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Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate fertility and integrate hormonal status with environmental cues to ensure reproductive success. Here we show that GnRH neurons in the olfactory bulb (GnRH OB ) of adult mice can mediate social recognition. Specifically, we show that GnRH OB neurons extend neurites into the vomeronasal organ and olfactory epithelium and project to the median eminence. GnRH OB neurons in males express vomeronasal and olfactory receptors, are activated by female odors and mediate gonadotropin release in response to female urine. Male preference for female odors required the presence and activation of GnRH OB neurons, was impaired after genetic inhibition or ablation of these cells and relied on GnRH signaling in the posterodorsal medial amygdala. GnRH receptor expression in amygdala kisspeptin neurons appear to be required for GnRH OB neurons’ actions on male mounting behavior. Taken together, these results establish GnRH OB neurons as regulating fertility, sex recognition and mating in male mice. Studying GnRH neuroendocrine cells in the mouse olfactory bulb (GnRH OB neurons), Decoster et al. show that these cells respond to female odors and their activation regulates males’ female-odor preference and mating behavior.

Aggression is controlled by the olfactory system in many animal species. In male mice, territorial and infant-directed aggression are tightly regulated by the vomeronasal organ (VNO), but how diverse subsets of sensory neurons convey pheromonal information to limbic centers is not yet known. Here, we employ genetic strategies to show that mouse vomeronasal sensory neurons expressing the G protein subunit Gαi2 regulate male-male and infant-directed aggression through distinct circuit mechanisms. Conditional ablation of Gαi2 enhances male-male aggression and increases neural activity in the me-dial amygdala (MeA), bed nucleus of the stria terminalis, and lateral septum. By contrast, conditional Gαi2 ablation causes reduced infant-directed aggression and decreased activity in MeA neurons during male-infant interactions. Strikingly, these mice also display enhanced parental behavior and elevated neural activity in the medial preoptic area, whereas sexual behavior remains normal. These results identify Gαi2 as the primary G protein α-subunit mediating the detection of volatile chemosignals in the apical layer of the VNO, and they show that Gαi2 + VSNs and the brain circuits activated by these neurons play a central role in orchestrating and balancing territorial and infant-directed aggression of male mice through bidirectional activation and inhibition of different targets in the limbic system.

Abstract Cartilaginous fishes are renowned for a keen sense of smell, a reputation based on behavioral observations and supported by the presence of large and morphologically complex olfactory organs. At the molecular level, genes belonging to the four families coding for most olfactory chemosensory receptors in other vertebrates have been identified in a chimera and a shark, but it was unknown whether they actually code for olfactory receptors in these species. Here, we describe the evolutionary dynamics of these gene families in cartilaginous fishes using genomes of a chimera, a skate, a sawfish, and eight sharks. The number of putative OR, TAAR, and V1R/ORA receptors is very low and stable, whereas the number of putative V2R/OlfC receptors is higher and much more dynamic. In the catshark Scyliorhinus canicula, we show that many V2R/OlfC receptors are expressed in the olfactory epithelium in the sparsely distributed pattern characteristic for olfactory receptors. In contrast, the other three vertebrate olfactory receptor families are either not expressed (OR) or only represented with a single receptor (V1R/ORA and TAAR). The complete overlap of markers of microvillous olfactory sensory neurons with pan-neuronal marker HuC in the olfactory organ suggests the same cell-type specificity of V2R/OlfC expression as for bony fishes, that is, in microvillous neurons. The relatively low number of olfactory receptors in cartilaginous fishes compared with bony fishes could be the result of an ancient and constant selection in favor of a high olfactory sensitivity at the expense of a high discrimination capability.

Driven to tears Pheromones and their detection by the vomeronasal organ are known to govern social behaviour in mice, but few chemical signals have been linked to specific behavioural responses. Haga et al . now show that the ESP1 peptide secreted in male tears makes females sexually receptive, and have identified its specific vomeronasal receptor (V2Rp5) and the sex-specific neuronal circuits activated during the behavioural response. Whether such 'labelled line' logic extends to the regulation of reproductive behaviour in other mammals remains unclear. Although pheromones and their detection by the vomeronasal organ are known to govern social behaviour in mice, specific chemical signals have rarely been linked to selective behavioural responses. Here the authors show that the ESP1 peptide secreted in male tears makes females sexually receptive, and identify its specific vomeronasal receptor and the sex-specific neuronal circuits activated during the behavioural response. Various social behaviours in mice are regulated by chemical signals called pheromones that act through the vomeronasal system 1 , 2 , 3 . Exocrine gland-secreting peptide 1 (ESP1) is a 7-kDa peptide that is released into male tear fluids and stimulates vomeronasal sensory neurons in female mice 4 . Here, we describe the molecular and neural mechanisms that are involved in the decoding of ESP1 signals in the vomeronasal system, which leads to behavioural output in female mice. ESP1 is recognized by a specific vomeronasal receptor, V2Rp5, and the ligand–receptor interaction results in sex-specific signal transmission to the amygdaloid and hypothalamic nuclei via the accessory olfactory bulb. Consequently, ESP1 enhances female sexual receptive behaviour upon male mounting (lordosis), allowing successful copulation. In V2Rp5-deficient mice, ESP1 induces neither neural activation nor sexual behaviour. These findings show that ESP1 is a crucial male pheromone that regulates female reproductive behaviour through a specific receptor in the mouse vomeronasal system.

Most terrestrial mammals have a vomeronasal system to detect specific chemicals. The peripheral organ of this system is a vomeronasal organ (VNO) opening to the incisive duct, and its primary integrative center is an accessory olfactory bulb (AOB). The VNO in seals is thought to be degenerated like whales and manatees, unlike otariids, because of the absence of the AOB. However, olfaction plays pivotal roles in seals, and thus we conducted a detailed morphological evaluation of the vomeronasal system of three harbor seals ( Phoca vitulina ). The VNO lumen was not found, and the incisive duct did not open into the oral cavity but was recognized as a fossa on the anteroventral side of the nasal cavity. This fossa is rich in mucous glands that secrete acidic mucopolysaccharides, which might originate from the vomeronasal glands. The olfactory bulb consisted only of a main olfactory bulb that received projections from the olfactory mucosa, but an AOB region was not evident. These findings clarified that harbor seals do not have a VNO to detect some chemicals, but the corresponding region is a specialized secretory organ.

The vomeronasal system (VNS) is responsible for the perception mainly of pheromones and kairomones. Primarily studied in laboratory rodents, it plays a crucial role in their socio-sexual behaviour. As a wild rodent, the capybara offers a more objective and representative perspective to understand the significance of the system in the Rodentia, avoiding the risk of extrapolating from laboratory rodent strains, exposed to high levels of artificial selection pressure. We have studied the main morphological and immunohistochemical features of the capybara vomeronasal organ (VNO) and accessory olfactory bulb (AOB). The study was done in newborn individuals to investigate the maturity of the system at this early stage. We used techniques such as histological stains, lectins-labelling and immunohistochemical characterization of a range of proteins, including G proteins (Gαi2, Gαo) and olfactory marking protein. As a result, we conclude that the VNS of the capybara at birth is capable of establishing the same function as that of the adult, and that it presents unique features as the high degree of differentiation of the AOB and the active cellular migration in the vomeronasal epithelium. All together makes the capybara a promising model for the study of chemical communication in the first days of life.

Innate immune chemoreceptors of the formyl peptide receptor (Fpr) family are expressed by vomeronasal sensory neurons (VSNs) in the accessory olfactory system. Their biological function and coding mechanisms remain unknown. We show that mouse Fpr3 (Fpr-rs1) recognizes the core peptide motif f-MKKFRW that is predominantly present in the signal sequence of the bacterial protein MgrB, a highly conserved regulator of virulence and antibiotic resistance in Enterobacteriaceae . MgrB peptide can be produced and secreted by bacteria, and is selectively recognized by a subset of VSNs. Exposure to the peptide also stimulates VSNs in freely behaving mice and drives innate avoidance. Our data shows that Fpr3 is required for neuronal detection and avoidance of peptides derived from a conserved master virulence regulator of enteric bacteria. The role of chemoreceptors on vomeronasal neurons are not fully understood. Here the authors show that in mice, the vomeronasal chemoreceptor Fpr3 responds to peptides from the bacterial MgrB protein, and that exposure to these peptides drives an avoidance response.

Neuronal identity dictates the position in an epithelium, and the ability to detect, process, and transmit specific signals to specified targets. Transcription factors (TFs) determine cellular identity via direct modulation of genetic transcription and recruiting chromatin modifiers. However, our understanding of the mechanisms that define neuronal identity and their magnitude remain a critical barrier to elucidate the etiology of congenital and neurodegenerative disorders. The rodent vomeronasal organ provides a unique system to examine in detail the molecular mechanisms underlying the differentiation and maturation of chemosensory neurons. Here, we demonstrated that the identity of postmitotic/maturing vomeronasal sensory neurons (VSNs), and vomeronasal-dependent behaviors can be reprogrammed through the rescue of Tfap2e/ AP-2ε expression in the Tfap2e Null mice, and partially reprogrammed by inducing ectopic Tfap2e expression in mature apical VSNs. We suggest that the TF Tfap2e can reprogram VSNs bypassing cellular plasticity restrictions, and that it directly controls the expression of batteries of vomeronasal genes.

In numerous animals, one essential chemosensory organ that detects chemical signals is the vomeronasal organ (VNO), which is involved in species-specific behaviors, including social and sexual behaviors. The purpose of this study is to investigate the mechanism underlying the processing of chemosensory cues in semi-aquatic mammals using muskrats as the animal model. Muskrat (Ondatra zibethicus) has a sensitive VNO system that activates seasonal breeding behaviors through receiving specific substances, including pheromones and hormones. Vomeronasal organ receptor type 1 (V1R) and type 2 (V2R) and estrogen receptor α and β (ERα and ERβ) were found in sensory epithelial cells, non-sensory epithelial cells and lamina propria cells of the female muskrats’ VNO. V2R and ERα mRNA levels in the VNO during the breeding period declined sharply, in comparison to those during the non-breeding period, while V1R and ERβ mRNA levels were detected reversely. Additionally, transcriptomic study in the VNO identified that differently expressed genes might be related to estrogen signal and metabolic pathways. These findings suggested that the seasonal structural and functional changes in the VNO of female muskrats with different reproductive status and estrogen was regulated through binding to ERα and ERβ in the female muskrats’ VNO.

The scent of aggression Pheromones are chemical signals that regulate innate behaviours between members of the same species. In mice, pup suckling, aggression and mating are all influenced by pheromones detected by neurons in the nasal cavity. Now Chamero et al . report the identification of the protein component of the major urinary protein complex as a potential pheromone ligand mediating male–male aggression via the accessory olfactory neural pathway. This work is a significant step towards understanding intraspecific communication in a mammal and characterizing the neuronal circuitry involved in such behaviour. The protein component of the major urinary protein complex is identified as a potential pheromone ligand mediating male–male aggression via the accessory olfactory pathway. Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating 1 . Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE) 2 . Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male–male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules 1 , 3 , 4 . Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Gα o subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male–male aggression through the accessory olfactory neural pathway.