The nose knows who's who: chemosensory individuality and mate recognition in mice

Individual recognition is an important component of behaviors, such as mate choice and maternal bonding that are vital for reproductive success. This article highlights recent developments in our understanding of the chemosensory cues and the neural pathways involved in individuality discrimination in rodents. There appear to be several types of chemosensory signal of individuality that are influenced by the highly polymorphic families of major histocompatibility complex (MHC) proteins or major urinary proteins (MUPs). Both have the capability of binding small molecules and may influence the individual profile of these chemosignals in biological fluids such as urine, skin secretions, or saliva. Moreover, these proteins, or peptides associated with them, can be taken up into the vomeronasal organ (VNO) where they can potentially interact directly with the vomeronasal receptors. This is particularly interesting given the expression of major histocompatibility complex Ib proteins by the V2R class of vomeronasal receptor and the highly selective responses of accessory olfactory bulb (AOB) mitral cells to strain identity. These findings are consistent with the role of the vomeronasal system in mediating individual discrimination that allows mate recognition in the context of the pregnancy block effect. This is hypothesized to involve a selective increase in the inhibitory control of mitral cells in the accessory olfactory bulb at the first level of processing of the vomeronasal stimulus.     

Mating Increases Neuronal Tyrosine Hydroxylase Expression and Selectively Gates Transmission of Male Chemosensory Information in Female Mice

Exposure to chemosensory signals from unfamiliar males can terminate pregnancy in recently mated female mice. The number of tyrosine hydroxylase-positive neurons in the main olfactory bulb has been found to increase following mating and has been implicated in preventing male-induced pregnancy block during the post-implantation period. In contrast, pre-implantation pregnancy block is mediated by the vomeronasal system, and is thought to be prevented by selective inhibition of the mate’s pregnancy blocking chemosignals, at the level of the accessory olfactory bulb. The objectives of this study were firstly to identify the level of the vomeronasal pathway at which selective inhibition of the mate’s pregnancy blocking chemosignals occurs. Secondly, to determine whether a post-mating increase in tyrosine hydroxylase-positive neurons is observed in the vomeronasal system, which could play a role in preventing pre-implantation pregnancy block. Immunohistochemical staining revealed that mating induced an increase in tyrosine-hydroxylase positive neurons in the arcuate hypothalamus of BALB/c females, and suppressed c-Fos expression in these neurons in response to mating male chemosignals. This selective suppression of c-Fos response to mating male chemosignals was not apparent at earlier levels of the pregnancy-blocking neural pathway in the accessory olfactory bulb or corticomedial amygdala. Immunohistochemical staining revealed an increase in the number of tyrosine hydroxylase-positive neurons in the accessory olfactory bulb of BALB/c female mice following mating. However, increased dopamine-mediated inhibition in the accessory olfactory bulb is unlikely to account for the prevention of pregnancy block to the mating male, as tyrosine hydroxylase expression did not increase in females of the C57BL/6 strain, which show normal mate recognition. These findings reveal an association of mating with increased dopaminergic modulation in the pregnancy block pathway and support the hypothesis that mate recognition prevents pregnancy block by suppressing the activation of arcuate dopamine release.     

Roles for learning in mammalian chemosensory responses

This article is part of a Special Issue “Chemosignals and Reproduction”.A rich variety of chemosignals have been identified that influence mammalian behaviour, including peptides, proteins and volatiles. Many of these elicit innate effects acting either as pheromones within species or allelochemicals between species. However, even innate pheromonal responses in mammals are not as hard-wired as the original definition of the term would suggest. Many, if not most mammalian pheromonal responses are only elicited in certain behavioural or physiological contexts. Furthermore, certain pheromones are themselves rewarding and act as unconditioned stimuli to link non-pheromonal stimuli to the pheromonal response, via associative learning. The medial amygdala, has emerged as a potential site for this convergence by which learned chemosensory input is able to gain control over innately-driven output circuits. The medial amygdala is also an important site for associating social chemosensory information that enables recognition of conspecifics and heterospecifics by association of their complex chemosensory signatures both within and across olfactory chemosensory systems. Learning can also influence pheromonal responses more directly to adapt them to changing physiological and behavioural context. Neuromodulators such as noradrenaline and oxytocin can plasticise neural circuits to gate transmission of chemosensory information. More recent evidence points to a role for neurogenesis in this adaptation, both at the peripheral level of the sensory neurons and via the incorporation of new neurons into existing olfactory bulb circuits. The emerging picture is of integrated and flexible responses to chemosignals that adapt them to the environmental and physiological context in which they occur.     

The rodent accessory olfactory system

The accessory olfactory system contributes to the perception of chemical stimuli in the environment. This review summarizes the structure of the accessory olfactory system, the stimuli that activate it, and the responses elicited in the receptor cells and in the brain. The accessory olfactory system consists of a sensory organ, the vomeronasal organ, and its central projection areas: the accessory olfactory bulb, which is connected to the amygdala and hypothalamus, and also to the cortex. In the vomeronasal organ, several receptors—in contrast to the main olfactory receptors—are sensitive to volatile or nonvolatile molecules. In a similar manner to the main olfactory epithelium, the vomeronasal organ is sensitive to common odorants and pheromones. Each accessory olfactory bulb receives input from the ipsilateral vomeronasal organ, but its activity is modulated by centrifugal projections arising from other brain areas. The processing of vomeronasal stimuli in the amygdala involves contributions from the main olfactory system, and results in long-lasting responses that may be related to the activation of the hypothalamic–hypophyseal axis over a prolonged timeframe. Different brain areas receive inputs from both the main and the accessory olfactory systems, possibly merging the stimulation of the two sensory organs to originate a more complex and integrated chemosensory perception.     

Pheromonal communication in amphibians

Pheromonal communication is widespread in salamanders and newts and may also be important in some frogs and toads. Several amphibian pheromones have been behaviorally, biochemically and molecularly identified. These pheromones are typically peptides or proteins. Study of pheromone evolution in plethodontid salamanders has revealed that courtship pheromones have been subject to continual evolutionary change, perhaps as a result of co-evolution between the pheromonal ligand and its receptor. Pheromones are detected by the vomeronasal organ and main olfactory epithelium. Chemosensory neurons express vomeronasal receptors or olfactory receptors. Frogs have relatively large numbers of vomeronasal receptors that are transcribed in both the vomeronasal organ and the main olfactory epithelium. Salamander vomeronasal receptors apparently are restricted to the vomeronasal organ. To date, no chemosensory ligands have been matched to vomeronasal receptors or olfactory receptors so it is unknown whether particular receptor types are (1) specialized for detection of pheromones versus other chemosignals, or (2) specialized for detection of volatile, nonvolatile, or water-borne chemosignals. Despite progress in understanding amphibian pheromonal communication, only a small fraction of amphibian species have been examined. Study of additional species of amphibians will indicate which traits related to pheromonal communication are evolutionarily conserved and which traits have diverged over time.     

The combined role of the main olfactory and vomeronasal systems in social communication in mammals

The main olfactory and the vomeronasal systems are the two systems by which most vertebrates detect chemosensory cues that mediate social behavior. Much research has focused on how one system or the other is critical for particular behaviors. This has lead to a vision of two distinct and complexly autonomous olfactory systems. A closer look at research over the past 30 years reveals a different picture however. These two seemingly distinct systems are much more integrated than previously thought. One novel set of chemosensory cues in particular (MHC Class I peptide ligands) can show us how both systems are capable of detecting the same chemosensory cues, through different mechanisms yet provide the same general information (genetic individuality). Future research will need to now focus on how two seemingly distinct chemosensory systems together detect pheromones and mediate social behaviors. Do these systems work independently, synergistically or competitively in communicating between individuals of the same species?     

The combined role of the main olfactory and vomeronasal systems in social communication in mammals

The main olfactory and the vomeronasal systems are the two systems by which most vertebrates detect chemosensory cues that mediate social behavior. Much research has focused on how one system or the other is critical for particular behaviors. This has lead to a vision of two distinct and complexly autonomous olfactory systems. A closer look at research over the past 30 years reveals a different picture however. These two seemingly distinct systems are much more integrated than previously thought. One novel set of chemosensory cues in particular (MHC Class I peptide ligands) can show us how both systems are capable of detecting the same chemosensory cues, through different mechanisms yet provide the same general information (genetic individuality). Future research will need to now focus on how two seemingly distinct chemosensory systems together detect pheromones and mediate social behaviors. Do these systems work independently, synergistically or competitively in communicating between individuals of the same species?     

HRP uptake by olfactory and vomeronasal receptor neurons: use as an indicator of incomplete lesions and relevance for non-volatile chemoreception

The transport of HRP (horseradish peroxidase) from the nasalcavity to the brain by intact olfactory receptor axons was usedto investigate the effectiveness of methods commonly used inbehavioral studies for deafferenting nasal chemoreceptor systems.The HRP experiments demonstrated that routine intranasal lavagewith zinc sulfate solution fails to destroy all olfactory receptorneurons in hamsters, in spite of the distinct behavioral deficitthat this treatment can cause in the male hamster. The intracranialdeafferentation of the accessory olfactory bulb by surgicalsection of the vomeronasal nerves was generally effective butthere was much incidental damage to main olfactory nerves thatwould probably not be detected without the HRP tracer. The distribution pattern of HRP molecules introduced into themammalian nasal cavity, as shown by the uptake of HRP by nasalchemoreceptors and its transport to the brain, was also usedto identify potential pathways for non-volatile stimulus moleculeswithin the nose. HRP reaction product was reliably detectedin the glomeruli of the main olfactory bulb after HRP was depositedat the nostril, demonstrating that nonvolatile materials, oncethey have entered the nasal cavity, can reach the main olfactoryreceptor neurons in the posterior nasal epithelium. Significantamounts of HRP reaction product were never observed in the accessoryolfactory bulbunlessa large dose of epinephrine had been givento activate the vomeronasal organ pumping mechanism, which drawssubstances into the vomeronasal organ lumen. Thus, it seemsthat stimulus access to vomeronasal receptor neurons is controlledindependently of access to main olfactory receptor neurons.     

Mammalian pheromone sensing

The traditional distinction that the mammalian main olfactory system recognizes general odor molecules and the accessory (vomeronasal) system detects pheromones is no longer valid. The emerging picture is that both systems have considerable overlap in terms of the chemosignals they detect and the effects that they mediate. Recent investigations have discovered large families of pheromonal signals together with a rich variety of specific receptor systems and nasal detection pathways. Selective genetic targeting of these subsystems should help to unravel their biological role in pheromone-mediated behavioral responses.     

Aggression and courtship in Drosophila: pheromonal communication and sex recognition

Upon encountering a conspecific in the wild, males have to rapidly detect, integrate and process the most relevant signals to evoke an appropriate behavioral response. Courtship and aggression are the most important social behaviors in nature for procreation and survival: for males, making the right choice between the two depends on the ability to identify the sex of the other individual. In flies as in most species, males court females and attack other males. Although many sensory modalities are involved in sex recognition, chemosensory communication mediated by specific molecules that serve as pheromones plays a key role in helping males distinguish between courtship and aggression targets. The chemosensory signals used by flies include volatile and non-volatile compounds, detected by the olfactory and gustatory systems. Recently, several putative olfactory and gustatory receptors have been identified that play key roles in sex recognition, allowing investigators to begin to map the neuronal circuits that convey this sensory information to higher processing centers in the brain. Here, we describe how Drosophila melanogaster males use taste and smell to make correct behavioral choices.     

Something in the air? New insights into mammalian pheromones

Olfaction is the dominant sensory modality for most animals and chemosensory communication is particularly well developed in many mammals. Our understanding of this form of communication has grown rapidly over the last ten years since the identification of the first olfactory receptor genes. The subsequent cloning of genes for rodent vomeronasal receptors, which are important in pheromone detection, has revealed an unexpected diversity of around 250 receptors belonging to two structurally different classes. This review will focus on the chemical nature of mammalian pheromones and the complementary roles of the main olfactory system and vomeronasal system in mediating pheromonal responses. Recent studies using genetically modified mice and electrophysiological recordings have highlighted the complexities of chemosensory communication via the vomeronasal system and the role of this system in handling information about sex and genetic identity. Although the vomeronasal organ is often regarded as only a pheromone detector, evidence is emerging that suggests it might respond to a much broader variety of chemosignals.     

From sexual attraction to maternal aggression: When pheromones change their behavioural significance

This article is part of a Special Issue “Chemosignals and Reproduction”.This paper reviews the role of chemosignals in the socio-sexual interactions of female mice, and reports two experiments testing the role of pup-derived chemosignals and the male sexual pheromone darcin in inducing and promoting maternal aggression. Female mice are attracted to urine-borne male pheromones. Volatile and non-volatile urine fractions have been proposed to contain olfactory and vomeronasal pheromones. In particular, the male-specific major urinary protein (MUP) MUP20, darcin, has been shown to be rewarding and attractive to females. Non-urinary male chemosignals, such as the lacrimal protein ESP1, promote lordosis in female mice, but its attractive properties are still to be tested. There is evidence indicating that ESP1 and MUPs are detected by vomeronasal type 2 receptors (V2R).When a female mouse becomes pregnant, she undergoes dramatic changes in her physiology and behaviour. She builds a nest for her pups and takes care of them. Dams also defend the nest against conspecific intruders, attacking especially gonadally intact males. Maternal behaviour is dependent on a functional olfactory system, thus suggesting a role of chemosignals in the development of maternal behaviour. Our first experiment demonstrates, however, that pup chemosignals are not sufficient to induce maternal aggression in virgin females. In addition, it is known that vomeronasal stimuli are needed for maternal aggression. Since MUPs (and other molecules) are able to promote intermale aggression, in our second experiment we test if the attractive MUP darcin also promotes attacks on castrated male intruders by lactating dams. Our findings demonstrate that the same chemosignal, darcin, promotes attraction or aggression according to female reproductive state.     

Emerging views on the distinct but related roles of the main and accessory olfactory systems in responsiveness to chemosensory signals in mice

In rodents, the nasal cavity contains two separate chemosensory epithelia, the main olfactory epithelium, located in the posterior dorsal aspect of the nasal cavity, and the vomeronasal/accessory olfactory epithelium, located in a capsule in the anterior aspect of the ventral floor of the nasal cavity. Both the main and accessory olfactory systems play a role in detection of biologically relevant odors. The accessory olfactory system has been implicated in response to pheromones, while the main olfactory system is thought to be a general molecular analyzer capable of detecting subtle differences in molecular structure of volatile odorants. However, the role of the two systems in detection of biologically relevant chemical signals appears to be partially overlapping. Thus, while it is clear that the accessory olfactory system is responsive to putative pheromones, the main olfactory system can also respond to some pheromones. Conversely, while the main olfactory system can mediate recognition of differences in genetic makeup by smell, the vomeronasal organ (VNO) also appears to participate in recognition of chemosensory differences between genetically distinct individuals. The most salient feature of our review of the literature is that there are no general rules that allow classification of the accessory olfactory system as a pheromone detector and the main olfactory system as a detector of general odorants. Instead, each behavior must be considered within a specific behavioral context to determine the role of these two chemosensory systems. In each case, one system or the other (or both) participates in a specific behavioral or hormonal response.     

A map of pheromone receptor activation in the mammalian brain

In mammals, the detection of pheromones is mediated by the vomeronasal system. We have employed gene targeting to visualize the pattern of projections of axons from vomeronasal sensory neurons in the accessory olfactory bulb. Neurons expressing a specific receptor project to multiple glomeruli that reside within spatially restricted domains. The formation of this sensory map in the accessory olfactory bulb and the survival of vomeronasal organ sensory neurons require the expression of pheromone receptors. In addition, we observe individual glomeruli in the accessory olfactory bulb that receive input from more than one type of sensory neuron. These observations indicate that the organization of the vomeronasal sensory afferents is dramatically different from that of the main olfactory system, and these differences have important implications for the logic of olfactory coding in the vomeronasal organ.     

哺乳动物主要嗅觉系统和犁鼻系统信息识别的编码模式

哺乳动物具有两套嗅觉系统, 即主要嗅觉系统和犁鼻系统。前者对环境中的大多数挥发性化学物质进行识别, 后者对同种个体释放的信息素进行识别。本文从嗅觉感受器、嗅球、嗅球以上脑区三个水平综述了这两种嗅觉系统对化学信息识别的编码模式。犁鼻器用较窄的调谐识别信息素成分, 不同于嗅上皮用分类性合并受体的方式识别气味; 副嗅球以接受相同受体输入的肾丝球所在区域为单位整合信息, 而主嗅球通过对肾丝球模块的特异性合并编码信息; 在犁鼻系统, 信息素的信号更多地作用于下丘脑区域, 引起特定的行为和神经内分泌反应。而在主要嗅觉系统, 嗅皮层可能采用时间模式编码神经元群, 对气味的最终感受与脑的不同区域有关。犁鼻系统较主要嗅觉系统的编码简单, 可能与其执行的功能较少有关。     

Encoding olfactory signals via multiple chemosensory systems

Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world.     

Developmental changes in cytochrome oxidase histochemistry in the main and accessory olfactory bulbs of embryonic and neonatal garter snakes (Thamnophis sirtalis spp.)

Developmental studies examining the changes in oxidative metabolic activity are useful for understanding how and if the vomeronasal and olfactory systems respond to stimulation during embryogenesis. Garter snakes are good candidates for examining the potential functionality of the vomeronasal system in utero. In adult garter snakes, the vomeronasal system mediates many behaviors. Neonatal garter snakes exhibit these same behaviors, and the vomeronasal system has been shown to mediate feeding behavior in neonates. Using cytochrome oxidase histochemistry, we examined changes in the oxidative metabolic activity of main and accessory olfactory bulbs of embryonic and neonatal garter snakes (Thamnophis sirtalis sirtalis and T. s. parietalis). Cytochrome oxidase staining is greater in the accessory olfactory bulb than in the main olfactory bulb of embryonic garter snakes. However, neonates show no differences in the staining of the accessory and main olfactory bulbs, suggesting a change in the stimulation of the main olfactory bulb after birth. This is the first report of cytochrome oxidase histochemistry in reptiles and in the vomeronasal system of embryonic vertebrates. © 1993 Wiley-Liss, Inc.     

The vomeronasal system in mice: from the nose to the hypothalamus- and back!

The vomeronasal pathway in rodents runs parallel to the main olfactory pathway and mediates responses to different classes of chemosensory stimuli. Both olfactory systems can converge and synergize to control reproductive behaviors and hormonal changes triggered by chemosensory cues. Novel experimental approaches expressing genetic transneuronal tracers in hypothalamic neurons regulating reproduction have set the stage to analyze how chemosensory inputs are integrated in the brain to elicit reproductive behaviors and hormonal changes, and how neuroendocrine status might modulate susceptibility to chemosensory cues.     

Encoding Olfactory Signals via Multiple Chemosensory Systems

ABSTRACT

Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world.