pheromones and mammalian behavior

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Chapter 6Pheromones and Mammalian Behavior

Peter A. Brennan.

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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 !"#"$ 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 e&ample, a definite behavior or

developmental process.' (lthough 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 )yatt *++$. -n this case, selective pressures usually lead to the coevolution

specialied sending and receiving systems for pheromones.

The identification of pheromones started in the !"#+s with the purification of only #. mg of the male silk moth

attractant bombykol, from the scent glands of !,+++ female silk moths /utenandt et al. !"#"$. /ombykol has since

become a classic e&ample of a se& attractant pheromone, attracting male silk moths over large distances. 0owever,there has been considerable debate regarding whether the term pheromone, which was initially applied to insect

chemosignals, can be usefully applied to vertebrates 1oty *++$. The issue comes down to what is meant by a

%definite response.' 2ertebrate, especially mammalian, behavior is generally more dependent on conte&t 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 e&ert significant influence over mammalian physiology and behavior. -n doing so, it

takes a relatively broad view in discussing all intraspecific, specialied semiochemical signals as potential

pheromones, while acknowledging that they may not meet the narrower interpretations of some researchers in the

field.

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6.2. TH CHMIC!" N!TUR O# PHROMON$

( wide variety of chemicals are used as pheromones, including small, volatile molecules, proteins, and peptides

Figure 3.!$, in which their chemical nature is linked to their function. -mportant features of chemicals used as

pheromonal signals are their sie and polarity, which determine their volatility in air and solubility in water. -n 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$methanethiol 4T4T$, which attracts female investigation Lin et al. *++#$. Their small sie and

volatility not only ensures that such pheromones are dispersed rapidly, but also makes these signals transient. -n

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 e&ample, male mice deposit urine marks

containing !56*+ k1a major urinary proteins 478s$, the stability and involatility of which make them ideal for their

territorial marking role 0urst and /eynon *++9$.

#I%UR 6.1

:timulus selectivity of mouse vomeronasal class ! 2!;$<e&pressing vomeronasal sensory neurons 2:=s$ recorded

by >a*?

imaging from slices of the vomeronasal epithelium. ($ 2:=s that responded to volatile pheromones were

located in the apical region more...$

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6.&. PHROMON PRODUCTION

http://www.ncbi.nlm.nih.gov/books/NBK55973/

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(nimals use an enormous variety of different mechanisms for releasing pheromones into the environment Table 3.!$.-n many cases, pheromonal release takes advantage of e&isting routes for e&cretion, such as urine and feces, which

may be deliberately placed in the environment as territorial marks. For instance, the urine marks used by rodents, suchas mice, are known to contain a variety of small, volatile pheromones =ovotny *++$, as well as sulfated steroids and

proteins that are also likely to have a pheromonal function >hamero et al. *++@A =odari et al. *++5$. Bther routes of pheromone release involve biological secretions. 0amsters release the se&ual attractant protein, aphrodisin, in their

vaginal secretions 4Cgert et al. !"""$. The rabbit mammary pheromone is produced by glands around the nipples andis present in rabbit milk :chaal et al. *++$. :everal potential chemosignals have been identified in the saliva of

different species, including the well<known se&ual attractant pheromone of boars Loebel et al. *+++$. /ut, there arealso a wide variety of specialied 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, flankglands in hamsters can be used to leave marks that convey information about individual identity 4ateo and Dohnston

*+++$. 4ost species of carnivora have anal glands, including ferrets, which produce se&<specific volatiles that couldfunction as pheromones Ehang et al. *++#$. Bther specialied scent glands include chin glands, interdigital glands,

and sternal glands.

T!B" 6.1

The >hemical =ature, :ource, and 8heromonal ffects of a ;ange of >ommonly (ccepted 4ammalian 8heromones.

-n 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. ( family of peptides, called e&ocrine gland secreting peptides :8s$, has recently been

identified in mice. The starting point for TouharaGs group was the realiation that chemicals released from the facial

area of mice activated sensory neurons in the vomeronasal system. They tested the activity of e&tracts from glands in

the head region, which ultimately led to the identification of @ k1a peptide, which they named :8! Kimoto et al.

*++#$. They went on to show that the gene encoding :8! was a member of a family of at least 5 related genes in

mice, and !+ in rats Kimoto et al. *++@$. :8s are produced by several glands, in addition to the e&traorbital lacrimal

glands, including salivary and 0arderian glands. The finding that some :8s are e&pressed in a se&< and strain<

dependent manner, suggests that they could convey information about gender and individual identity, although their

behavioral role is unknown Kimoto et al. *++@$.

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6.'. PHROMON!" DTCTION

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. 8robably the most significant of these changes was the

transition from aquatic to terrestrial environments, due to their different physiochemical nature. )ith the evolution ofa terrestrial lifestyle came the possibility to e&ploit the large range of airborne chemosignals by the ciliated cells of

what came to be the main olfactory system. 0owever, sensitivity to water<soluble, but relatively involatile

chemosignals of the aquatic environment was not lost. -nstead, 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 2=B$, at the same time that the main olfactory system was adapting to sense airborne volatile

stimuli. 0owever, the detailed picture is considerably more complicated isthen *++9$ and the division between cell

types is not absolute. (lthough the majority of olfactory sensory neurons B:=s$ in the mammalian main olfactory

epithelium 4B$ are ciliated and e&press olfactory receptors B;s$, there are also microvillar cells that appear to

form a distinct chemosensory system lsaesser et al. *++#$.

For many years, the established view has been that these two chemosensory systems were not only anatomically

distinct, but also functionally separate. The 4B was thought to detect volatile odors for general odor perception andlearning. -n contrast, the 2=B was specialied for the detection of pheromonal signals affecting physiology and

behavior, via a separate and relatively direct neural pathway. 0owever, more recent studies have shown that bothB:=s and vomeronasal sensory neurons 2:=s$ can respond to the same chemical stimuli, and both sensory systems

send projections to brain areas that are involved in mediating pheromonal responses /rennan and Eufall *++3$.

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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 specialied subsystems within both the main olfactory

system and the vomeronasal system.

6.'.1. (OMRON!$!" $ )$TM

The vomeronasal system is often regarded as having a role e&clusively in pheromonal detection. 0owever, this iscertainly not true in nonmammalian vertebrates, as the 2=B is used to detect predator and prey odors in many reptiles

0alpern and 4artine<4arcos *++$, and may have a similar role in some mammals. The 2=B is a blind<ended

tubular structure situated in the nasal septum and connected to the nasal andHor oral cavities via a narrow duct 1Iving

and Trotier !""5$. The sensory epithelium containing the 2:=s 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. -n rodents, such as hamsters and mice, the

2=B is tightly enclosed in a cartilaginous capsule. >hanges in the blood flow to a large laterally positioned blood

vessel cause pressure changes in the 2=B lumen, resulting in chemosignals being pumped into the organ, along with

mucus 4eredith and BG>onnell !"@"$. This vascular pumping mechanism is activated by the sympathetic nervous

system in situations of behavioral arousal 4eredith !""9$. 0owever, in other species, uptake of stimuli into the 2=B

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.

(lthough the 2=B is undoubtedly specialied for the detection of involatile stimuli, there is still some doubt aboutwhether it responds to volatile airborne stimuli. 4any pheromonal stimuli that are sensed by the 2=B are small,

volatile molecules, and they act as stimuli for 2:=s in vitro Leinders<Eufall et al. *+++$. 0owever, their binding to

lipocalins, such as 478s, could be required to transport them into the 2=B. Functional magnetic resonance imaging

of the accessory olfactory bulb (B/$, which receives the input from the 2=B, in anaesthetied mice has revealed

robust changes in activity in response to urine odors delivered via the nasal airstream Ju et al. *++#$. 0owever, this

activation of the (B/ could have occurred via a centrifugal pathway activated by main olfactory input, rather than

being a direct sensory response 4artel and /aum *++@$.

6.'.1.1. (omeronasal Re*eptors

Two classes of vomeronasal receptors are e&pressed by spatially distinct populations of 2:=s. Latest analyses of the

mouse genome has revealed !5@ functional genes for 2!;s rus et al. *++#$, which are e&pressed by 2:=s in the

apical layer of the vomeronasal epithelium. ( further @+ functional receptors of the 2*; class have been identified,which are e&pressed by 2:=s in the basal layer of the sensory epithelium :hi and Ehang *++@$. 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. 0owever, the vomeronasal receptor repertoire

of mice and perhaps other rodents is not representative of all mammals. 4any mammals have a much more restricted

range of 2!;s and no functional 2*;s at all Table 3.*$.

T!B" 6.2( >omparison of the =umber of enes and pseudogenes for 4ajor 7rinary 8roteins 478s$, 2omeronasal ;eceptor

>lass ! 2!;s$, and >lass * 2*;s$ in a ;ange of 4ammalian :pecies That 0ave /een -dentified by >omparative

enomic (nalysis.

lectrophysiological recordings and calcium imaging have revealed that the 2!; and 2*; classes of vomeronasal

receptor respond to different classes of stimuli. 2!;<e&pressing 2:=s typically respond to small, volatile

chemosignals, including the testosterone<dependent volatiles of male mouse urine Figure 3.!$ Leinders<Eufall et al.

*+++$. They are also likely to respond to sulfated steroids that have recently been found to activate a large proportion

of 2:=s in the vomeronasal epithelium =odari et al. *++5$. -n contrast, the 2*;<e&pressing population of 2:=s is

stimulated by a variety of protein and peptide stimuli, including 478s, major histocompatibility comple& 40>$

peptides, and :8s Leinders<Eufall et al. *++9A >hamero et al. *++@A Kimoto et al. *++@$. :imultaneous recordings

from large populations of 2:=s in 2=B slices have shown that natural stimuli, such as urine and tear secretions,

contain a wealth of information about se& and individual identity, which could potentially be e&tracted bycombinatorial analysis Figure 3.*$ 0oly et al. *+++A Kimoto et al. *++@A 0e et al. *++5A =odari et al. *++5$.

(lthough, the e&tent to which the vomeronasal system processes information in this way is not known.





















































#I%UR 6.2

1ifferences in the patterns of responses of vomeronasal sensory neurons 2:=s$ to urine from different individuals

and major histocompatibility comple& 40>$ peptides. ;esponses recorded by >a*?

imaging from slices of

vomeronasal epithelium in response more...$

(s would be e&pected of a pheromonal detection system, the responses of 2:=s are highly sensitive. 2!;<e&pressing

2:=s typically respond to concentrations of urinary volatiles, such as ;,;$<,9<dehydro<e&o<brevicomin 1/$ and:$<*<sec<butyl<9,#<dihydrothiaole :/T$, with thresholds of !+ !+ to !+ 4 Leinders<Eufall et al. *+++$. 2*;<

e&pressing 2:=s appear to be even more sensitive, responding to 40> peptides at the astonishingly lowconcentration of !+M! 4 Leinders<Eufall et al. *++9$. 2:=s respond more selectively than classical B:=s Figure

3.!$, and maintain their selectivity as the stimulus concentration is increased Leinders<Eufall et al. *+++$.2omeronasal transduction differs from the classical B:= transduction mechanism. 2:= transduction appears to

involve the phospholipase * signaling pathway and transient receptor potential channels of the T;8>* variety, in theapical microvilli of 2:=s 0oly et al. *+++A Leypold et al. *++*A :towers et al. *++*$. 0owever, the responses of

2*;<e&pressing 2:=s to 40> peptides are unaffected in T;8>* knockout mice, implying that they use a differentand so far unknown transduction mechanism Kelliher et al. *++3$. arlier reports of maintained firing rate during

current injection into 2:=s suggested that they failed to show significant adaptation 0oly et al. *+++$. 0owever,more recent studies have shown that 2:=s do show adaptation to maintained or repeated stimulus presentation

mediated by a >alcium<calmodulin<dependent feedback on T;8>* cation channels :pehr et al. *++"$.

6.'.1.2. (omeronasal Ne+ral Path,a-s

2:=s project their a&ons to the (B/ where they synapse with the primary dendrites of mitral cell projection neurons

in glomerular structures. 2!; and 2*; classes of 2:=, which are segregated in apical and basal regions of the

vomeronasal epithelium, project separately to anterior and posterior subdivisions of the (B/, respectively 0alpera

and 4artine<4arcos *++$. ;ecently, a third subsystem within the (B/ has been identified -shii and 4ombaerts

*++5$. ( subpopulation of 2*;<e&pressing 2:=s coe&press nonclassical class - 40> genes. This population of 2:=s

is located in the deeper sublayer of the basal one of the sensory epithelium and project to the posterior subdomain of

the posterior subdivision of the (B/ -shii and 4ombaerts *++5$. 0owever, the significance of this tripartite

organiation of the (B/ remains unclear.

enetically manipulated mice in which 2:=s that e&press different 2!;s have been labeled with different fluorescent

markers has provided the first glimpse of the pattern of information flow within the anterior subdivision of the (B/

)agner et al. *++3$. This has revealed that (B/ mitral cells send a branched primary dendritic tree to sample

information from glomeruli that receive input from different, but closely related 2!; receptor types. These findings

suggest that the integration of information from different receptor types is already occurring at the level of the (B/.

This is consistent with recordings of (B/ mitral cell activity from freely behaving mice, which found highly selective

responses of individual neurons to specific combinations of se& and strain identity Luo et al. *++$. ( similar

convergence of information at the level of the (B/ is evident in the suppression of mitral cell responses to a mi&ture

of male and female urine, compared to their responses to male or female urine presented individually 0endrickson et

al. *++5$.(B/ mitral cells appear to send a distributed projection to the medial amygdala 4e($, posteromedial cortical

amygdala 84>o($, bed nucleus of the stria terminalis, and the bed nucleus of the accessory olfactory tract

von>ampenhausen and 4ori *+++$. 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. 4ale

and female chemosignals activate different subpopulations of neurons in the 4e(, which can be identified on the

basis of their homeodomain gene e&pression >hoi et al. *++#$. ;etrograde neural tracing in male mice showed that

the 4e( neurons that responded to female chemosignals provided input to areas of the hypothalamus involved in

mating behavior. -n contrast, 4e( neurons that responded to male chemosignals projected to areas of the

hypothalamus known to be involved in mediating defensiveHaggressive behavior. -mportantly, these male<responsive

4e( neurons also sent antagonistic projections to the hypothalamic areas controlling reproductive behavior >hoi et

al. *++#$. 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 atthe level of hypothalamic output as well as in the level of the (B/.
































































6.'.1.&. Behavioral e*ts o (omeronasal D-s+n*tion

The importance of the vomeronasal system in influencing behavior has been demonstrated by e&periments in which

the 2=B has been physically ablated in genetically normal mice, or vomeronasal transduction disrupted in genetically

manipulated mice lacking T;8>* ion channel function. ( 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 4aruniak et al. !"53A Leypold et al. *++*A :towers et al. *++*$. This is consistent withthe role of the 2=B in detecting volatile and involatile male urinary constituents that elicit aggressive behavior

=ovotny et al. !"5#A >hamero et al. *++@$.

There appear to be significant species differences in the importance of vomeronasal sensation for male se&ual

behavior. Forty percent of male hamsters show severe deficits in se&ual behavior, following section of their

vomeronasal nerves Licht and 4eredith !"5@$. The effects were particularly severe in se&ually naive males, with

significant impairment of their ability to mate. 0owever, se&ually e&perienced 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 se&ual e&perience. -n male mice, vomeronasal ablation prevents the normal rise in luteiniing hormone levels

in response to female chemosignals. 4ale se&ual 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.

*++"$. =otably, T;8>* knockout mice that have severely impaired vomeronasal function still show se&ual behavior

directed toward females, but also mount other males, rather than behaving aggressively toward them 4aruniak et al.

!"53A Leypold et al. *++*A :towers et al. *++*$.

8hysical lesions of the 2=B impair lordosis behavior in female mice Keller et al. *++3$, suggesting that pheromones

sensed by the vomeronasal system also play an important role in female se&ual behavior Keller et al. *++"$.

0owever, once again, the behavioral deficits of T;8>* knockout mice appear to differ from the effects of physical

lesions of the 2=B. 1ulac reported that T;8>* knockout female mice showed significantly higher levels of malelike

se&ual behavior, including ultrasonic vocaliation and mounting of other females )ysocki and Lepri, !""!A Kimchi

et al. *++@$. This would suggest that se&<specific behavioral patterns of male and female mice are at least partly

dependent on ongoing sensory input rather than being developmentally determined. /ut, other groups have not

reported such effects, and both male and female mice with physical 2=B lesions are capable of discriminating se&ual

identity of urine odors Keller et al. *++"$. The differences that have been reported between the behavioral effects of

physical 2=B lesions and knockout of the T;8>* gene might arise due to developmental effects of the knockout, or

due to the presence of 2:=s that do not use the T;8>* transduction pathway Kelliher et al. *++3$.

6.'.2. M!IN O"#!CTOR) $ )$TM

(lthough previously often overlooked, it has been known for many years that not all pheromonal responses aremediated by the vomeronasal system. For e&ample, the mammary pheromone that guides nipple search behavior of

rabbit pups is still effective following 2=B lesion 0udson and 1istel !"53b$. :imilarly, the boar se&ual attractant pheromone is still effective in eliciting standing behavior following 2=B lesions in sows 1orries et al. !""@$.

-nstead, these pheromonal effects and many others are likely to be mediated by the main olfactory system. The mainolfactory 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 comple& odorant mi&tures that make up naturalodors. The emphasis has been very much on the role of learning in the piriform corte& in forming these odorant

representations and associating them with their conte&t and an appropriate behavioral response )ilson and :tevenson*++$. This provides considerable fle&ibility 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. 0owever, it is becomingincreasingly apparent that the main olfactory system is not a unitary sensory system, but is composed of a number of

functionally specialied subsystems that might be involved in pheromonal detection.

(mong these main olfactory subsystems, B:=s e&pressing members of the trace amine receptor T((;$ family have

been found in the mouse 4B and can respond to volatile amines that are found in mouse urine Liberles and /uck

*++3$. (nother subpopulation of B:=s are distinguished by their guanyl cyclase<dependent transduction pathway. (t

least some of this population have been shown to respond to the peptides guanylin and uroguanylin, which are also

found in mouse urine Leinders<Eufall et al. *++@$, although what pheromonal role they might perform is still

unknown. :omewhat more surprising is the finding of a subpopulation of B:=s that respond to involatile 40>

peptides. -n a challenge to the dogma that the 4B only responded to volatile odors carried in the nasal

airstream,:pehr et al. *++3$ showed that the nonvolatile fluorescent dye, rhodamine, gained access to a large e&tent

of the 4B following direct physical investigation of a rhodamine<painted conspecific. This suggests that other

nonvolatile peptides, and possibly even proteins, could gain access to the 4B of mice following direct investigation

of a stimulus.

The functions of the vomeronasal and main olfactory systems are more integrated than previously thought Eufall

andLeinders<Eufall *++@$. The same chemosignals can act as stimuli for both B:=s and 2:=s with low response

































































thresholds typical for pheromonal detection. The mouse 4B responds to urinary volatiles, such as heptanone, atconcentrations of !+M!+ 4 :pehr et al. *++3$, similar to the sensitivity of 2l;b* e&pressing 2:=s Leinders<Eufall et

al. *+++$. The responses of the two systems to 40> peptides are also highly sensitive, with responses at !+<!+ 4 forB:=s :pehr et al. *++3$, and down to !+! 4 for 2:=s Leinders<Eufall et al. *++9$. Furthermore, trans<synaptic

tracing of the afferent connections of neurons e&pressing luteiniing 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 /oehm et al. *++#A Noon et al. *++#$./y its very nature, input from releaser and primer pheromones is likely to mediate innate responses via specialied

neural pathways, separate from the general odor<sensing pathway of the main olfactory system. -ndeed, part of the4B/ has been found to mediate innate responses to odors Kobayakawa et al. *++@$. (blation of B:= input to the

dorsal one of the 4B/, using targeted e&pression of the diphtheria to&in gene, disrupted the innate aversive responseof 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 conditionedaversion to them. (lthough 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 4B/ Kobayakawa et al. *++@$.

7ntil recently, the (B/ and 4B/ were thought to project to separate brain areas. ven their projections to the

amygdala were thought to target different nuclei. The (B/ projects to the 4e( and 84>o(, which together are often

referred to as the vomeronasal amygdala von >ampenhausen and 4ori *+++$. These areas, in turn, project to medial

regions of the hypothalamus involved in the control of reproductive and social behavior. The 4B/ projects to the

neighboring anterior cortical and posterolateral cortical regions of the amygdala. lectrophysiological recording in

hamsters has found that information from the main olfactory system and vomeronasal system converges on individual

neurons in the 4e( Licht and 4eredith !"5@$.

This influence of the main olfactory input on the 4e( was thought to be mediated by indirect intra<amygdala

connections. 0owever, a recent study using anterograde tracing has identified a previously neglected, direct projection

from the 4B/ to the 4e( in mice and rats Figure 3.$ Kang et al. *++"$. This potentially provides a more direct

pathway by which main olfactory input could control reproductive and social behavior. ;etrograde tracing from the

4e( revealed that these projections originated from a subpopulation of mitral and tufted 4HT$ neurons located

mainly in the ventral region of the 4B/. -nterestingly, these retrogradely labeled 4HT neurons in the 4B/ of female

mice responded to chemosignals from male mice, but not to chemosignals from other female mice, or to a predator

odor. These 4HT neurons were in a similar location to the ventrally located 4B/ glomeruli that receive input from

T;84#<e&pressing B:=s Lin et al. *++@$. 4oreover, 4HT neurons in this region of the 4B/ respond to social

chemosignals present in male urine, such as the urinary attractant 4T4T Lin et al. *++@$, and suggest that this is alikely pathway for many pheromonal effects on reproductive behavior that are mediated by the main olfactory system.

#I%UR 6.&

>onvergence of input from the ventral main olfactory bulb 4B/$ and the accessory olfactory bulb (B/$ onto the

medial amygdala 4e($ of the female mouse. ($ Location of injections of anterograde tracer into the ventral 4B/

in green, shown by filled more...$

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6./. PHROMON!" ##CT$ ON BH!(IOR

>hemical signals that elicit a specific and immediate behavioral effect are known as releaser pheromones.

8heromones that elicit longer<term effects on endocrine state or development are termed primer pheromones.

0owever, pheromonal signals can have different effects in different conte&ts. For e&ample, testosterone<dependent

constituents of male mouse urine, including 1/, :/T, ,<O<farnesene, <P<farnesene, and 3<hydro&y<3<methyl<<

heptanone, are all effective individually in accelerating puberty in prepubertal female mice =ovotny et al. !"""$. (

mi&ture of two of these compounds, 1/ and :/T, is also effective in inducing and synchroniing estrus cycles in

adult females 4a et al. !"""$, and also has a releaser pheromonal effect in eliciting aggression from males or

maternal females, when presented in the conte&t of an intruder male =ovotny et al. !"5#$. -t 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.

(s 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 )yatt *++$. This has led some researchers to propose




















































new categories of pheromonal effects )ysocki and 8reti *++9$. The term signaler pheromone has been used forchemosignals conveying information about the producer that might bias behavioral choices, without mediating a

definite responseA for instance, chemical signals that convey information about individual identity that are used interritorial marking. ( 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 acalming effect on their offspring, or the an&iety<promoting effects of alarm pheromones. 0owever, these new

classifications are not as widely accepted as the original distinction between primer and releaser effects. (nalternative, and potentially more useful classification has been proposed by )yatt *++"$, which distinguishes

between pheromones that mediate innate responses and %signature odors,' such as individuality signals, that conveyinformation and for which learning determines the nature of the response.

6./.1. $0U!" !TTR!CT!NT PHROMON$

(ttractant pheromones are often used to arouse, attract investigation, and release specific behavioral responses from

conspecifics. Bne well<known e&ample is the boar se&ual attractant pheromone, which has even been e&ploited

commercially as a test for sow receptivity. /oar saliva contains high levels of the androgen derivatives #O<androst<!3<

en<<one and #O<androst<!3<en<<ol. These steroids are bound and concentrated in the saliva by proteins :(L! and

:(L*, which are members of the lipocalin family of ligand<binding proteins Loebel et al. *+++$. )hen se&ually

aroused, boars salivate profusely and foam at the mouth, which disperses these volatile pheromones in the air. The #a<

androst<!3<en<<one and #a<androst<!3<en<<ol act as releaser pheromones to attract receptive sows and elicit a

specific mating posture, known as standing, which allows mounting by the boar 1orries et al. !""@$.

(nother e&ample of a se&ual attractant is aphrodisin, a !@ k1a protein found in the vaginal fluid of female hamsters,

which elicits mounting behavior in se&ually naive, male hamsters. (phrodisin 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 /riand et al. *++9$. 4ouse urine also contains attractive chemosignals

that promote investigation by opposite se& conspecifics. The urinary constituents responsible for the innate

attractiveness of urine appear to be involatile and likely to be 478s, which are also lipocalins ;amm et al. *++5$.

7rinary volatiles, such as the 4T4T produced by male mice, have also been reported to have attractant properties.

(lthough synthetic 4T4T was relatively ineffective in isolation, it increased the investigation time of females when

added to urine Lin et al. *++@$.

6./.2. R!BBIT M!MM!R) PHROMON

Bther pheromones that elicit a strong behavioral attraction are the nipple guidance pheromones. The best understoode&ample is the rabbit mammary pheromone, but similar pheromonal stimuli may be of importance in guiding offspringto nipples and facilitating nursing in most mammals, including humans. ;abbits have an e&treme form of maternal

care, in which they only make brief 96# min nursing visits to their pups once a day. 1uring this short period, the rabbit pups are guided to the motherGs nipples by a pheromone produced by the nipples and which is present in the milk

0udson and 1istel !"53a$. This pheromone elicits a specific pattern of behavior known as nipple searching, in whichthe pupGs forelimbs are splayed laterally and the head makes rapid side<to<side searching movements, scanning the

motherGs ventrum. The gradient of mammary pheromone guides the pupGs nose to the nipples to which it can attach onthe basis of somatosensory cues 1istel and 0udson !"5#$.

(nalysis of the volatile constituents of rabbit milk showed that a single constituent, *<methylbut<*<enal, was capableof eliciting full nipple search behavior :chaal et al. *++$. 7nusually for mammalian pheromones, the synthetic

compound was also effective when presented on a glass rod, outside the normal suckling conte&t. The effect of themammary pheromone to releases nipple search response appears to be automatic in young rabbit pups, irrespective of

whether or not they have recently fied. 0owever, in five<day<old pups, its effectiveness was found to declineimmediately after suckling, showing that the pheromoneGs influence over behavior lessened during development to

become modulated by prandial state 4ontigny et al. *++3$.

6./.&. MOU$ !%%R$$ION PHROMON$

( mi&ture of the testosterone<dependent urinary volatiles 1/ and :/T are able to elicit aggressive behavior from male

mice when added to castrated male urine =ovotny et al. !"5#$, consistent with their response being mediated by the

2-;<e&pressing class of 2:= Leinders<Eufall et al. *+++$. ;ecently, it has been reported that the nonvolatile fraction

of male mouse urine is also effective in elicting male aggression >hamero et al. *++@$. (nalysis of this fraction

revealed this involatile aggression<promoting pheromone to be a 478 Furthermore, a synthetic 478 was able to elict

aggression and stimulate 2*;<e&pressing 2:=s, even in the absence of the aggression<promoting volatiles 1/ and

:/T >hamero et al. *++@A Kimoto et al. *++@$. Therefore, 478s and the testosterone<dependent volatile that they

bind act via separate vomeronasal receptor pathways to elicit aggressiveHdefensive behavior in mice.






































6./.'. !"!RM PHROMON$

7nder stressful conditions, such as elevated levels of carbon dio&ide, mice release alarm pheromones that elicit

freeing 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 rueneberg ganglion, as the freeing response is

abolished in mice with section of sensory nerve from the ganglion /rechbQhl et al. *++5$.

6././. PHROMON$ !ND "!RNIN%

;ecent evidence suggests that some pheromones can be innately rewarding and promote associative learning. =aive

female mice do not normally show a preference for investigating volatile urinary odors from males. 0owever, 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 4oncho</ogani et al. *++#A ;amm et al. *++5$. :urprisingly, this prior e&perience with the nonvolatile

constituents does not generally increase the attractiveness of the urinary volatiles of all males, but only the

attractiveness of the individual maleGs volatiles to which the females were e&posed ;amm et al. *++5$. :imilarly,

e&posure 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 >oureaud et al.

*++3$. :uch 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 thelearned response to associated conte&tual cues.

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6.6. CHMIC!" $I%N!"$ O# INDI(IDU!" IDNTIT)

4ammals release an enormous variety of molecules into the environment that contribute to their chemical profile, and

which could potentially be used to recognie the individuality of the producer. /ut which, if any, of these can usefully

thought of as pheromonesR This remains a controversial area, with many researchers in this field deliberately avoiding

the use of the term. >hemicals 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. :uch

biasing effects are often associated with learning and as they are dependent on both past and present conte&t, they do

not meet the conventional definition of a pheromone. =evertheless, 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 /rennan and Kendrick *++3$.

6.6.1. M!OR URIN!R) PROTIN$ !ND TRRITORI!" M!RIN%

Territorial behavior is seen in a wide variety of species in which individuals compete to monopolie desirable

territories and resources. 4any mammals deposit scent cues around their environment, advertising their presence tocompetitors 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 0urst and /eynon *++9$. Like many other species that use urine marking, mice e&crete large quantities of

protein in their urine. Typically, ""S of the protein content of the urine is made<up of 478s, members of the lipocalin

family of ligand<binding proteins /eynon and 0urst *++$. The concentration of 478s is four to five times higher in

male mouse urine than that of females, and some 478 variants are found only in males ;obertson et al. !""@$.

478s bind certain volatile urinary constituents, including the testosterone<dependent male mouse pheromones 1/and :/T, which have been shown to have pheromonal effects on the female reproductive state and the initiation of

male aggression. 478s are highly stable in the environment and act as a reservoir for the volatile ligands, prolonging

their release over a period of days 0urst et al. !""5$. These characteristics make 478s ideally suited as a territorial

marker. =ot 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. )hen a resident male comes across a urine mark of a rival male, the resident deposits his

fresh urine mark ne&t 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 478s that are

being sensed by the 2=B :herborne et al. *++@$. 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 0umphries et al. !"""$.

-n order to use urine marking as an indicator of the competitive fitness, urine marks have to be associated with the

individual that produced them. -n addition to their physiochemical properties that make 478s ideal as territorial

markers, 478s are highly polymorphic and a wild mouse will produce an individual profile of different 478 types



































capable of conveying individual identity. -ndividual mice captured from the wild produce between # and !# variantsfrom the polymorphic 478 family, the profile of which is specific for an individual ;obertson et al. !""@$.

4oreover, the recognition of urine marks can be influenced by the addition of an artificially produced recombinant478 to change their 478 profile 0urst et al. !""5A ;obertson et al. *++@$. 478s without bound ligands have been

shown to act as stimuli at 2*;<e&pressing 2:=s >hamero et al. *++@A Kimoto et al. *++@$. This role of these 2:=sin detecting individual 478 variants is consistent with genomic analysis that has found an association between the

number of genes for 478 isoforms and for 2*;s in certain species Table 3.*$. 0owever, although genomic analysishas revealed e&pansions of the 478 gene family in mice, rats, horses, and gray lemurs, many species have only a

single 478 iso<form and appear to be unable to use 478s to encode individual identity Logan et al. *++5$.

6.6.2. M!OR HI$TOCOMP!TIBI"IT) COMP"0 3MHC45!$$OCI!TD CHMO$I%N!"$

-n identifying chemosensory signals of individual identity, most attention has focused on genes of the 40>, 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 40> types in addition, but unrelated, to other genetic

differences such as 478 genotype.

6.6.2.1. Maor Histo*ompati7ilit- Comple8 3MHC45!sso*iated (olatiles

4any years of research have shown that both trained and untrained mice can discriminate the volatile urine odors of40><congenic mice that differ genetically only at the 0* region of their 40> Namaguchi et al. !"5!A 8enn and

8otts !""5b$. 7rine samples from 40><congenic mice have consistently different proportions of volatile carbo&ylicacids :inger et al. !""@$ and elicit significantly different patterns of activity in the 4B/ :chaefer et al. *++*$. The

ability of mice to discriminate 40><congenic urine odors has been reported as being related to polymorphism in their peptide<binding groove >arroll et al. *++*$. 0owever, genetically identical inbred mice have a significant variability

in the proportion of volatile urinary components, suggesting that nongenetic factors, such as nutrition andenvironmental condition, also have significant effects on individual urine odor ;ck et al. *++@$. 1espite several

theories having been proposed, no mechanism has been established by which 40> genotype could affect metabolic pathways to account for the reported quantitative differences in urinary volatiles.

6.6.2.2. Maor Histo*ompati7ilit- Comple8 3MHC4 Peptides

The 0* region of the mouse 40> codes for 40> proteins of classical class - type, which are e&pressed 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 immunesurveillance /oehm and Eufall *++3$. 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 40> class - peptide<bindinggroove. Therefore, individuals with different 40> type will bind different subsets of peptides having anchor residue

positions that mirror the polymorphic differences in the peptide<binding groove of their 40> class - proteins. Fore&ample, 40> class - proteins of >#@/LH3 inbred mice 0<*b haplotype$ preferentially bind peptides having

asparagine =$ at position #, such as ((81=;TF, whereas 40> class - proteins of the /(L/Hc inbred strain 0<*dhaplotype$ preferentially bind peptides with tyrosine N$ at position *, such as :NF8-T0-. (s the anchor residue

structure of 40><peptide ligands reflect the peptide<binding cleft of the 40> class - peptide that bound them, theycould potentially function as robust signals of 40> identity.

This hypothesis has been investigated using electrophysiological recording and calcium imaging of slices of mouse

vomeronasal epithelium. ;esponses to synthetic peptides possessing the characteristic features of 40><peptideligands have been reported at concentrations from !+<" to !+! 4 >hamero et al. *++@A 0e et al. *++5$, although the percentage of 40><peptide<responsive cells varied widely among the studies. -ndividual 2:=s responded selectively

to synthetic /(L/Hc<type :NF8-T0-$ or >#@/LH3<type ((81=;TF$ peptides Figure 3.9$ Leinders<Eufall etal. *++9$. 2:= 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. >hanging the position of the anchor residues abolished the responses of 2:=s, whereas the selectivity of responses from individual

2:=s were not affected when the anchor residues were left unchanged, but the intervening sequence of amino acidswas varied. 4ost 2:=s responded selectively to synthetic peptides of either /(L/Hc<type or >#@H/L3<type, however,

a small proportion responded to both peptides Leinders<Eufall et al. *++9$, suggesting the e&pression of more than aone 2*; receptor type per 2:=. /ut only a limited amount of evidence has been found for such coe&pression

4artini et al. *++!$. Future e&periments testing a wider range of 40><peptide types will be required to determinewhether individual 2:=s respond to specific combinations of 40> peptides that could encode individual identity.


















































#I%UR 6.'

2omeronasal sensory neurons 2:=s$ respond to major histocompatibility comple& 40>$ peptides. >a*?

imaging in

slices of vomeronasal epithelium of responses from four 2:=s in response to synthetic 40> peptide of ($

>#@H/L3<type ((81=;TF pseudocolored more...$

>alcium imaging of 40><peptide sensitive 2:=s revealed them to be located in the basal layer of the vomeronasal

epithelium, colocaliing with 2:=s e&pressing the 2*; class of vomeronasal receptor Leinders<Eufall et al. *++9$.These receptors possess a large e&tracellular =<terminal domain, possibly involved in binding proteins or peptides and

are coe&pressed with atypical 40> proteins of the !b class -shii et al. *++A Loconto et al. *++$. These nonclassical40> !b proteins have only been found e&pressed in the 2=B and form a receptor comple& with 2*;s and P<

microglobulin, suggesting that they might have a specific chemosensory function Loconto et al. *++$. >ertaincombinations of 40> -b proteins are coe&pressed with particular 2*;s, which could affect receptor specificity -shii

et al. *++$. :equence variability among the nine members of the nonclassical 40> lb family is localied to the peptide<binding groove. /ut structural considerations suggest that they are unlikely to bind peptides Blson et al.

*++#$ and their role in 2:= function remains unknown.

-t is becoming increasingly apparent that there is considerable overlap between stimuli that are sensed by the main

olfactory and vomeronasal systems /rennan and Eufall *++3$. /ut, it is nevertheless surprising that responses to40><peptide ligands have also been recorded from the 4B :pehr et al. *++3$. >alcium imaging of individual

B:=s in the 4B revealed that they respond selectively to 40> peptides down to !+ 6!! 4. This is one to two ordersof magnitude higher than the threshold for 40><peptide<responsive 2:=s, which along with their lack of absolute

dependence on anchor residues suggests that a different type of receptor may be involved. )hereas replacement ofanchor residues with alanines abolished the responses of 2:=s, it shifted the stimulus response curve of individual

B:=s, although B:=s still failed to respond to the scrambled version of the peptide in which the position of theanchor residues had been changed :pehr et al. *++3$. Therefore, B:= responses to 40> peptides may be more

dependent on the overall sequence of amino acids, rather than the position of the anchor residues. :uch ability torecognie specific 40> 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, althoughthere is no evidence for this conjecture at present.

6.6.&. RO" O# M!OR HI$TOCOMP!TIBI"IT) COMP"0 3MHC45!$$OCI!TD CHMO$I%N!"$ IN N!TUR!" CONT0T$

6.6.&.1. Mate Choi*e

1espite over + years of research, the importance of any influence 40> genotype might have on mammalian

behavior remains unclear. (n influence of 40> genotype on mate choice in mice was first reported by /oyse, andinvestigated in a series of further studies by Namaaki and /eauchamp /oyse et al. !"5@$. They reported a

disassortative pattern of mating in which male mice preferred to mate with females of dissimilar 40> type, thusavoiding inbreeding. This influence of 40> 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 40><dissimilar mothers Namaaki

et al. !"55A 8enn and 8otts !""5a$. 0owever, many similar studies of mate choice have produced inconsistent andsometimes conflicting results Dordan and /ruford !""5$. This failure to consistently find a clear effect of 40> typeis likely to be due to the difficulties inherent in studying such comple& behavior as mate choice in a limited laboratory

environment. For mate choice tests, mice are frequently restrained and deprived of the normal behavioral conte&t inwhich they can assess the reproductive fitness of potential mates. 4oreover, the use of congenic mice that only differ

in 40> type removes much of the genetic variability that may normally contribute to mate choice decisions.

1isassortative mate preference has been observed in seminatural enclosures, in which colonies of mice produced

fewer 40> homoygous offspring than e&pected from random matings 8otts et al. !""!$. 0owever, a recent largestudy 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 40> type :herborne et al. *++@$. ;ather, mate choice was related to 478 similarity,with a deficit in matings between individuals that shared both 478 haplotypes. (n important point of this e&periment

was its use of mice bred from wild<captured individuals, which have considerably more genetic variability, especiallywith regard to 478 profiles, than inbred strains >heetham et al. *++"$. 4ore e&periments will be required, using

wild<derived mice in natural conte&ts, before the relative importance of 40> genotype, 478 profile, and generalheteroygosity in mate choice decisions can be fully understood.















































6.6.&.2. Mother5Osprin9 Intera*tions

Female mice are more likely to form communal nests with kin of 40><similar genotype 4anning et al. !""*$.

Female mice also preferentially retrieved pups of similar 40> type to themselves, which had been removed from the

nest and mi&ed with 40><dissimilar pups Namaaki et al. *+++$. Furthermore, mouse pups themselves appear to use

40><related cues to learn the odor of their mother and siblings, as revealed by their preference for odors of maternal

40> type in an odor choice test Namaaki et al. *+++$. These 40> 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 recognie comple& mi&tures of odorants that make up

individual odors, whether or not those are genetically determined.

6.6.&.&. ! Behavioral Role or Maor Histo*ompati7ilit- Comple8 3MHC4Peptides:

40> genotype has also been linked to mate recognition in the /ruce effect. This is a primer pheromonal effect in

which e&posure of a recently mated female mouse to urine from an unfamiliar male causes implantation failure and a

return to estrus /ruce !"#"$. 0owever, 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 mateGs pregnancy. /oth

the /ruce effect and the recognition of the mating male are mediated by the vomeronasal system Lloyd<Thomas and

Keverne !"5*A 4a et al. *++*$. This ability of the female to recognie the urinary chemosignals of her mate is due toher learning their identity at mating, which subsequently inhibits the transmission of the pregnancy<blocking signal at

the level of the (B/ /rennan and Eufall *++3$. >ongenic male mice, differing from the mating male only in their

40> genotype, were not recognied and blocked the pregnancy of recently mated females in a similar manner to an

unfamiliar male of a different inbred strain Namaaki et al. !"5$, suggesting an involvement of 40><associated

chemosignals.

The role of 40> 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 40> peptides of a different strain

type Leinders<Eufall et al. *++9$. The addition of >#@/LH3<type peptides to /(L/Hc male urine significantly

increased its pregnancy<blocking effectiveness following mating with a /(L/Hc male. >onversely, the addition of

/(L/Hc<type peptides to >#@/LH3 male urine increased its effectiveness in blocking the pregnancy of females that

had mated with a >#@/LH3 male. This suggests that 40><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<Eufall et al. *++9A Thompson et al. *++@$.

0owever, a major problem with the hypothesis that 40> peptides convey individuality in the pregnancy block effect,

or indeed any other biologically important conte&t, is the failure to find them, to date, in any biological secretion,

including male mouse urine. Furthermore, >a*? imaging of vomeronasal epithelial slices has found that although some

2:=s did respond to both the >#@H/L3<type 40> peptide ((81=;TF and to urine from >#@H/L3 males 0e et al.

*++5$, a significant number of 2:=s only responded to one or the other, implying that this 40> peptide is not

normally present in >#@H/L3 male urine Figure 3.*$. Therefore, although 40> peptides may influence the

pregnancy block effect, it is unlikely that they are the endogenous individuality signal present in urine.

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6.;. HUM!N PHROMON$

The idea that human physiology and behavior might also be influenced by pheromonal cues is a natural e&tension ofthe finding of pheromonal responses in other animals. /ut, despite a widespread research effort, it has been difficult to

identify robust and reproducible effects. This doesnGt necessarily mean that human pheromones donGt e&ist, butcomple&ities of modern human society may diminish their biological significance and make it difficult to identify

consistent effects. 0uman a&illary secretions from the armpit and genital regions provide a rich source of putative pheromonal signals. 4icrobial action on a&illary apocrine secretions produces the comple& mi&ture of odorants

responsible for body odor, including androgen derivatives and volatile acids Leyden et al. !"5!$. $<<methyl<*<he&anoic acid <4*0$ is one of the major a&illary secretions Eeng et al. !""!$. This is particularly interesting as it

is bound by apolipoprotein 1, a member of the lipocalin family of ligand<binding proteins that are often associatedwith pheromonal volatiles in other species Eeng et al. !""3$.

( 2=B is present early in human fetal development, but appears to degenerate before birth, and the e&perimentalevidence suggests that any residual structure that has been identified as the human 2=B is nonfunctional 4eredith

*++!$. =ot only does it lack the well<developed sensory epithelium found in the 2=Bs of other species, but also the

sensory nerves to connect it to the brain )itt and 0ummel *++3$. Furthermore the gene encoding the T;8>* cationchannel is a pseudogene in humans, the selection pressure on it having been rela&ed around * million years ago,

















































shortly before the separation of hominoids and Bld )orld monkeys Liman and -nnan *++A Ehang and )ebb *++$.(nalysis 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 the4B or possibly the rueneberg ganglion, about which little is known, apart from a single report of its presence in

humans. 8ossible candidates for human pheromonal receptors include members of the T((; family of receptorsLiberles and /uck *++3$. Four potentially functional 2!;<like genes have also been identified in the human genome,

of which h2l;Ll is e&pressed in the 4B, but whether it has any role in pheromonal communication is unknown;odrigue et al. *+++$.

8erhaps 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. 9,!3<(ndrostadien<<

one, a compound present in male a&illary secretions, has been found to increase levels of the hormone cortisol )yartet al. *++@$, and to influence the frequency of luteiniing hormone pulses in females 8reti et al. *++$. &posure to

a&illary secretions from other females has also been found to influence female menstrual cyclicity. (&illary odorstimuli from females in the late follicular and ovulatory phases of their menstrual cycle have been found to shorten

and lengthen, respectively, the cycles of e&posed females :tern and 4c>lintock !""5$.

)hether pheromones can enhance se&ual attraction in adult humans is a comple& issue )ysocki and 8reti *++9$.

ffects of a&illary secretions and synthetic putative pheromones on attractiveness ratings have been reported under

laboratory conditions )ysocki and 8reti *++9$. 0owever, there has been a shortage of rigorous, placebo<controlled,

double<blind studies on pheromonal effects on attractiveness and se&ual 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 se&ual interactions. -maging 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 conte&ts and concentrations in which the putative pheromones are presented :avic et al. *++!$.

(lthough 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. 4ontgomeryGs 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 4arlier and :chaal *++#$, similar to the attractant effects of the rabbit mammary

pheromone. 0owever, newborn babies show similar orientation responses to components of the motherGs diet during

gestation :chaal et al. *+++$, implying that it may be a learned response to maternal odors that the fetus was e&posed

to in utero. This potentially makes distinguishing an innate pheromonal response from a learned response to incidentalmaternal odors all the more difficult.

-t is common knowledge that humans have individual odor signatures that can be discriminated by trained sniffer dogs

and may also be influenced by 40> genotype. Bverall, it seems that humans rate the odors of other individuals as

being more pleasant if they share a few 40> alleles with the rater, ratha than either no matches or a high degree of

similarity )edekind and Furi !""@A Dacob et al. *++*$. )hether 40><related odor preferences play a role in

behaviors such as partner preference is difficult to investigate given the comple&ities of modern human society.

0owever, fathers, grandmothers, and aunts have been reported to successfully identify the odor of a related infant

without prior e&perience, which could point to a role in parental or nepotistic behavior of these learned odor

signatures 8orter et al. !"53$.

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6.<. CONC"UDIN% RM!R$

Bur understanding of the important influence of pheromones on mammalian behavior has advanced dramatically in

the #+ years since the term was first proposed. These invisible chemical signals can elicit equally dramatic behavioral

responses in mammals to those seen in insects. 0owever, our understanding is fragmentary, with few e&amples 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 speciesUthe mouse. enetic

technologies have revealed a surprisingly large repertoire of chemosensory receptors in mice that potentially detect

pheromones. 0owever, 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.

8heromones and the effects that they mediate are, by their nature, species<specific and may not be found in even

closely related species. For e&ample, the diversity of 478s 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 ;obertson et al. *++@$. =evertheless,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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R#RNC$

• /eynon ;.D., 0urst D.L. 4ultiple roles of major urinary proteins in the house mouse, 4us

domesticus. /iochem. :oc. Trans. *++A!V!9*693. W8ub4edX

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pheromones and mammalian behavior

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