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Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

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The Neurobiology of Olfaction.

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Chapter 6Pheromones and Mammalian Behavior

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6.1. INTRODUCTION

From the most gregarious to the most solitary, all animals have to coordinate their activity with other members of their species if they are to survive and reproduce. This requires some form of communication, which for the majority of animals involves the use of chemical signals, known as pheromones. Karlson and Luscher (1959) initially proposed the term pheromone. They defined pheromones as “substances secreted to the outside of an individual and received by a second individual of the same species in which they release a specific reaction, for example, a definite behavior or developmental process.” Although not part of the original definition, the term pheromone is usually reserved for chemical signals that are produced and received by members of the same species, in which both the sender and receiver of the signal gain benefit (Wyatt 2003). In this case, selective pressures usually lead to the coevolution specialized sending and receiving systems for pheromones.

The identification of pheromones started in the 1950s with the purification of only 5.3 mg of the male silk moth attractant bombykol, from the scent glands of 313,000 female silk moths (Butenandt et al. 1959). Bombykol has since become a classic example of a sex attractant pheromone, attracting male silk moths over large distances. However, there has been considerable debate regarding whether the term pheromone, which was initially applied to insect chemosignals, can be usefully applied to vertebrates (Doty 2003). The issue comes down to what is meant by a “definite response.” Vertebrate, especially mammalian, behavior is generally more dependent on context and learning than insect behavior, and therefore, responses to chemical signals are more difficult to observe, and rarely consistently effective in all individuals all of the time. This chapter reviews the recent evidence that has accumulated in support of mammalian pheromones that exert significant influence over mammalian physiology and behavior. In doing so, it takes a relatively broad view in discussing all intraspecific, specialized semiochemical signals as potential pheromones, while acknowledging that they may not meet the narrower interpretations of some researchers in the field.

6.2. THE CHEMICAL NATURE OF PHEROMONES

A wide variety of chemicals are used as pheromones, including small, volatile molecules, proteins, and peptides (Figure 6.1), in which their chemical nature is linked to their function. Important features of chemicals used as pheromonal signals are their size and polarity, which determine their volatility in air and solubility in water. In the terrestrial environment, airborne signals that are required to act at a distance from the producer, such as attractant and alarm pheromones, need to be small and volatile, such as the male mouse urinary constituent, (methylthio)methanethiol (MTMT), which attracts female investigation (Lin et al. 2005). Their small size and volatility not only ensures that such pheromones are dispersed rapidly, but also makes these signals transient. In contrast, pheromonal signals that need to be associated with a specific individual or place in the environment are ideally nonvolatile, so that they do not disperse and are longer lasting. For example, male mice deposit urine marks containing 18–20 kDa major urinary proteins (MUPs), the stability and involatility of which make them ideal for their territorial marking role (Hurst and Beynon 2004).

FIGURE 6.1. Stimulus selectivity of mouse vomeronasal class 1 (V1R)-expressing vomeronasal sensory neurons (VSNs) recorded by Ca2+ imaging from slices of the vomeronasal epithelium.

FIGURE 6.1

Stimulus selectivity of mouse vomeronasal class 1 (V1R)-expressing vomeronasal sensory neurons (VSNs) recorded by Ca2+ imaging from slices of the vomeronasal epithelium. (A) VSNs that responded to volatile pheromones were located in the apical region (more...)

6.3. PHEROMONE PRODUCTION

Animals use an enormous variety of different mechanisms for releasing pheromones into the environment (Table 6.1). In many cases, pheromonal release takes advantage of existing routes for excretion, such as urine and feces, which may be deliberately placed in the environment as territorial marks. For instance, the urine marks used by rodents, such as mice, are known to contain a variety of small, volatile pheromones (Novotny 2003), as well as sulfated steroids and proteins that are also likely to have a pheromonal function (Chamero et al. 2007; Nodari et al. 2008). Other routes of pheromone release involve biological secretions. Hamsters release the sexual attractant protein, aphrodisin, in their vaginal secretions (Mägert et al. 1999). The rabbit mammary pheromone is produced by glands around the nipples and is present in rabbit milk (Schaal et al. 2003). Several potential chemosignals have been identified in the saliva of different species, including the well-known sexual attractant pheromone of boars (Loebel et al. 2000). But, there are also a wide variety of specialized scent glands that have no known role other than the release of pheromonal signals, even if, in most cases, little is known of the nature of the signals or the role that they perform. For instance, flank glands in hamsters can be used to leave marks that convey information about individual identity (Mateo and Johnston 2000). Most species of carnivora have anal glands, including ferrets, which produce sex-specific volatiles that could function as pheromones (Zhang et al. 2005). Other specialized scent glands include chin glands, interdigital glands, and sternal glands.

TABLE 6.1. The Chemical Nature, Source, and Pheromonal Effects of a Range of Commonly Accepted Mammalian Pheromones.

TABLE 6.1

The Chemical Nature, Source, and Pheromonal Effects of a Range of Commonly Accepted Mammalian Pheromones.

In addition to the analytical chemistry used for the analysis of volatile components of glandular secretions, modern molecular biological approaches are revealing a wide variety of proteins and peptides that are likely candidates for pheromonal signaling. A family of peptides, called exocrine gland secreting peptides (ESPs), has recently been identified in mice. The starting point for Touhara’s group was the realization that chemicals released from the facial area of mice activated sensory neurons in the vomeronasal system. They tested the activity of extracts from glands in the head region, which ultimately led to the identification of 7 kDa peptide, which they named ESP1 (Kimoto et al. 2005). They went on to show that the gene encoding ESP1 was a member of a family of at least 38 related genes in mice, and 10 in rats (Kimoto et al. 2007). ESPs are produced by several glands, in addition to the extraorbital lacrimal glands, including salivary and Harderian glands. The finding that some ESPs are expressed in a sex- and strain-dependent manner, suggests that they could convey information about gender and individual identity, although their behavioral role is unknown (Kimoto et al. 2007).

6.4. PHEROMONAL DETECTION

The species specificity of pheromonal signals is reflected in the high rate of evolutionary change of the signals and the chemosensory systems responsible for their detection. Probably the most significant of these changes was the transition from aquatic to terrestrial environments, due to their different physiochemical nature. With the evolution of a terrestrial lifestyle came the possibility to exploit the large range of airborne chemosignals by the ciliated cells of what came to be the main olfactory system. However, sensitivity to water-soluble, but relatively involatile chemosignals of the aquatic environment was not lost. Instead, the microvillar cells of the ancestral olfactory organ became largely segregated in an anatomically separate organ, in early terrestrial vertebrates, known as the vomeronasal organ (VNO), at the same time that the main olfactory system was adapting to sense airborne volatile stimuli. However, the detailed picture is considerably more complicated (Eisthen 2004) and the division between cell types is not absolute. Although the majority of olfactory sensory neurons (OSNs) in the mammalian main olfactory epithelium (MOE) are ciliated and express olfactory receptors (ORs), there are also microvillar cells that appear to form a distinct chemosensory system (Elsaesser et al. 2005).

For many years, the established view has been that these two chemosensory systems were not only anatomically distinct, but also functionally separate. The MOE was thought to detect volatile odors for general odor perception and learning. In contrast, the VNO was specialized for the detection of pheromonal signals affecting physiology and behavior, via a separate and relatively direct neural pathway. However, more recent studies have shown that both OSNs and vomeronasal sensory neurons (VSNs) can respond to the same chemical stimuli, and both sensory systems send projections to brain areas that are involved in mediating pheromonal responses (Brennan and Zufall 2006). Furthermore, the simple story of a distinction between the roles of the main olfactory and vomeronasal systems has become considerably more complicated by the discovery of specialized subsystems within both the main olfactory system and the vomeronasal system.

6.4.1. Vomeronasal System

The vomeronasal system is often regarded as having a role exclusively in pheromonal detection. However, this is certainly not true in nonmammalian vertebrates, as the VNO is used to detect predator and prey odors in many reptiles (Halpern and Martinez-Marcos 2003), and may have a similar role in some mammals. The VNO is a blind-ended tubular structure situated in the nasal septum and connected to the nasal and/or oral cavities via a narrow duct (Døving and Trotier 1998). The sensory epithelium containing the VSNs is found on the medial side of the organ, which respond to stimuli that are pumped into the lumen of the organ following direct physical contact with a scent source. The mechanism of this pumping action is likely to vary among species. In rodents, such as hamsters and mice, the VNO is tightly enclosed in a cartilaginous capsule. Changes in the blood flow to a large laterally positioned blood vessel cause pressure changes in the VNO lumen, resulting in chemosignals being pumped into the organ, along with mucus (Meredith and O’Connell 1979). This vascular pumping mechanism is activated by the sympathetic nervous system in situations of behavioral arousal (Meredith 1994). However, in other species, uptake of stimuli into the VNO is thought to be associated with a behavior known as flehmen, involving curling of the upper lip and facial grimacing, which can often be observed in ungulates and felines following direct contact with a scent source.

Although the VNO is undoubtedly specialized for the detection of involatile stimuli, there is still some doubt about whether it responds to volatile airborne stimuli. Many pheromonal stimuli that are sensed by the VNO are small, volatile molecules, and they act as stimuli for VSNs in vitro (Leinders-Zufall et al. 2000). However, their binding to lipocalins, such as MUPs, could be required to transport them into the VNO. Functional magnetic resonance imaging of the accessory olfactory bulb (AOB), which receives the input from the VNO, in anaesthetized mice has revealed robust changes in activity in response to urine odors delivered via the nasal airstream (Xu et al. 2005). However, this activation of the AOB could have occurred via a centrifugal pathway activated by main olfactory input, rather than being a direct sensory response (Martel and Baum 2007).

6.4.1.1. Vomeronasal Receptors

Two classes of vomeronasal receptors are expressed by spatially distinct populations of VSNs. Latest analyses of the mouse genome has revealed 187 functional genes for V1Rs (Grus et al. 2005), which are expressed by VSNs in the apical layer of the vomeronasal epithelium. A further 70 functional receptors of the V2R class have been identified, which are expressed by VSNs in the basal layer of the sensory epithelium (Shi and Zhang 2007). This surprising number of functional vomeronasal receptors indicates that there are likely to be a wide variety of chemosensory signals sensed by the vomeronasal system that remain to be identified. However, the vomeronasal receptor repertoire of mice and perhaps other rodents is not representative of all mammals. Many mammals have a much more restricted range of V1Rs and no functional V2Rs at all (Table 6.2).

TABLE 6.2. A Comparison of the Number of Genes and pseudogenes for Major Urinary Proteins (MUPs), Vomeronasal Receptor Class 1 (V1Rs), and Class 2 (V2Rs) in a Range of Mammalian Species That Have Been Identified by Comparative Genomic Analysis.

TABLE 6.2

A Comparison of the Number of Genes and pseudogenes for Major Urinary Proteins (MUPs), Vomeronasal Receptor Class 1 (V1Rs), and Class 2 (V2Rs) in a Range of Mammalian Species That Have Been Identified by Comparative Genomic Analysis.

Electrophysiological recordings and calcium imaging have revealed that the V1R and V2R classes of vomeronasal receptor respond to different classes of stimuli. V1R-expressing VSNs typically respond to small, volatile chemosignals, including the testosterone-dependent volatiles of male mouse urine (Figure 6.1) (Leinders-Zufall et al. 2000). They are also likely to respond to sulfated steroids that have recently been found to activate a large proportion of VSNs in the vomeronasal epithelium (Nodari et al. 2008). In contrast, the V2R-expressing population of VSNs is stimulated by a variety of protein and peptide stimuli, including MUPs, major histocompatibility complex (MHC) peptides, and ESPs (Leinders-Zufall et al. 2004; Chamero et al. 2007; Kimoto et al. 2007). Simultaneous recordings from large populations of VSNs in VNO slices have shown that natural stimuli, such as urine and tear secretions, contain a wealth of information about sex and individual identity, which could potentially be extracted by combinatorial analysis (Figure 6.2) (Holy et al. 2000; Kimoto et al. 2007; He et al. 2008; Nodari et al. 2008). Although, the extent to which the vomeronasal system processes information in this way is not known.

FIGURE 6.2. Differences in the patterns of responses of vomeronasal sensory neurons (VSNs) to urine from different individuals and major histocompatibility complex (MHC) peptides.

FIGURE 6.2

Differences in the patterns of responses of vomeronasal sensory neurons (VSNs) to urine from different individuals and major histocompatibility complex (MHC) peptides. Responses recorded by Ca2+ imaging from slices of vomeronasal epithelium in response (more...)

As would be expected of a pheromonal detection system, the responses of VSNs are highly sensitive. V1R-expressing VSNs typically respond to concentrations of urinary volatiles, such as (R,R)-3,4-dehydro-exo-brevicomin (DB) and (S)-2-sec-butyl-4,5-dihydrothiazole (SBT), with thresholds of 1010 to 10" M (Leinders-Zufall et al. 2000). V2R-expressing VSNs appear to be even more sensitive, responding to MHC peptides at the astonishingly low concentration of 10−13 M (Leinders-Zufall et al. 2004). VSNs respond more selectively than classical OSNs (Figure 6.1), and maintain their selectivity as the stimulus concentration is increased (Leinders-Zufall et al. 2000). Vomeronasal transduction differs from the classical OSN transduction mechanism. VSN transduction appears to involve the phospholipase 2 signaling pathway and transient receptor potential channels of the TRPC2 variety, in the apical microvilli of VSNs (Holy et al. 2000; Leypold et al. 2002; Stowers et al. 2002). However, the responses of V2R-expressing VSNs to MHC peptides are unaffected in TRPC2 knockout mice, implying that they use a different and so far unknown transduction mechanism (Kelliher et al. 2006). Earlier reports of maintained firing rate during current injection into VSNs suggested that they failed to show significant adaptation (Holy et al. 2000). However, more recent studies have shown that VSNs do show adaptation to maintained or repeated stimulus presentation mediated by a Calcium-calmodulin-dependent feedback on TRPC2 cation channels (Spehr et al. 2009).

6.4.1.2. Vomeronasal Neural Pathways

VSNs project their axons to the AOB where they synapse with the primary dendrites of mitral cell projection neurons in glomerular structures. V1R and V2R classes of VSN, which are segregated in apical and basal regions of the vomeronasal epithelium, project separately to anterior and posterior subdivisions of the AOB, respectively (Halpera and Martinez-Marcos 2003). Recently, a third subsystem within the AOB has been identified (Ishii and Mombaerts 2008). A subpopulation of V2R-expressing VSNs coexpress nonclassical class I MHC genes. This population of VSNs is located in the deeper sublayer of the basal zone of the sensory epithelium and project to the posterior subdomain of the posterior subdivision of the AOB (Ishii and Mombaerts 2008). However, the significance of this tripartite organization of the AOB remains unclear.

Genetically manipulated mice in which VSNs that express different V1Rs have been labeled with different fluorescent markers has provided the first glimpse of the pattern of information flow within the anterior subdivision of the AOB (Wagner et al. 2006). This has revealed that AOB mitral cells send a branched primary dendritic tree to sample information from glomeruli that receive input from different, but closely related V1R receptor types. These findings suggest that the integration of information from different receptor types is already occurring at the level of the AOB. This is consistent with recordings of AOB mitral cell activity from freely behaving mice, which found highly selective responses of individual neurons to specific combinations of sex and strain identity (Luo et al. 2003). A similar convergence of information at the level of the AOB is evident in the suppression of mitral cell responses to a mixture of male and female urine, compared to their responses to male or female urine presented individually (Hendrickson et al. 2008).

AOB mitral cells appear to send a distributed projection to the medial amygdala (MeA), posteromedial cortical amygdala (PMCoA), bed nucleus of the stria terminalis, and the bed nucleus of the accessory olfactory tract (von Campenhausen and Mori 2000). From these regions, vomeronasal information can gain direct access to the hypothalamic areas involved in the generation of a coordinated endocrine, autonomic, and behavioral output. Male and female chemosignals activate different subpopulations of neurons in the MeA, which can be identified on the basis of their homeodomain gene expression (Choi et al. 2005). Retrograde neural tracing in male mice showed that the MeA neurons that responded to female chemosignals provided input to areas of the hypothalamus involved in mating behavior. In contrast, MeA neurons that responded to male chemosignals projected to areas of the hypothalamus known to be involved in mediating defensive/aggressive behavior. Importantly, these male-responsive MeA neurons also sent antagonistic projections to the hypothalamic areas controlling reproductive behavior (Choi et al. 2005). This suggests that female pheromonal input normally drives mating behavior in males, but in the presence of male pheromones from a potential competitor, reproductive behavior is inhibited and defensive aggressive behavior promoted. Thus, there appear to be antagonistic interactions between male and female chemosensory information at the level of hypothalamic output as well as in the level of the AOB.

6.4.1.3. Behavioral Effects of Vomeronasal Dysfunction

The importance of the vomeronasal system in influencing behavior has been demonstrated by experiments in which the VNO has been physically ablated in genetically normal mice, or vomeronasal transduction disrupted in genetically manipulated mice lacking TRPC2 ion channel function. A common finding across these studies is that the removal of vomeronasal function abolishes the aggressive responses that both male and lactating female mice normally show in response to a male intruder (Maruniak et al. 1986; Leypold et al. 2002; Stowers et al. 2002). This is consistent with the role of the VNO in detecting volatile and involatile male urinary constituents that elicit aggressive behavior (Novotny et al. 1985; Chamero et al. 2007).

There appear to be significant species differences in the importance of vomeronasal sensation for male sexual behavior. Forty percent of male hamsters show severe deficits in sexual behavior, following section of their vomeronasal nerves (Licht and Meredith 1987). The effects were particularly severe in sexually naive males, with significant impairment of their ability to mate. However, sexually experienced males were much less affected, as their mating behavior could be maintained by main olfactory input that had become associated with mating during their previous sexual experience. In male mice, vomeronasal ablation prevents the normal rise in luteinizing hormone levels in response to female chemosignals. Male sexual behavior is not prevented in mice lacking vomeronasal function, suggesting that the pheromonal cues mediated by the main olfactory system may play an important role (Keller et al. 2009). Notably, TRPC2 knockout mice that have severely impaired vomeronasal function still show sexual behavior directed toward females, but also mount other males, rather than behaving aggressively toward them (Maruniak et al. 1986; Leypold et al. 2002; Stowers et al. 2002).

Physical lesions of the VNO impair lordosis behavior in female mice (Keller et al. 2006), suggesting that pheromones sensed by the vomeronasal system also play an important role in female sexual behavior (Keller et al. 2009). However, once again, the behavioral deficits of TRPC2 knockout mice appear to differ from the effects of physical lesions of the VNO. Dulac reported that TRPC2 knockout female mice showed significantly higher levels of malelike sexual behavior, including ultrasonic vocalization and mounting of other females (Wysocki and Lepri, 1991; Kimchi et al. 2007). This would suggest that sex-specific behavioral patterns of male and female mice are at least partly dependent on ongoing sensory input rather than being developmentally determined. But, other groups have not reported such effects, and both male and female mice with physical VNO lesions are capable of discriminating sexual identity of urine odors (Keller et al. 2009). The differences that have been reported between the behavioral effects of physical VNO lesions and knockout of the TRPC2 gene might arise due to developmental effects of the knockout, or due to the presence of VSNs that do not use the TRPC2 transduction pathway (Kelliher et al. 2006).

6.4.2. Main Olfactory System

Although previously often overlooked, it has been known for many years that not all pheromonal responses are mediated by the vomeronasal system. For example, the mammary pheromone that guides nipple search behavior of rabbit pups is still effective following VNO lesion (Hudson and Distel 1986b). Similarly, the boar sexual attractant pheromone is still effective in eliciting standing behavior following VNO lesions in sows (Dorries et al. 1997). Instead, these pheromonal effects and many others are likely to be mediated by the main olfactory system. The main olfactory system has traditionally been thought to function as a pattern recognition system, associating patterns of activity across broadly tuned receptors into a representation of the complex odorant mixtures that make up natural odors. The emphasis has been very much on the role of learning in the piriform cortex in forming these odorant representations and associating them with their context and an appropriate behavioral response (Wilson and Stevenson 2003). This provides considerable flexibility to the main olfactory system in its ability to respond to novel odors, but does not really fit with a role in mediating innate responses to specific pheromonal stimuli. However, it is becoming increasingly apparent that the main olfactory system is not a unitary sensory system, but is composed of a number of functionally specialized subsystems that might be involved in pheromonal detection.

Among these main olfactory subsystems, OSNs expressing members of the trace amine receptor (TAAR) family have been found in the mouse MOE and can respond to volatile amines that are found in mouse urine (Liberles and Buck 2006). Another subpopulation of OSNs are distinguished by their guanyl cyclase-dependent transduction pathway. At least some of this population have been shown to respond to the peptides guanylin and uroguanylin, which are also found in mouse urine (Leinders-Zufall et al. 2007), although what pheromonal role they might perform is still unknown. Somewhat more surprising is the finding of a subpopulation of OSNs that respond to involatile MHC peptides. In a challenge to the dogma that the MOE only responded to volatile odors carried in the nasal airstream, Spehr et al. (2006) showed that the nonvolatile fluorescent dye, rhodamine, gained access to a large extent of the MOE following direct physical investigation of a rhodamine-painted conspecific. This suggests that other nonvolatile peptides, and possibly even proteins, could gain access to the MOE of mice following direct investigation of a stimulus.

The functions of the vomeronasal and main olfactory systems are more integrated than previously thought (Zufall and Leinders-Zufall 2007). The same chemosignals can act as stimuli for both OSNs and VSNs with low response thresholds typical for pheromonal detection. The mouse MOE responds to urinary volatiles, such as heptanone, at concentrations of 10−10 M (Spehr et al. 2006), similar to the sensitivity of VlRb2 expressing VSNs (Leinders-Zufall et al. 2000). The responses of the two systems to MHC peptides are also highly sensitive, with responses at 10-10 M for OSNs (Spehr et al. 2006), and down to 1013 M for VSNs (Leinders-Zufall et al. 2004). Furthermore, trans-synaptic tracing of the afferent connections of neurons expressing luteinizing hormone-releasing hormone have revealed that both the main olfactory system and the vomeronasal system provide input to these hypothalamic neurons that regulate reproductive physiology and behavior (Boehm et al. 2005; Yoon et al. 2005).

By its very nature, input from releaser and primer pheromones is likely to mediate innate responses via specialized neural pathways, separate from the general odor-sensing pathway of the main olfactory system. Indeed, part of the MOB has been found to mediate innate responses to odors (Kobayakawa et al. 2007). Ablation of OSN input to the dorsal zone of the MOB, using targeted expression of the diphtheria toxin gene, disrupted the innate aversive response of mice to rancid food odors and to predator odors. This failure to show an innate aversive response to the odors was not due to an anosmia, as the mice were still able to detect the odors and could be trained to show conditioned aversion to them. Although these are not pheromonal effects, they demonstrate that information about innate odor responses is handled by a separate pathway to that of learned odor responses in the MOB (Kobayakawa et al. 2007).

Until recently, the AOB and MOB were thought to project to separate brain areas. Even their projections to the amygdala were thought to target different nuclei. The AOB projects to the MeA and PMCoA, which together are often referred to as the vomeronasal amygdala (von Campenhausen and Mori 2000). These areas, in turn, project to medial regions of the hypothalamus involved in the control of reproductive and social behavior. The MOB projects to the neighboring anterior cortical and posterolateral cortical regions of the amygdala. Electrophysiological recording in hamsters has found that information from the main olfactory system and vomeronasal system converges on individual neurons in the MeA (Licht and Meredith 1987).

This influence of the main olfactory input on the MeA was thought to be mediated by indirect intra-amygdala connections. However, a recent study using anterograde tracing has identified a previously neglected, direct projection from the MOB to the MeA in mice and rats (Figure 6.3) (Kang et al. 2009). This potentially provides a more direct pathway by which main olfactory input could control reproductive and social behavior. Retrograde tracing from the MeA revealed that these projections originated from a subpopulation of mitral and tufted (M/T) neurons located mainly in the ventral region of the MOB. Interestingly, these retrogradely labeled M/T neurons in the MOB of female mice responded to chemosignals from male mice, but not to chemosignals from other female mice, or to a predator odor. These M/T neurons were in a similar location to the ventrally located MOB glomeruli that receive input from TRPM5-expressing OSNs (Lin et al. 2007). Moreover, M/T neurons in this region of the MOB respond to social chemosignals present in male urine, such as the urinary attractant MTMT (Lin et al. 2007), and suggest that this is a likely pathway for many pheromonal effects on reproductive behavior that are mediated by the main olfactory system.

FIGURE 6.3. Convergence of input from the ventral main olfactory bulb (MOB) and the accessory olfactory bulb (AOB) onto the medial amygdala (MeA) of the female mouse.

FIGURE 6.3

Convergence of input from the ventral main olfactory bulb (MOB) and the accessory olfactory bulb (AOB) onto the medial amygdala (MeA) of the female mouse. (A) Location of injections of anterograde tracer into the ventral MOB in green, shown by filled (more...)

6.5. PHEROMONAL EFFECTS ON BEHAVIOR

Chemical signals that elicit a specific and immediate behavioral effect are known as releaser pheromones. Pheromones that elicit longer-term effects on endocrine state or development are termed primer pheromones. However, pheromonal signals can have different effects in different contexts. For example, testosterone-dependent constituents of male mouse urine, including DB, SBT, E,E-α-farnesene, E-β-farnesene, and 6-hydroxy-6-methyl-3-heptanone, are all effective individually in accelerating puberty in prepubertal female mice (Novotny et al. 1999). A mixture of two of these compounds, DB and SBT, is also effective in inducing and synchronizing estrus cycles in adult females (Ma et al. 1999), and also has a releaser pheromonal effect in eliciting aggression from males or maternal females, when presented in the context of an intruder male (Novotny et al. 1985). It is, therefore, more useful to classify the effect of a pheromone as being releaser or primer, rather than applying the terms as labels to particular substances.

As our understanding of vertebrate chemical signaling has advanced, new classes of chemosignals have been identified that do not fit the original definition of a pheromone (Wyatt 2003). This has led some researchers to propose new categories of pheromonal effects (Wysocki and Preti 2004). The term signaler pheromone has been used for chemosignals conveying information about the producer that might bias behavioral choices, without mediating a definite response; for instance, chemical signals that convey information about individual identity that are used in territorial marking. A further category of modulator pheromone has been used to describe the effects of chemical signals that alter mood, such as appeasement pheromones that are reportedly produced by nursing females and have a calming effect on their offspring, or the anxiety-promoting effects of alarm pheromones. However, these new classifications are not as widely accepted as the original distinction between primer and releaser effects. An alternative, and potentially more useful classification has been proposed by Wyatt (2009), which distinguishes between pheromones that mediate innate responses and “signature odors,” such as individuality signals, that convey information and for which learning determines the nature of the response.

6.5.1. Sexual Attractant Pheromones

Attractant pheromones are often used to arouse, attract investigation, and release specific behavioral responses from conspecifics. One well-known example is the boar sexual attractant pheromone, which has even been exploited commercially as a test for sow receptivity. Boar saliva contains high levels of the androgen derivatives 5α-androst-16-en-3-one and 5α-androst-16-en-3-ol. These steroids are bound and concentrated in the saliva by proteins SAL1 and SAL2, which are members of the lipocalin family of ligand-binding proteins (Loebel et al. 2000). When sexually aroused, boars salivate profusely and foam at the mouth, which disperses these volatile pheromones in the air. The 5a-androst-16-en-3-one and 5a-androst-16-en-3-ol act as releaser pheromones to attract receptive sows and elicit a specific mating posture, known as standing, which allows mounting by the boar (Dorries et al. 1997).

Another example of a sexual attractant is aphrodisin, a 17 kDa protein found in the vaginal fluid of female hamsters, which elicits mounting behavior in sexually naive, male hamsters. Aphrodisin is also a member of the lipocalin family of ligand-binding proteins, although it is still unclear whether synthetic aphrodisin that lacks its endogenous ligand is effective in stimulating mounting behavior (Briand et al. 2004). Mouse urine also contains attractive chemosignals that promote investigation by opposite sex conspecifics. The urinary constituents responsible for the innate attractiveness of urine appear to be involatile and likely to be MUPs, which are also lipocalins (Ramm et al. 2008). Urinary volatiles, such as the MTMT produced by male mice, have also been reported to have attractant properties. Although synthetic MTMT was relatively ineffective in isolation, it increased the investigation time of females when added to urine (Lin et al. 2007).

6.5.2. Rabbit Mammary Pheromone

Other pheromones that elicit a strong behavioral attraction are the nipple guidance pheromones. The best understood example is the rabbit mammary pheromone, but similar pheromonal stimuli may be of importance in guiding offspring to nipples and facilitating nursing in most mammals, including humans. Rabbits have an extreme form of maternal care, in which they only make brief 4–5 min nursing visits to their pups once a day. During this short period, the rabbit pups are guided to the mother’s nipples by a pheromone produced by the nipples and which is present in the milk (Hudson and Distel 1986a). This pheromone elicits a specific pattern of behavior known as nipple searching, in which the pup’s forelimbs are splayed laterally and the head makes rapid side-to-side searching movements, scanning the mother’s ventrum. The gradient of mammary pheromone guides the pup’s nose to the nipples to which it can attach on the basis of somatosensory cues (Distel and Hudson 1985).

Analysis of the volatile constituents of rabbit milk showed that a single constituent, 2-methylbut-2-enal, was capable of eliciting full nipple search behavior (Schaal et al. 2003). Unusually for mammalian pheromones, the synthetic compound was also effective when presented on a glass rod, outside the normal suckling context. The effect of the mammary pheromone to releases nipple search response appears to be automatic in young rabbit pups, irrespective of whether or not they have recently fied. However, in five-day-old pups, its effectiveness was found to decline immediately after suckling, showing that the pheromone’s influence over behavior lessened during development to become modulated by prandial state (Montigny et al. 2006).

6.5.3. Mouse Aggression Pheromones

A mixture of the testosterone-dependent urinary volatiles DB and SBT are able to elicit aggressive behavior from male mice when added to castrated male urine (Novotny et al. 1985), consistent with their response being mediated by the VIR-expressing class of VSN (Leinders-Zufall et al. 2000). Recently, it has been reported that the nonvolatile fraction of male mouse urine is also effective in elicting male aggression (Chamero et al. 2007). Analysis of this fraction revealed this involatile aggression-promoting pheromone to be a MUP Furthermore, a synthetic MUP was able to elict aggression and stimulate V2R-expressing VSNs, even in the absence of the aggression-promoting volatiles DB and SBT (Chamero et al. 2007; Kimoto et al. 2007). Therefore, MUPs and the testosterone-dependent volatile that they bind act via separate vomeronasal receptor pathways to elicit aggressive/defensive behavior in mice.

6.5.4. Alarm Pheromones

Under stressful conditions, such as elevated levels of carbon dioxide, mice release alarm pheromones that elicit freezing behavior in other mice. These alarm pheromones are volatile and water soluble, but their chemical identity is unknown. They are sensed by chemosensory neurons in the Grueneberg ganglion, as the freezing response is abolished in mice with section of sensory nerve from the ganglion (Brechbühl et al. 2008).

6.5.5. Pheromones and Learning

Recent evidence suggests that some pheromones can be innately rewarding and promote associative learning. Naive female mice do not normally show a preference for investigating volatile urinary odors from males. However, they are innately attracted to the involatile (presumably protein) constituents of male mouse urine, and will spend significantly more time investigating them than those from female urine or urine from castrated males. These urinary proteins are not only innately attractive to females, but also promote learning of the volatile urinary odors with which they are associated (Moncho-Bogani et al. 2005; Ramm et al. 2008). Surprisingly, this prior experience with the nonvolatile constituents does not generally increase the attractiveness of the urinary volatiles of all males, but only the attractiveness of the individual male’s volatiles to which the females were exposed (Ramm et al. 2008). Similarly, exposure of rabbit pups to an artificial odor that has been paired with the mammary pheromone without suckling, will condition the full nipple search response to the artificial odor when subsequently presented alone (Coureaud et al. 2006). Such findings are consistent with certain pheromones being intrinsically rewarding, which not only promotes further investigation of the pheromonal stimulus, but also potentially reinforces the pheromonal effect due to the learned response to associated contextual cues.

6.6. CHEMICAL SIGNALS OF INDIVIDUAL IDENTITY

Mammals release an enormous variety of molecules into the environment that contribute to their chemical profile, and which could potentially be used to recognize the individuality of the producer. But which, if any, of these can usefully thought of as pheromones? This remains a controversial area, with many researchers in this field deliberately avoiding the use of the term. Chemicals that convey information about individual identity do not generally elicit a direct response, but provide information that may bias the current response, or a future response of an individual. Such biasing effects are often associated with learning and as they are dependent on both past and present context, they do not meet the conventional definition of a pheromone. Nevertheless, the finding of specific classes of chemosignal, and sensory responses that appear to be adapted to convey individual information, suggests that these “signature odors” are likely to have important influences on behavior (Brennan and Kendrick 2006).

6.6.1. Major Urinary Proteins and Territorial Marking

Territorial behavior is seen in a wide variety of species in which individuals compete to monopolize desirable territories and resources. Many mammals deposit scent cues around their environment, advertising their presence to competitors and to signal their reproductive fitness to potential mates. This is perhaps best understood in mice, in which dominant males deposit urine marks throughout their territory, and especially along boundaries and access routes (Hurst and Beynon 2004). Like many other species that use urine marking, mice excrete large quantities of protein in their urine. Typically, 99% of the protein content of the urine is made-up of MUPs, members of the lipocalin family of ligand-binding proteins (Beynon and Hurst 2003). The concentration of MUPs is four to five times higher in male mouse urine than that of females, and some MUP variants are found only in males (Robertson et al. 1997).

MUPs bind certain volatile urinary constituents, including the testosterone-dependent male mouse pheromones DB and SBT, which have been shown to have pheromonal effects on the female reproductive state and the initiation of male aggression. MUPs are highly stable in the environment and act as a reservoir for the volatile ligands, prolonging their release over a period of days (Hurst et al. 1998). These characteristics make MUPs ideally suited as a territorial marker. Not only does the release of volatiles attract investigation to the urine mark, advertising the presence of the nonvolatile protein component, but the amount of volatiles being released from the mark is also a reliable indicator of the age of the urine mark. When a resident male comes across a urine mark of a rival male, the resident deposits his fresh urine mark next to the aging mark of his competitor. This countermarking behavior depends on the male being able to make physical contact with the involatile protein components in the urine mark, presumably MUPs that are being sensed by the VNO (Sherborne et al. 2007). The assessment of the relative ages of urine marks therefore, provides females with an honest signal of the competitive ability of males to dominate their territory without the males engaging in potentially damaging direct confrontation (Humphries et al. 1999).

In order to use urine marking as an indicator of the competitive fitness, urine marks have to be associated with the individual that produced them. In addition to their physiochemical properties that make MUPs ideal as territorial markers, MUPs are highly polymorphic and a wild mouse will produce an individual profile of different MUP types capable of conveying individual identity. Individual mice captured from the wild produce between 5 and 15 variants from the polymorphic MUP family, the profile of which is specific for an individual (Robertson et al. 1997). Moreover, the recognition of urine marks can be influenced by the addition of an artificially produced recombinant MUP to change their MUP profile (Hurst et al. 1998; Robertson et al. 2007). MUPs without bound ligands have been shown to act as stimuli at V2R-expressing VSNs (Chamero et al. 2007; Kimoto et al. 2007). This role of these VSNs in detecting individual MUP variants is consistent with genomic analysis that has found an association between the number of genes for MUP isoforms and for V2Rs in certain species (Table 6.2). However, although genomic analysis has revealed expansions of the MUP gene family in mice, rats, horses, and gray lemurs, many species have only a single MUP iso-form and appear to be unable to use MUPs to encode individual identity (Logan et al. 2008).

6.6.2. Major Histocompatibility Complex (MHC)-Associated Chemosignals

In identifying chemosensory signals of individual identity, most attention has focused on genes of the MHC, which determine the recognition of self from non-self by the immune system. This is a highly polymorphic family of genes, therefore individuals in the wild generally have different MHC types in addition, but unrelated, to other genetic differences such as MUP genotype.

6.6.2.1. Major Histocompatibility Complex (MHC)-Associated Volatiles

Many years of research have shown that both trained and untrained mice can discriminate the volatile urine odors of MHC-congenic mice that differ genetically only at the H2 region of their MHC (Yamaguchi et al. 1981; Penn and Potts 1998b). Urine samples from MHC-congenic mice have consistently different proportions of volatile carboxylic acids (Singer et al. 1997) and elicit significantly different patterns of activity in the MOB (Schaefer et al. 2002). The ability of mice to discriminate MHC-congenic urine odors has been reported as being related to polymorphism in their peptide-binding groove (Carroll et al. 2002). However, genetically identical inbred mice have a significant variability in the proportion of volatile urinary components, suggesting that nongenetic factors, such as nutrition and environmental condition, also have significant effects on individual urine odor (Röck et al. 2007). Despite several theories having been proposed, no mechanism has been established by which MHC genotype could affect metabolic pathways to account for the reported quantitative differences in urinary volatiles.

6.6.2.2. Major Histocompatibility Complex (MHC) Peptides

The H2 region of the mouse MHC codes for MHC proteins of classical class I type, which are expressed on the cell membrane of nearly all nucleated cells in vertebrates. Their immunological role is to bind peptides resulting from proteosomal degradation of endogenous and foreign proteins, and present them at the cell surface for immune surveillance (Boehm and Zufall 2006). The specificity of peptide binding is determined by the position of bulky amino acid side chains, known as anchor residues, which fit into binding pockets in the MHC class I peptide-binding groove. Therefore, individuals with different MHC type will bind different subsets of peptides having anchor residue positions that mirror the polymorphic differences in the peptide-binding groove of their MHC class I proteins. For example, MHC class I proteins of C57BL/6 inbred mice (H-2b haplotype) preferentially bind peptides having asparagine (N) at position 5, such as AAPDNRETF, whereas MHC class I proteins of the BALB/c inbred strain (H-2d haplotype) preferentially bind peptides with tyrosine (Y) at position 2, such as SYFPEITHI. As the anchor residue structure of MHC-peptide ligands reflect the peptide-binding cleft of the MHC class I peptide that bound them, they could potentially function as robust signals of MHC identity.

This hypothesis has been investigated using electrophysiological recording and calcium imaging of slices of mouse vomeronasal epithelium. Responses to synthetic peptides possessing the characteristic features of MHC-peptide ligands have been reported at concentrations from 10-9 to 1013 M (Chamero et al. 2007; He et al. 2008), although the percentage of MHC-peptide-responsive cells varied widely among the studies. Individual VSNs responded selectively to synthetic BALB/c-type (SYFPEITHI) or C57BL/6-type (AAPDNRETF) peptides (Figure 6.4) (Leinders-Zufall et al. 2004). VSN responses were abolished when the bulky anchor residues were substituted with alanine residues, which lack a side chain. Furthermore, the position of the anchor residues was shown to be critical. Changing the position of the anchor residues abolished the responses of VSNs, whereas the selectivity of responses from individual VSNs were not affected when the anchor residues were left unchanged, but the intervening sequence of amino acids was varied. Most VSNs responded selectively to synthetic peptides of either BALB/c-type or C57/BL6-type, however, a small proportion responded to both peptides (Leinders-Zufall et al. 2004), suggesting the expression of more than a one V2R receptor type per VSN. But only a limited amount of evidence has been found for such coexpression (Martini et al. 2001). Future experiments testing a wider range of MHC-peptide types will be required to determine whether individual VSNs respond to specific combinations of MHC peptides that could encode individual identity.

FIGURE 6.4. Vomeronasal sensory neurons (VSNs) respond to major histocompatibility complex (MHC) peptides.

FIGURE 6.4

Vomeronasal sensory neurons (VSNs) respond to major histocompatibility complex (MHC) peptides. Ca2+ imaging in slices of vomeronasal epithelium of responses from four VSNs in response to synthetic MHC peptide of (A) C57/BL6-type AAPDNRETF (pseudocolored (more...)

Calcium imaging of MHC-peptide sensitive VSNs revealed them to be located in the basal layer of the vomeronasal epithelium, colocalizing with VSNs expressing the V2R class of vomeronasal receptor (Leinders-Zufall et al. 2004). These receptors possess a large extracellular N-terminal domain, possibly involved in binding proteins or peptides and are coexpressed with atypical MHC proteins of the 1b class (Ishii et al. 2003; Loconto et al. 2003). These nonclassical MHC 1b proteins have only been found expressed in the VNO and form a receptor complex with V2Rs and (β-microglobulin, suggesting that they might have a specific chemosensory function (Loconto et al. 2003). Certain combinations of MHC Ib proteins are coexpressed with particular V2Rs, which could affect receptor specificity (Ishii et al. 2003). Sequence variability among the nine members of the nonclassical MHC lb family is localized to the peptide-binding groove. But structural considerations suggest that they are unlikely to bind peptides (Olson et al. 2005) and their role in VSN function remains unknown.

It is becoming increasingly apparent that there is considerable overlap between stimuli that are sensed by the main olfactory and vomeronasal systems (Brennan and Zufall 2006). But, it is nevertheless surprising that responses to MHC-peptide ligands have also been recorded from the MOE (Spehr et al. 2006). Calcium imaging of individual OSNs in the MOE revealed that they respond selectively to MHC peptides down to 10–11 M. This is one to two orders of magnitude higher than the threshold for MHC-peptide-responsive VSNs, which along with their lack of absolute dependence on anchor residues suggests that a different type of receptor may be involved. Whereas replacement of anchor residues with alanines abolished the responses of VSNs, it shifted the stimulus response curve of individual OSNs, although OSNs still failed to respond to the scrambled version of the peptide in which the position of the anchor residues had been changed (Spehr et al. 2006). Therefore, OSN responses to MHC peptides may be more dependent on the overall sequence of amino acids, rather than the position of the anchor residues. Such ability to recognize specific MHC peptides could theoretically confer the ability to detect peptides of pathogenic origin, and convey information about the health status of a conspecific, rather than information about genetic identity, although there is no evidence for this conjecture at present.

6.6.3. Role of Major Histocompatibility Complex (MHC)-Associated Chemosignals in Natural Contexts

6.6.3.1. Mate Choice

Despite over 30 years of research, the importance of any influence MHC genotype might have on mammalian behavior remains unclear. An influence of MHC genotype on mate choice in mice was first reported by Boyse, and investigated in a series of further studies by Yamazaki and Beauchamp (Boyse et al. 1987). They reported a disassortative pattern of mating in which male mice preferred to mate with females of dissimilar MHC type, thus avoiding inbreeding. This influence of MHC type on mate choice depended on learning of kin odors in the nest environment, as it was substantially reversed by cross-fostering mouse pups onto MHC-dissimilar mothers (Yamazaki et al. 1988; Penn and Potts 1998a). However, many similar studies of mate choice have produced inconsistent and sometimes conflicting results (Jordan and Bruford 1998). This failure to consistently find a clear effect of MHC type is likely to be due to the difficulties inherent in studying such complex behavior as mate choice in a limited laboratory environment. For mate choice tests, mice are frequently restrained and deprived of the normal behavioral context in which they can assess the reproductive fitness of potential mates. Moreover, the use of congenic mice that only differ in MHC type removes much of the genetic variability that may normally contribute to mate choice decisions.

Disassortative mate preference has been observed in seminatural enclosures, in which colonies of mice produced fewer MHC homozygous offspring than expected from random matings (Potts et al. 1991). However, a recent large study that followed wild-derived mice, which were allowed to breed freely in a large outdoor enclosure, failed to find any evidence for an effect of MHC type (Sherborne et al. 2007). Rather, mate choice was related to MUP similarity, with a deficit in matings between individuals that shared both MUP haplotypes. An important point of this experiment was its use of mice bred from wild-captured individuals, which have considerably more genetic variability, especially with regard to MUP profiles, than inbred strains (Cheetham et al. 2009). More experiments will be required, using wild-derived mice in natural contexts, before the relative importance of MHC genotype, MUP profile, and general heterozygosity in mate choice decisions can be fully understood.

6.6.3.2. Mother-Offspring Interactions

Female mice are more likely to form communal nests with kin of MHC-similar genotype (Manning et al. 1992). Female mice also preferentially retrieved pups of similar MHC type to themselves, which had been removed from the nest and mixed with MHC-dissimilar pups (Yamazaki et al. 2000). Furthermore, mouse pups themselves appear to use MHC-related cues to learn the odor of their mother and siblings, as revealed by their preference for odors of maternal MHC type in an odor choice test (Yamazaki et al. 2000). These MHC influences on behavior could be largely reversed by cross-fostering, showing their dependence on learning of signature odors in the nest environment. This is consistent with the role of the main olfactory system in learning to recognize complex mixtures of odorants that make up individual odors, whether or not those are genetically determined.

6.6.3.3. A Behavioral Role for Major Histocompatibility Complex (MHC) Peptides?

MHC genotype has also been linked to mate recognition in the Bruce effect. This is a primer pheromonal effect in which exposure of a recently mated female mouse to urine from an unfamiliar male causes implantation failure and a return to estrus (Bruce 1959). However, the pregnancy-blocking effectiveness is also affected by individuality chemosignals present in the urine, as urine from the mating male is ineffective in blocking his mate’s pregnancy. Both the Bruce effect and the recognition of the mating male are mediated by the vomeronasal system (Lloyd-Thomas and Keverne 1982; Ma et al. 2002). This ability of the female to recognize the urinary chemosignals of her mate is due to her learning their identity at mating, which subsequently inhibits the transmission of the pregnancy-blocking signal at the level of the AOB (Brennan and Zufall 2006). Congenic male mice, differing from the mating male only in their MHC genotype, were not recognized and blocked the pregnancy of recently mated females in a similar manner to an unfamiliar male of a different inbred strain (Yamazaki et al. 1983), suggesting an involvement of MHC-associated chemosignals.

The role of MHC peptides in this mate recognition has been investigated by testing the pregnancy-blocking effectiveness of urine from the mating male that had been spiked with synthetic MHC peptides of a different strain type (Leinders-Zufall et al. 2004). The addition of C57BL/6-type peptides to BALB/c male urine significantly increased its pregnancy-blocking effectiveness following mating with a BALB/c male. Conversely, the addition of BALB/c-type peptides to C57BL/6 male urine increased its effectiveness in blocking the pregnancy of females that had mated with a C57BL/6 male. This suggests that MHC-peptide ligands influence the individual signature of the mating male urine, providing support for the theory that they can convey information about individual identity via the vomeronasal system (Leinders-Zufall et al. 2004; Thompson et al. 2007).

However, a major problem with the hypothesis that MHC peptides convey individuality in the pregnancy block effect, or indeed any other biologically important context, is the failure to find them, to date, in any biological secretion, including male mouse urine. Furthermore, Ca2+ imaging of vomeronasal epithelial slices has found that although some VSNs did respond to both the C57/BL6-type MHC peptide AAPDNRETF and to urine from C57/BL6 males (He et al. 2008), a significant number of VSNs only responded to one or the other, implying that this MHC peptide is not normally present in C57/BL6 male urine (Figure 6.2). Therefore, although MHC peptides may influence the pregnancy block effect, it is unlikely that they are the endogenous individuality signal present in urine.

6.7. HUMAN PHEROMONES

The idea that human physiology and behavior might also be influenced by pheromonal cues is a natural extension of the finding of pheromonal responses in other animals. But, despite a widespread research effort, it has been difficult to identify robust and reproducible effects. This doesn’t necessarily mean that human pheromones don’t exist, but complexities of modern human society may diminish their biological significance and make it difficult to identify consistent effects. Human axillary secretions from the armpit and genital regions provide a rich source of putative pheromonal signals. Microbial action on axillary apocrine secretions produces the complex mixture of odorants responsible for body odor, including androgen derivatives and volatile acids (Leyden et al. 1981). (E)-3-methyl-2-hexanoic acid (E-3M2H) is one of the major axillary secretions (Zeng et al. 1991). This is particularly interesting as it is bound by apolipoprotein D, a member of the lipocalin family of ligand-binding proteins that are often associated with pheromonal volatiles in other species (Zeng et al. 1996).

A VNO is present early in human fetal development, but appears to degenerate before birth, and the experimental evidence suggests that any residual structure that has been identified as the human VNO is nonfunctional (Meredith 2001). Not only does it lack the well-developed sensory epithelium found in the VNOs of other species, but also the sensory nerves to connect it to the brain (Witt and Hummel 2006). Furthermore the gene encoding the TRPC2 cation channel is a pseudogene in humans, the selection pressure on it having been relaxed around 23 million years ago, shortly before the separation of hominoids and Old World monkeys (Liman and Innan 2003; Zhang and Webb 2003). Analysis of the human genome reveals that almost all of the genes for vomeronasal receptors and transduction mechanisms are pseudogenes in humans. Therefore, any receptors for human pheromones are likely to be found in the MOE or possibly the Grueneberg ganglion, about which little is known, apart from a single report of its presence in humans. Possible candidates for human pheromonal receptors include members of the TAAR family of receptors (Liberles and Buck 2006). Four potentially functional V1R-like genes have also been identified in the human genome, of which hVlRLl is expressed in the MOE, but whether it has any role in pheromonal communication is unknown (Rodriguez et al. 2000).

Perhaps the clearest pheromonal effects to detect in humans are primer effects on hormone levels and changes in physiological state, which are more easily measured and quantified than behavioral responses. 4,16-Androstadien-3-one, a compound present in male axillary secretions, has been found to increase levels of the hormone cortisol (Wyart et al. 2007), and to influence the frequency of luteinizing hormone pulses in females (Preti et al. 2003). Exposure to axillary secretions from other females has also been found to influence female menstrual cyclicity. Axillary odor stimuli from females in the late follicular and ovulatory phases of their menstrual cycle have been found to shorten and lengthen, respectively, the cycles of exposed females (Stern and McClintock 1998).

Whether pheromones can enhance sexual attraction in adult humans is a complex issue (Wysocki and Preti 2004). Effects of axillary secretions and synthetic putative pheromones on attractiveness ratings have been reported under laboratory conditions (Wysocki and Preti 2004). However, there has been a shortage of rigorous, placebo-controlled, double-blind studies on pheromonal effects on attractiveness and sexual activity in natural social situations. There are several problems with the interpretation of such studies, not least of which are the individual differences in the opportunities for and the nature of any social or sexual interactions. Imaging human brain activity has the potential to detect responses to putative pheromones, but these can be difficult to link to their behavioral effects due to the unnatural contexts and concentrations in which the putative pheromones are presented (Savic et al. 2001).

Although it is difficult to demonstrate convincing pheromonal effects on adult human behavior, the relative simplicity of human neonatal behavior potentially makes identifying the human equivalent of a mammary pheromone more feasible. Montgomery’s glands, found in the areolar region around the nipple, produce a milky secretion, which has been suggested to contain a mammary pheromone that facilitates suckling. The breast odor of human mothers has been reported to attract newborn babies, and human babies spend significantly longer orienting toward human breast milk compared with formula milk (Marlier and Schaal 2005), similar to the attractant effects of the rabbit mammary pheromone. However, newborn babies show similar orientation responses to components of the mother’s diet during gestation (Schaal et al. 2000), implying that it may be a learned response to maternal odors that the fetus was exposed to in utero. This potentially makes distinguishing an innate pheromonal response from a learned response to incidental maternal odors all the more difficult.

It is common knowledge that humans have individual odor signatures that can be discriminated by trained sniffer dogs and may also be influenced by MHC genotype. Overall, it seems that humans rate the odors of other individuals as being more pleasant if they share a few MHC alleles with the rater, ratha than either no matches or a high degree of similarity (Wedekind and Furi 1997; Jacob et al. 2002). Whether MHC-related odor preferences play a role in behaviors such as partner preference is difficult to investigate given the complexities of modern human society. However, fathers, grandmothers, and aunts have been reported to successfully identify the odor of a related infant without prior experience, which could point to a role in parental or nepotistic behavior of these learned odor signatures (Porter et al. 1986).

6.8. CONCLUDING REMARKS

Our understanding of the important influence of pheromones on mammalian behavior has advanced dramatically in the 50 years since the term was first proposed. These invisible chemical signals can elicit equally dramatic behavioral responses in mammals to those seen in insects. However, our understanding is fragmentary, with few examples in which the pheromonal signal, the sensory receptors on which it acts, and the behavioral response elicited have all been identified. The major advances in recent years have been based mainly on a single species—the mouse. Genetic technologies have revealed a surprisingly large repertoire of chemosensory receptors in mice that potentially detect pheromones. However, our knowledge of their natural ligands and behavioral role is limited by our lack of understanding of the natural behavior of mice and by the artificial laboratory environment in which they are studied.

Pheromones and the effects that they mediate are, by their nature, species-specific and may not be found in even closely related species. For example, the diversity of MUPs found in the house mouse, Mus musculus, appears to be a relatively recent evolutionary adaptation to its commensural lifestyle and is not observed in a closely related species of aboriginal mouse, M. macedonicus, which live at lower population densities (Robertson et al. 2007). Nevertheless, the genetic approaches used in mice, coupled with genomic analysis, provide a much needed focus for where and how to look for pheromonal signaling systems in other species.

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