorous stimuli include the olfactory nerve projection to the olfactory bulb, the trigeminal nerve projection to somatosensory and insular cortex, and the projection from the accessory olfactory bulb to the hypothalamus. In the majority of tetrapods, the sex-specific effects of pheromones on reproductive behavior is mediated via the hypothalamic projection. However, the existence of this projection in humans has been regarded as improbable because humans lack a discernable accessory olfactory bulb. Here, we show that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.
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An anatomical parcellation of the spatially normalized single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) (D. L. Collins et al., 1998, Trans. Med. Imag. 17, 463-468) was performed. The MNI single-subject main sulci were first delineated and further used as landmarks for the 3D definition of 45 anatomical volumes of interest (AVOI) in each hemisphere. This procedure was performed using a dedicated software which allowed a 3D following of the sulci course on the edited brain. Regions of interest were then drawn manually with the same software every 2 mm on the axial slices of the high-resolution MNI single subject. The 90 AVOI were reconstructed and assigned a label. Using this parcellation method, three procedures to perform the automated anatomical labeling of functional studies are proposed: (1) labeling of an extremum defined by a set of coordinates, (2) percentage of voxels belonging to each of the AVOI intersected by a sphere centered by a set of coordinates, and (3) percentage of voxels belonging to each of the AVOI intersected by an activated cluster. An interface with the Statistical Parametric Mapping package (SPM, J. Ashburner and K. J. Friston, 1999, Hum. Brain Mapp. 7, 254-266) is provided as a freeware to researchers of the neuroimaging community. We believe that this tool is an improvement for the macroscopical labeling of activated area compared to labeling assessed using the Talairach atlas brain in which deformations are well known. However, this tool does not alleviate the need for more sophisticated labeling strategies based on anatomical or cytoarchitectonic probabilistic maps.
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Although it has been known for some time that olfactory receptors (ORs) reside in spermatozoa, the function of these ORs is unknown. Here, we identified, cloned, and functionally expressed a previously undescribed human testicular OR, hOR17-4. With the use of ratiofluorometric imaging, Ca2+ signals were induced by a small subset of applied chemical stimuli, establishing the molecular receptive fields for the recombinantly expressed receptor in human embryonic kidney (HEK) 293 cells and the native receptor in human spermatozoa. Bourgeonal was a powerful agonist for both recombinant and native receptor types, as well as a strong chemoattractant in subsequent behavioral bioassays. In contrast, undecanal was a potent OR antagonist to bourgeonal and related compounds. Taken together, these results indicate that hOR17-4 functions in human sperm chemotaxis and may be a critical component of the fertilization process.
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DURING the past few decades, investigations have been made into various active substances which, though they resemble hormones in some respects, cannot be included among them. For example, the sexual attractants of butterflies are, like hormones, produced and secreted by special glands; minute amounts cause a specific reaction in the receptor organ (the antenna of the male), which eventually leads to a state of copulative readiness. Unlike hormones, however, the substance is not secreted into the blood but outside the body; it does not serve humoral correlation within the organism but communication between individuals.
Article
Research on human putative pheromones has recently focused on the effects of exposure to 4,16-androstadien-3-one (androstadienone). This steroid has been observed in the skin, axillary hair, and blood plasma, primarily in males. In addition to effects of the steroid on measures of physiological arousal and brain blood flow, positive mood effects have also been reported. The current study further investigated mood effects of androstadienone exposure (250 microM) in women in two experiments. Through psychophysical testing of each individual we controlled for whether any observed mood effects could be related to sensory detection of the steroid. In both experiments, we observed positive changes of women's feeling of being focused, which could not be related to sensory detection of the steroid. Overall, the patterns of results were significantly correlated between the two experiments. In conclusion, this study corroborates earlier findings suggesting that androstadienone exposure yields effects on women's mood; the feeling of being focused. The mood effects were not dependent on menstrual cycle phase. Further, these effects are replicable and occur also when androstadienone detection is rigorously controlled for across variation in menstrual cycle.
Article
We asked whether the effects of exposure to two human sex-steroid derived compounds were context dependent. The effects of sniffing 4,16-androstadien-3-one (AND) and 1,3,5(10),16-estratetraen-3-ol (EST) on mood, memory, and autonomic nervous system responses were explored in 72 participants. Subjects were tested with AND, EST, or a Control compound within four mood contexts: neutral, sexually aroused, sad and happy. These moods were successfully induced using selected film segments (P < 0.0001). During the neutral context, none of the compounds affected mood or autonomic nervous system function. However, compound effects were significantly increased within arousing contexts. During the sexually arousing context, both compounds increased sexual arousal (P < 0.029). During the sad context, AND maintained positive mood in women (P< 0.050) and increased negative mood in men (P < 0.031). Memory for events during the sad context was impaired by AND in women (P < 0.047) but not in men. Finally, effects of AND on physiology were observed during the sexually arousing context whereby AND increased skin temperature in both sexes (P < 0.022) but reduced abdominal respiration rate in men only (P < 0.034). These results suggest that sex-steroidal compounds modulate mood, memory and autonomic nervous system responses and increase their significance within specific behavioral contexts. These findings lend support to a specific role for these compounds in chemical communication between humans.
Article
Among primates in general, pheromones are of variable importance to social communication. Data on humans have generated the greatest controversy regarding the existence of pheromonal communication. In this review, the likelihood of pheromonal communication in humans is assessed with a discussion of chemical compounds produced by the axilla that may function as pheromones; the likelihood that the vomeronasal organ (VNO), a putative pheromone receptor organ in many other mammals, is functional in humans; and the possible ways pheromones operate in humans. In the human axilla, the interactions between the cutaneous microflora and axillary secretions render this region analogous to scent glands found in other primates. Both the chemistry of axillary secretions and their effects on conspecifics in humans appear to be analogous to other mammalian pheromone systems. Whichever chemical compounds serve a pheromonal function in humans, another unknown is the receptor. Although the VNO has been implicated in the reception of pheromones in many vertebrates, it is not the only pathway through which such information has access to the central nervous system; there is ample evidence to support the view that the olfactory epithelium can respond to pheromones. Furthermore, if a chemical activates receptors within the VNO, this does not necessarily mean that the compound is a pheromone. An important caveat for humans is that critical components typically found within the functioning VNO of other, nonprimate, mammals are lacking, suggesting that the human VNO does not function in the way that has been described for other mammals. In a broader perspective, pheromones can be classified as primers, signalers, modulators, and releasers. There is good evidence to support the presence of the former three in humans. Examples include affects on the menstrual cycle (primer effects); olfactory recognition of newborn by its mother (signaler); individuals may exude different odors based on mood (suggestive of modulator effects). However, there is no good evidence for releaser effects in adult humans. It is emphasized that no bioassay-guided study has led to the isolation of true human pheromones, a step that will elucidate specific functions to human chemical signals.
Article
We reported previously that jasmonates can kill human cancer cells. Many chemotherapeutic drugs induce mitochondrial membrane permeability transition, membrane depolarization, osmotic swelling, and release of cytochrome c, involving the opening of the permeability transition pore complex (PTPC). Because jasmonates exert their cytotoxic effects independent of transcription, translation, and p53 expression, we hypothesized that these compounds may act directly on mitochondria. Mitochondrial membrane depolarization was determined by flow cytometry, and cytochrome c release by Western blotting. Mitochondria were isolated by mechanical lysis and differential centrifugation. Cytotoxicity was measured by a tetrazolium-based assay, and mitochondrial swelling by spectrophotometry. Jasmonates induced membrane depolarization and cytochrome c release in intact human cancer cell lines. Jasmonates induced swelling in mitochondria isolated from Hep 3B hepatoma cells, but not in mitochondria isolated from 3T3 nontransformed cells or from normal lymphocytes, in a PTPC-mediated manner. Methyl jasmonate induced the release of cytochrome c from mitochondria isolated from cancer cell lines in a PTPC-mediated manner, but not from mitochondria isolated from normal lymphocytes. A correlation was found between cytotoxicity of methyl jasmonate and the percentage of leukemic cells in the blood of patients with chronic lymphocytic leukemia (CLL). Jasmonates induced membrane depolarization in CLL cells, and swelling and release of cytochrome c in mitochondria isolated from these cells. In conclusion, jasmonates act directly on mitochondria derived from cancer cells in a PTPC-mediated manner, and could therefore bypass premitochondrial apoptotic blocks. Jasmonates are promising candidates for the treatment of CLL and other types of cancer.