Neuroscience and Biobehavioral Reviews 35 (2011) 1916–1928

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Review

From models to mechanisms: Odorant communication as a key determinant ofsocial behavior in rodents during illness-associated states

Hiroyuki Arakawaa, Stephanie Cruzb, Terrence Deakb,!

a Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn St. HFSII, Rm. S251, Baltimore, MD 21201, United Statesb Behavioral Neuroscience Program, Department of Psychology, State University of New York (SUNY) at Binghamton, Binghamton, NY 13902-6000, United States

a r t i c l e i n f o

Article history:Received 3 September 2010Received in revised form 4 March 2011Accepted 7 March 2011

Keywords:Parasite recognitionChemosignalsSickness behaviorInflammationCytokinesSickness odorDefensive behaviorSocial interaction

a b s t r a c t

Pheromones and other social odor cues convey rich information among rodents. Social investigation isdescribed as a key element in olfactory communication, which involves motivated approaches to con-specifics and other socially relevant stimuli. This behavior is activated by the detection of social cues togather information about conspecifics for subsequent strategies such as avoidance or further approach,thereby determining the extent and nature of physical contact that ensues. This feature indicates a usefulway for describing the process of social communication in distance-based manner. In particular, air-borne odorant signals in rodent species guide social investigation at a distance, and provide informationregarding the health status of the odor donors. In this review, we will address the role of the inflammatoryresponse in the release of odor cues that involve information about several illness-associated conditions(bacterial or parasitic infection, stressor exposure, etc.). We will provide an overview of how sex anddevelopmental epoch in odor donors serve as predictors of subsequent social behavior. We conclude thatinflammatory processes have a profound impact on social behavior through a direct effect on the sickindividual (i.e., reduced motivation to engage in social interaction), while the release of illness-related,aversive odor cues from the sick individual serves to inhibit social investigation by healthy conspecifics.Together, this dual impact of acute illness is thought to minimize disease transmission across individualsand promote healthy group living.

© 2011 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19172. Distance-based social strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1917

2.1. Sensory modalities and physical distance from social stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19172.2. Odor information process through volatile and non-volatile chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19172.3. Body parts associated social investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1917

3. Communication of health information via odorant cues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19193.1. Odor recognition of parasitized conspecifics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19193.2. Aversive odor released from infected animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19193.3. The relationship between illness-associated odor cues and cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19203.4. Inflammation-driven odor cues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19203.5. Possible mechanisms for signaling illness state in airborne odor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1922

3.5.1. Steroid hormone modulation of illness-associated odor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19223.5.2. Immune cascade mediation in odor: MHC class I molecules hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1924Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1924References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1924

! Corresponding author.E-mail address: tdeak@binghamton.edu (T. Deak).

0149-7634/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.neubiorev.2011.03.007

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1. Introduction

Rodents such as mice and rats, the most commonly used animalmodels in neuroscience, are highly social species that form complexsocial systems in the wild (Grant and Mackintosh, 1963; Whishawet al., 2001; Lacey and Sherman, 2007). They have developed severaltypes of social communication for gathering information throughvisual, auditory, and olfactory senses and for engaging in physi-cal contact through tactile and taste senses and other behavioralresponses (Wyatt, 2003). These involve a complex system of sen-sory and behavioral components between conspecifics includingthe abilities to recognize and identify other individuals (Winslowand Camacho, 1995; Wyatt, 2003; Insel and Fernald, 2004). Thisinvestigation–recognition strategy heavily relies on the physicaldistance toward conspecific-relevant stimuli (e.g., Blanchard et al.,2001, 2003; Brennan and Keverne, 2004; Broad and Keverne, 2008).In this review, we will argue that the distance-based feature ofsocial communication between conspecifics provides a useful wayto analyze the processes of social behavior and its underlyingmechanisms. This review will focus on describing illness-associatedsocial cues that mediate social behavior at a distance, and possibleneural mechanisms modulating the release of this social cue.

2. Distance-based social strategies

2.1. Sensory modalities and physical distance from social stimuli

While nocturnal species use olfactory cues in the assessmentof conspecifics, most mammals combine this information withauditory and tactile senses as modalities for conspecific commu-nication (Eisenberg and Kleiman, 1972; Brown, 1979; Eisenberg,1981). While vocal components such as ultrasound vocalization(Blumberg, 1992; Burgdorf et al., 2005; Litvin et al., 2007) or alarmcalling (Brudzynski, 2005; Hollen and Radford, 2009) play a keyrole in communication at close proximity, olfactory componentsobtained via odorants provide complementary, and further qualita-tive information about the current state of a social partner. Auditorysignals exchanged with conspecifics or alarm cries of conspecificsare particularly important for group-living animals (Owings andMorton, 1998; Litvin et al., 2007; Hollen and Radford, 2009). Rapid-onset rapid-offset auditory signals are useful in acute emergenciesand real-time communication, while olfactory signals typicallyhave a delay between signal emission and reception (Eisenberg andKleiman, 1972; Brown, 1979). Such odor cues are shown to remainfunctionally for at least 24 h without the presence of odor owners inthe mouse (Hurst et al., 1998; Hurst and Beynon, 2004). Addition-ally, volatile chemicals and small molecules composed of odorantcues are able to disperse in air or water (Brown and Macdonald,1985; Brennan and Keverne, 2004). As a result, scent odors mayprovide information to a wider range of recipients concerning thelocations of animals that could no longer be present there (Brownand Macdonald, 1985; Blanchard et al., 2003; Hurst and Beynon,2004).

The laboratory rodent species utilizes odorant signals suchas scent marking (Brown and Macdonald, 1985; Arakawa et al.,2007b). They deposit scent marks from anogenital scent glandsor urinary components, thereby producing an individual odor sig-nature composed of rich information such as sex, social rank,sexual receptivity, hormonal status, and health/illness status ofodor donors (Mykytowycz and Goodrich, 1974; Natynczuk andMacdonald, 1994; Popik and van Ree, 1998; Stopka et al., 2007).Odor signatures also play a key role in the establishment of ter-ritorial boundary and mating processes (Hurst and Beynon, 2004;Arakawa et al., 2008b). Recent studies have indicated that the infor-mation contained in an individual odor signature depends on thedistance of the odor recipients to odor sources (Hurst et al., 2001).

2.2. Odor information process through volatile and non-volatilechemicals

Odorant chemicals can be grouped into airborne volatile andnon-volatile components (Brennan and Kendrick, 2006; Hurst,2009). Animals detect airborne scents by volatile chemical compo-nents and small airborne peptides via olfactory receptors primarilyin the olfactory epithelium of the main olfactory system (Brennanand Keverne, 2004; Broad and Keverne, 2008). This pathway causesthe detection of scents to be at some distance from their source.When animals detect scents in the air, the scent components areassessed based on their approximate adaptive value and stimu-late animals to either approach the source in order to gain furtherinformation, or to avoid the social source that may involve poten-tial dangers. In this way, the odor components inform conspecificsto about whether attraction or alarm would be an appropriateresponse to the conspecific. These airborne molecules are knownto contain information about genetic and sex differences (Schaeferet al., 2002; Keller et al., 2006a, b), age (Osada et al., 2003, 2008),and current health status such as stress (Mykytowycz and Goodrich,1974; Wheeler, 1976; Novotny et al., 1985; Schaal et al., 2003),parasitation (Kavaliers et al., 2000, 2005a), and illness (Yamazakiet al., 2002; Arakawa et al., 2010a). In contrast, non-volatile scentsare comprised of fixed information such as an individual’s geneticsignature, provided by proteins such as the major urinary proteins(MUPs) (Bacchini et al., 1992; Hurst et al., 2001, 2005; Armstronget al., 2005) and major histocompatibility complex (MHC) associ-ated peptides (Brown et al., 1987; Brown, 1995; Boehm and Zufall,2005; Lanyon et al., 2007).

In order to detect non-volatile components, animals must thenapproach and make nasal contact with the scent source indicat-ing an expenditure of energy and time consumption to gain furtherinformation (Keverne, 1999; Leinders-Zufall et al., 2000; Pankevichet al., 2004). When animals make nasal contact with a scentsource or a conspecific that releases odor, non-volatile moleculesof the odor source are pumped to, and detected mainly by, thevomeronasal organ of the accessory olfactory system (Meredith,1994; Halpern and Martinez-Marcos, 2003; Breer et al., 2006).Therefore, the detection of airborne scents may be necessary to acti-vate the delivery of non-volatile scent via the nasal pumping system(Hurst and Beynon, 2004; Keller et al., 2006a). Although recentfindings suggest that the main and accessory olfactory systemscan detect and process both volatile and non-volatile chemosig-nals (Restrepo et al., 2004; Spehr et al., 2006a), differences in thetype of chemosignals based on volatility appear to mediate specificbehavioral responses and, therefore, information gathering strate-gies would be altered based on the distance to the source of thesocial cues.

2.3. Body parts associated social investigation

When animals approach and make contact with a conspecific,they engage in intense social investigation that consists of sniffingand licking facial and anogenital areas, as well as other body parts(Grant and Mackintosh, 1963; Brown and Macdonald, 1985) (Fig. 1).Some of the behavioral postures described as social behaviors arestrongly associated with investigation strategies to exocrine bodyglands (Barnett, 1958; Blanchard et al., 1975, 1977, 1998). Giventhat non-volatile chemostimuli require active nasal pumping of airto be detected by olfactory receptors, it seems that animals detectnon-volatile chemostimuli as well as volatile molecules throughsniffing those body areas, each of which may produce differentialodor information.

Through detailed observation of social behavior in a semi-natural colony, it has been shown that mice display particularfeatures of social interaction; mice typically accept approaches to

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Fig. 1. Distance-based olfactory communication through chemosignals. (A) At a distance, animals would detect olfactory cues released from conspecifics. One of thesesocial cues, airborne volatile molecules, may involve information regarding attractant and alarm components about odor owners. The odor recipients may decide whetherto approach to or avoid the odor source. (B) If animals approach the odor source or conspecifics, animals would engage in nose-contact-based investigation to the odorsource. Odor recipients are able to pump up non-volatile molecules by nose-contact sniffing. The scent owners have several exocrine glands containing substantial chemicalinformation in the facial and anogenital areas. In the facial area, lacrimal, Harderian, and submaxillary glands as well as salivary glands are involved in chemosignal release,while breath from the mouth and muzzle also includes chemical information. In the anogenital area, the preputial, coagulating, and vaginal glands are significant sources forchemosignals, and anogenital secretion including urine, feces and vaginal and seminal fluids are a rich source for odorant signaling molecules. Depending on the body partsof these exocrine sources, approaching animals show typical behavioral postures of investigation as social behavior, and display behavioral responses to these chemosignalsas social communication.

their facial area, while they display avoidance to being approachedto the back area of the body (Arakawa et al., 2007a). This tendencyis consistently found in male same-sex and mixed sex colonies,as well as in juvenile male colonies (Blanchard et al., 2009). Thisindicates that an approach to the front of the body may be non-aversive, while approach to the back may be aversive. Thus, physicalinvestigation between mice involving the face and neck areas isshown more frequently and for longer periods of time than tothe anogenital area in short-term observations (Luo et al., 2003).This suggests that animals receive information that allows themto engage in distinctive interaction depending on the body partswhich are contacted such as front (facial) and back (anogenital)areas.

Male mice have two main glands in the anogenital area that areinvolved in scent communication. The preputial glands are locatedin front of the genitals and are thought to produce chemosignals(Bronson and Caroom, 1971; Novotny et al., 1990), and this glandhas been shown to contribute aggression-promoting chemicals tomouse urine (Novotny et al., 1985; Ingersoll, 1986; Chamero et al.,2007). Preputial hypertrophy results in male mice odor recipi-ents expressing aggressive behaviors (Hucklebridge et al., 1972;Bronson and Marsden, 1973), whereas preputial atrophy resultsin male mice odor recipients expressing subordinate behaviors(McKinney and Christian, 1970; Brain et al., 1991). These results

suggest that preputial extracts may promote the maintenance ofsocial status between males (Parmigiani et al., 1981; Thompsonet al., 2007). Another pair of glands that function similarly is thecoagulating glands which are found together with the large semi-nal vesicles and are involved in producing both a sperm coagulantand chemosignals (Cukierski et al., 1991). The coagulating glandsecretion is thought to contribute an aversive component to urine(Jones and Nowell, 1973a, 1974) as well as a reduction in aggression(Jones and Nowell, 1973b).

Although odor chemicals initially produced by the anogenitalarea might be transferred to the head by grooming, exocrine secre-tion from glands found in the facial area such as the Harderianglands and the submaxillary and salivary glands are also capableof stimulating the olfactory receptors of sniffing conspecifics. TheHarderian glands are located near the eyes and produce a lipidcontaining porphyrins, when the animals are stressed (so-calledporphyrin staining; Shanas and Terkel, 1996; Chen et al., 1997).This excretion from the Harderian glands has been found tohave a pheromonal effect on proceptive behaviors in hamsters(Payne, 1977; Thiessen and Harriman, 1986). On the other hand,the lacrimal glands are paired exocrine glands that sit alongsidethe eyeball within the orbit, nestled in the lacrimal fossa of thefrontal bone and secrete lacrimal fluid (Dulac and Torello, 2003;Thompson et al., 2007). Exocrine fluid from lacrimal glands has

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been shown to promote aggression in male mice (Thompson et al.,2007). Moreover, Kimoto et al. (2005) demonstrated that a peptidefrom the lacrimal gland of a male mouse is able to stimulatevomeronasal sensory neurons in the female mouse. Various glandsin the head and neck including the salivary glands were shownto express a variety of androgen binding proteins (Laukaitis et al.,2005). These proteins, produced by the salivary glands, mediatemate preference (Laukaitis et al., 2005) and sexual communication(Wickliffe et al., 2002), indicating that the chemosignals are alsolocated in the facial area of rodents, which is involved in a nasalcontact communication process.

In addition, sniffing the facial areas, especially around the muz-zle, brings information about the recent activities of the conspecific,is generally associated with recent food ingestion (Galef, 2002).This type of sniffing is usually observed when considering thesocial transmission of food preference in rodents because of thepresence of a volatile substance such as carbon disulfide (CS2),which is naturally carried in the exhaled breath of rodents, in addi-tion to the recently eaten food odor (Galef and Wigmore, 1983;Bean et al., 1988; Galef and Whiskin, 1998). The increase in therelative frequency of muzzle exploration leads to the investiga-tion of the functional relevance in this modification, passing oninformation regarding safe food by smelling it on another ani-mal’s breath (Valsecchi and Galef, 1989; Gass et al., 1998; Wrennet al., 2003). This social transmission phenomenon, once again,indicates the significance of facial investigation in social con-text.

Following the acquisition of information, animals establishsocial relationships by displaying affiliative behaviors such as hud-dling. Huddling occurs in many different environments but mainlyin a nest if available (Kareem and Barnard, 1982; Kareem, 1983;Van Someren, 2006). This behavior consists of animals in closebodily contact while they either sleep or engage in allogrooming(Arakawa et al., 2007a). Huddling is observed after a few hoursof colony formation and is constantly displayed at 30–40% oftime during the animals subjective day and at over 70% of timeduring subjective night of observation time (Mondragon et al.,1987; Arakawa et al., 2007a). A function of huddling may be ther-moregulation (Batchelder et al., 1983; Jans and Woodside, 1990),but it is noteworthy that animals who engage in huddling spenda considerable amount of time in allogrooming, which is con-sidered to be a component of affiliative behaviors (Vale et al.,1971; Mondragon et al., 1987; D’Amato, 1997). Given that, itseems likely that the tactile sense plays a key role for regulat-ing social behavior between familiar conspecifics. For instance,Dvi1 knockout mice display tactile and sensorimotor abnormal-ities, which thus show a significant deficit in huddling withfamiliar conspecifics (Lijam et al., 1997; Long et al., 2004). In addi-tion, olfactory bulbectomy showed little impact on social contacttoward familiar partners (Alberts and Galef, 1971; Edwards et al.,1990).

The investigatory strategies in which animals engage duringa social context could be described based on the physical dis-tance; in the far distance, animals detect and recognize socialstimuli, making a decision for further approach/avoidance behav-iors to a source of social stimuli, while in the contact distance,animals engage in social interaction with individual partners toassess further social features elicited by several specific bodyparts that are investigated. In the following section, therefore,we will focus on the sensing of airborne chemosignals that carryinformation on the health condition of odor donors. Recent workhas demonstrated that the health information contained in odorscent powerfully modulates the social behavior and relationshipsof rodents without direct contact to the odor source; thus, thisrecognition system facilitates adaptation to prevent infection frominfected conspecifics.

3. Communication of health information via odorant cues

3.1. Odor recognition of parasitized conspecifics

For a wide range of animals, especially social species, healthstatus including being parasitized or infected significantly influ-ences their social behavior and organization (Hart, 1990, 1992;Penn and Potts, 1998a). Animals prefer to contact, and are attractedby, parasite-free or healthy conspecifics, while generally avoid-ing sick conspecifics (Kavaliers et al., 2000, 2005a; Choleris et al.,2009). Because social behavior facilitates interaction between con-specifics, these behaviors can increase the transmission of parasitesfrom infected to susceptible individuals (Hart, 1990, 1992; Klein,2003, 2005). Therefore, various parasites including microparasites(e.g., viruses, and bacteria) and macroparasites (e.g., protozoan,helminth, and arthropod parasites), can exploit the proximatemechanisms that modulate social behaviors in animals to increasethe likelihood of transmission (Kavaliers et al., 1997; Moore andWilson, 2002; Vyas et al., 2007). In many cases, these mecha-nisms involve direct manipulation of host behavior to increasecontact between infected and susceptible individuals, involvinginflammatory immune responses, and altering the chemical signalsand endocrine secretions that underlie the expression of behav-ior. For instance, infection with Toxoplasma gondii is known toinduce behavioral alterations in both humans and rodents, such asan increase in exploratory behavior and a decrease in willingnessto accept normal inter-individual social solicitations (Arnott et al.,1990; Berdoy et al., 2000). Infected rodents show higher propensityto explore novel stimuli in their environment than uninfected indi-viduals, and are thus more active and more easily caught (Kavaliersand Colwell, 1995a; Klein et al., 1999; Klein et al., 2004; Vyas et al.,2007).

Parasites have evolved a wide range of subtle and sensitivemechanisms for locating and invading their host. In response, thehost has evolved remarkable defense strategies to avoid contactwith, and to reduce the deteriorating impact of, the parasites inor on their individual bodies. Grooming is a typical strategy usedto remove ectoparasites or pathogen from body/fur and one thatincreases the fitness of the host (Hart, 1990, 1992, 1994). Mice, forinstance, have specialized lower incisors teeth that are capable ofa lateral closure which effectively combs ectoparasites away fromthe fur (Murray, 1987; Hart, 1994, 2000). Another, effective strategythat is used to avoid contagion is to detect and recognize infectedanimals at a distance and avoid direct contact (Hart, 1990; Able,1996; Kavaliers et al., 2000). Olfactory information is a useful toolfor guiding the recognition of parasitized conspecifics and adjust-ing their responses to possible contagion, given that animals useodors to determine the quality and health condition of potentiallyinfected animals (Kavaliers et al., 2000; Thomas et al., 2005).

3.2. Aversive odor released from infected animals

Parasite recognition exists in several species showing that odorsfrom parasitized animals induce an avoidance response in con-specifics (Getty, 2002; Kavaliers et al., 2005a; Thomas et al., 2005).This infection-associated odor suggests that chemosensory signals,such as urinary scent, directly advertise an individual’s health andother aspects of the quality and health condition to rivals andpotential mates (Penn and Potts, 1998a; Zala et al., 2004). In alandmark paper, Hamilton and Zuk (1982) proposed a hypothe-sis, stating that animals should inspect both urine and fecal odorof a potential mate, by which a female should preferentially selectthe parasite-free or parasite-resistant males. The results of odorpreference studies in rodents have demonstrated that a wide arrayof infections, from gastrointestinal nematodes to viruses, influencethe odors of infected individuals and that females show a reduced

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preference for odors from infected males (Kavaliers and Colwell,1995b; Klein et al., 1999; Willis and Poulin, 2000; Ehman and Scott,2001, 2002).

This readily observed behavioral feature of avoidance to thescent odor of infected males is not associated with females’ ulti-mate mate choice as expressed by sexually receptive behavior.Avitsur et al. (1997a, 1997b, 1999) indicated that female rodentsequally show receptive behavior toward infected and non-infectedmales, although they can discriminate and avoid the scent odor ofinfected males. Several researchers have reported that an infectionhas no effect on the sexual receptiveness of a female partner, whichindicates that the initial preference to an odor does not correlatewith the ultimate mate choice made by the female (e.g., Bilbo et al.,1999; Klein et al., 1999; Ehman and Scott, 2002). This phase-basedfeature of behavior indicates that olfactory information associatedwith infection (danger) plays a critical role in regulating behaviorduring the initial investigation.

Given the key role of health-related odors for determining matechoice, and because mate choice is rarely performed by males,there are few studies investigating the influence of female odorcues signaling to male recipients during times of acute illness orparasitation. However, males also face the threat of parasitic infec-tion during social interaction (Moore and Wilson, 2002; Hinsonet al., 2004). Male mice showed a preference for uninfected femalesrather than for those infected by the nematode, Trichnella spiralis(Kavaliers et al., 1997, 2004). It has also been reported that malemice displayed analgesic responses to the odors of infected femalesas a defense response (Kavaliers et al., 1998). Aversive responseswere also observed in male mice when they were confronted withthe odors of infected males or males that were associated withthe odors of infected males (Kavaliers et al., 2004). As such, theuse of odor information for the discrimination and avoidance ofinfected conspecifics is equally significant for males and females.Accordingly, wild-caught animals are often infected and subse-quently develop antibodies throughout their lives (Klein, 2003;Hinson et al., 2004). In wild-caught rodents, infection as well as theincidence of wounding is higher among adult males than amongconspecific females or pre-pubertal males (Glass et al., 1988; Kleinet al., 2004), indicating that infection of adult male rodents maylikely occur during aggressive encounters (Hinson et al., 2004).

3.3. The relationship between illness-associated odor cues andcytokines

Infection-induced alterations in odor may be a pathologicalbyproduct of infection, or an adaptive response to cope with infec-tion (Thomas et al., 2005). Although several parasites have beenshown to manipulate endocrine function, behavior, and probablythe odor of their hosts (Kavaliers et al., 1997; Klein, 2000; Vyaset al., 2007), the fact that a wide array of infections influencesodor properties suggests a common mechanism. As it develops,certain odor cues or chemicals are released and consequentlylead to the induction of an aversive response in odor recipients.When parasites invade tissue, the host animal mounts an inflam-matory response which orchestrates bodily defenses against theoffending pathogen (Roitt et al., 1998; Kristensson et al., 2002;Zuk and Stoehr, 2002). This immune response is accompaniedby activation of general stress responsive systems, including thehypothalamus–pituitary–adrenal (HPA) axis and sympathetic ner-vous system (Barnard et al., 1996; Morales-Montor et al., 2001;Corrêa-de-Santana et al., 2006). As a result, it is important to dis-criminate between odor signatures that are a direct consequenceof inflammation (i.e., ones that are inflammation-dependent) andodor signatures that more generally reflect activation of the stressresponse (i.e., alarm-related substances or attraction).

Induction of proinflammatory cytokines appears to play animportant role in innate immune defense (Dantzer et al., 1991;Dantzer, 2004). Proinflammatory cytokines such as interleukin-1beta (IL-1!) and tumor necrosis factor alpha (TNF-") in theCNS produce a complex pattern of behavioral changes that aid inrecovery and survival following infection, which has been termedsickness behavior (Kent et al., 1992a; Aubert, 1999; Dantzer, 2001).This complex pattern of behavioral changes includes a reduction insocial and sexual motivation (Dinarello, 1988; Bluthé et al., 1991)and reduced activity/exploration (Spadaro and Dunn, 1990), whichare accompanied by physiological symptoms such as hyperther-mia (Krueger and Johannsen, 1989; Obal et al., 1990) and anorexia(Bluthé et al., 1989; Kent et al., 1992b, 1996). Because cytokine sig-naling appears to be the common biological mechanism controllingthe expression of sickness behavior in response to a diverse range ofpathogens (Dantzer, 2004), several studies have begun to examinethe potential role of cytokines as key mediators of illness-relatedodor signatures. In this sense, cytokines may profoundly influencesocial behavior in rodents by (i) directly reducing the motivationto engage in social interaction of the sick individual, while at thesame time (ii) inducing the release of illness-related, aversive odorcues, thereby signaling to would-be social partners to “stay at ahealthy distance”. This later, indirect mechanism by which illnessinfluences encounters has only recently been taken into account,and requires a more comprehensive experimental approach wherethe behavior of the healthy conspecific must be considered, not justthat of the sick individual.

With that said, infection by a parasite (relative to bacteria orviruses) requires specific consideration because parasites induceneuroendocrine alterations in the host, and are not always accom-panied by systemic inflammatory responses beyond the initialstage of infection (Fiore and Aloe, 2001; Klein, 2003). In addition,sickness behaviors are not observed as a universal response in ani-mals subclinically infected with the parasite, and the subsequentphysiological and behavioral responses in the host animals canvary depending on the parasite (Kraaijeveld and Godfray, 1997;Adamo, 1998; Morales-Montor and Hall, 2007). This is relevantin the present context because most of the literature surround-ing illness-related odor cues has come from studies using parasitesrather than bacterial/viral infection models. A parasite can inducespecific symptoms, which may modify non-specific inflammatoryresponses in a time-dependent manner (see reviews by Klein,2003; Thomas et al., 2005). Specifically, parasite infection appearsto modulate behavior only during the early phase of infection,not for the entire period of parasitation (Kavaliers et al., 1997;Elsen and DeNardo, 2000; Morales-Montor et al., 2001). Interest-ingly, parasites are able to produce immuno-modulatory moleculessuch as !-endorphin that decrease the immune response of thehosts (Salzet, 2000; Maizels et al., 2004). It should be noted alsothat many bacteria thrive (proliferate) in the presence of host-derived hormones such as epinephrine and norepinephrine, which,as described previously, are released during the acute phase ofinfection (Vlisidou et al., 2004; Freestone et al., 2008; Sandriniet al., 2010). Therefore, at least during the early phase of infec-tion, an inflammatory cascade is likely to predominantly modulatebehavior in host animals.

3.4. Inflammation-driven odor cues

Bacterial lipopolysaccharide (LPS) is widely known to induceactivation of the innate immune system as well as behavioral andphysiological modification such as sickness behavior (Hart, 1988;Kent et al., 1996; Aubert et al., 1997; Aubert, 1999). Recently, wedemonstrated an avoidance response of rats to the airborne odorcues released by sick animals (Arakawa et al., 2009c). Interestingly,this avoidance was observed in both male and female rat recipi-

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Fig. 2. Differential patterns of sniffing investigation depending on accessibility to odor source in male rats. (A) In an odor investigation test, where animals are exposed tosaline-moisturized bedding (No odor) or odored bedding collected from stimulus rats given saline (Saline) or LPS (100 #g/kg, ip), male rats showed substantial sniffing tosaline odor, but not to LPS odor (left panel). Additionally, rats displayed greater avoidance (location at farside) toward LPS odor, indicating clear aversion to LPS odor (rightpanel). (B) In a social investigation test, animals are placed into separated cages and allowed to investigate a wire-meshed hole connected to another section of the chamberin which a stimulus animal is placed for 10 min (developed by Panksepp et al. (1997); see also Deak et al., 2009). This task demonstrated that stimulus animals given salineshowed remarked sniffing to the hole, but those injected LPS (100 #g/kg, ip) 4 h prior to the test showed sickness behavior thus with lower sniffing to the hole. Healthysubjects displayed sniffing to the hole when saline-injected stimulus animals were placed to another side, but did not when no animal (Control) or LPS-injected stimulusanimals were used. (C) In social interaction test, healthy subjects were introduced into the cages with stimulus animals that received saline or LPS (100 #g/kg, ip) injection4 h prior to the test for 10 min. Rats given LPS injection showed lower frequency of sniffing approaches, but healthy subjects showed similar level of sniffing approachestoward saline-injected with LPS-injected animals. The comparison of behavioral features in three different situations suggests that odor cues released from sick animals (LPSinjected) are effective to induce avoidance when animals are not able to contact the odor donors, while those illness odors do not modulate behavior when animals are ableto engage in full physical contact with the odor donors.

ents (Arakawa et al., 2009c). When separated by a partition usinga wire-meshed small hole to permit investigation while restrictingphysical contact (Arakawa et al., 2009a; Deak et al., 2009), malerats reduced sniffing and activated burying behavior toward thehole when confronted with LPS-treated rats (Arakawa et al., 2009c)(Fig. 2). However, when male mice are in a social interaction situa-tion (also in rats; Fig. 2), a healthy familiar partner did not expressany reduction in contacts, but continued to share a common nestwith their sick nest-mates (Renault et al., 2008). The odor sensi-tivity of the avoidance response suggests that airborne odor per sereleased from LPS-treated animals contains aversive signals.

This aversive response was also observed when the stimulusanimals received an LPS infusion into the third ventricle of thebrain (Arakawa et al., 2010a), indicating that the release of uri-nary LPS following peripheral injection is probably not a necessarycomponent of illness-related odor signals and suggests that initi-ation of a central inflammatory cascade may play a key role. Thisis supported by a study which shows that activating an inflamma-tory cascade by injecting mice with foreign antigens (sheep redblood cells) (Moshkin et al., 2002) or by injecting female mice withIL-1! (Avitsur et al., 1997a), reduced the attractiveness of their bed-ding to conspecifics. Additionally, the bedding collected from malerats injected centrally with IL-1! induced an avoidance responsein healthy male rats (Arakawa et al., 2010a). This inflammationeffect was confirmed by a study showing that ICV injection of IL-10,a cytokine with well-documented anti-inflammatory properties,strongly attenuated systemic LPS-induced aversive odor release

(Arakawa et al., 2010a). Together, these studies provide compellingevidence for the involvement of central inflammatory processes inthe release of illness-related aversive odors in male rats.

The involvement of central cytokines in the release of aversiveodor cues is supported by a parallel line of experiments where theeffects of non-pathogenic stressors have been examined. Specifi-cally, exposure to psychological stress challenges such as footshockproduce well-documented changes in brain cytokines (Deak et al.,2003; Blandino et al., 2006; Arakawa et al., 2009a) and other inflam-matory markers (Blandino et al., 2009) in brain that are indicativeof stress-dependent neuroinflammation. This stress challenge alsoleads to a profound reduction in social investigation that wasreversed by pretreatment with IL-1 receptor antagonist (Arakawaet al., 2009a). At least some of the effects of central inflammationon social behavior can be explained by the release of aversive odorcues, since the odored bedding collected from stressed rats led to anavoidance response in naïve conspecifics. Importantly, these effectswere blocked by central administration of IL-10 prior to stressorexposure (Arakawa et al., 2011). Together, these findings provideconverging lines of evidence to support the role of central inflam-matory processes in controlling the release of illness-associated,aversive odor cues.

Several studies provide evidence that female odors have differ-ent characteristics than male odors when directed toward maleconspecifics. Airborne odors of female rats that are associatedwith health status are also effective in modulating the behav-ioral response of male rats (Avitsur et al., 1997a, 1999; Avitsur

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and Yirmiya, 1999a,b). Airborne odor cues of LPS-injected intactfemales decreased sniffing, but not avoidance in male recipients(unpublished data). The odor cues of females associated with anillness state are likely less attractive, unlike those of males whichare typically aversive for male odor recipients. It is well knownthat male rats are able to discriminate odor changes in femalesof different stages of the estrous cycle and those that have under-gone ovariectomy (Stern, 1970; Pietras and Moulton, 1974; Brown,1988). Odor cues collected from ovariectomized females clearlyinduced avoidance responses in males (Brown, 1988; unpublisheddata). However, LPS infusion into ovariectomized females had lit-tle effect on female odor properties (unpublished data). The sexdifferences in odor profiles suggest that female odor properties dur-ing infection are largely dependent on ovarian hormones, but notinflammatory cascades. Unlike sick males, induction of proinflam-matory cytokines such as TNF-", IL-1! and IL-6 in the CNS andcirculation were not associated with odor properties of stimulusfemale rats (unpublished data), which suggests that the expressionof inflammatory cytokines following an LPS challenge has no directinvolvement in regulating odor properties of female rats duringacute illness.

Interestingly, it seems that pre-pubertal males do not releaseillness-associated odors if they have been injected with LPS. Whenadult male rats were exposed to airborne odor cues collected frompre-pubertal males (postnatal days 28) injected with LPS injection(100 #g/kg), adult males showed little aversive response to the odorcues unlike to those collected from adult rats injected with LPS(Arakawa et al., 2009c). These low levels of aversiveness to odorcollected from LPS injected pre-pubertal males were even evidentwhen pre-pubertal were injected with a 10-fold higher concentra-tion (1000 #g/kg) of an LPS (Arakawa et al., 2009c) or when theodored bedding was collected and mixed from three pre-pubertalmale’s samples that had received LPS injections (unpublished data).This indicates that a lower concentration of scent in bedding col-lected from pre-pubertal males could not account for the odorproperties of LPS-treated, pre-pubertal males. In addition, thediminished aversiveness of odor from pre-pubertal males was con-sistently reported in a previous study using pups; LPS treatment inpups provoked licking by their mother rats, but induced no differ-ences in the pup retrieval (Breivik et al., 2002). This indicates thatmothers recognize differences in pups given saline and LPS, yet thedams did not avoid contact with these LPS-treated pups.

Considering the function of odor scent to signal specific informa-tion to conspecifics, the differential responses to odor cues collectedfrom pre-pubertal and adult males that were given LPS suggeststhat an alarm scent of pre-pubertal males plays a small role in func-tional signaling to conspecifics. In a natural environment, whilepre-pubertal males live in their nest with siblings and dams, adultmales immigrate to a new place and form their own territories withboundaries to other conspecifics (Lloyd, 1975; Butler, 1980; Laceyand Sherman, 2007). Given those living conditions, it seems that therelease of illness odors would be beneficial in adulthood but not inpre-puberty, in terms of an adaptive strategy to prevent the spreadof infection from infected animals. This developmental trajectory inodor signaling may be associated with defensive strategies in whichmale rodents develop typical features of territorial and defensivebehaviors through social interaction during puberty, and appearto display adult-like strategies after puberty (c.f. Arakawa, 2006,2007a, 2007b; Wiedenmayer, 2009).

3.5. Possible mechanisms for signaling illness state in airborneodor

Airborne odor scents associated with an illness state may be pri-marily released from exocrine glands in facial and anogenital areasand into their urine and/or feces (Yamazaki et al., 2002; Hurst and

Beynon, 2004; Arakawa et al., 2008b, 2009c). Thus, there are a num-ber of paths by which an airborne odor cue can signal an infection orhealth status. An infection might induce alteration of the intestinalflora through changes in the composition of communal microbes(the so-called microflora hypothesis; Howard, 1977; Schellincket al., 1991). Immune challenges induce gut motor function alter-ations that include inhibition of gastric emptying, stimulation ofcolonic propulsive motility, and hypersensitivity to colorectal dis-tension (Tache et al., 2001; Stengel and Tache, 2009). Therefore,induction of inflammatory cascades can activate defecation ofless digested excrement (Conte et al., 2006). Sick animals usu-ally deposit diarrhea-like feces in which less digested or degradedmicroflora production are involved (Brown and Schellinck, 1995).Animals are able to detect gut products through olfaction includ-ing guenylin (Leinders-Zufall et al., 2007) and microflora product(Schellinck et al., 1991; Brown and Schellinck, 1995; Migeotte et al.,2006). Production of microflora may be involved in the release ofairborne compounds from animals in an illness state, although littleis known about mechanisms that produce such chemicals in urineor feces. In addition, the most abundant products of metabolismthat occur in urine and feces are acidic (Chalmers and Lawson,1982), and such volatile acids are identifiable by many mammals(Gorman, 1976; Zeng et al., 1996). The increase in acidity of urineand feces from animals during an acute illness state may be asso-ciated with changes in airborne odor signals (Singer et al., 1997).

Another possible indirect effect of infection on odor cues maybe explained by scent marking communication. Rodents use scentmarking for social signaling (Bowers and Alexander, 1967; Brownand Macdonald, 1985; Arakawa et al., 2008a). Both sexes of animalsutilize scent marks as an odorant display for sexual appeal and terri-torial boundaries (Ralls, 1971; Hurst, 1993; Arakawa et al., 2007b),which results in alternation of approach/avoidance responses inconspecific odor recipients (Hurst and Beynon, 2004; Arakawa et al.,2007b, 2008a). Infection may act indirectly, causing the infectedmale mice to scent mark at a lower rate (Zala et al., 2004), thereforedisplaying their poor health to the conspecifics through decreasedmarking abilities (scent marking hypothesis: Coblentz, 1976). How-ever, it is clear from subsequent studies that the quantity of urinaryscent plays less of a role in regulating social responses, while thequality of urinary scent significantly modulates odor communi-cation (cf. Hurst et al., 1993; Arakawa et al., 2009b). Indeed, thequantity of urine and defecation is much greater in sick animalsthat receive LPS when compared to healthy animals.

Although the means by which infection alters urine or otherodors remains unclear, two possible mechanisms and/or somecombination of these mechanisms have been proposed; (i) modifi-cation of hormone levels, specifically decreased testosterone levelsfollowing infection might produce a less attractive or aversive odorprofile (Penn and Potts, 1998a), or (ii) activation of the inflamma-tory cascade might induce changes in immune- related genes suchas major histocompatibility complex (MHC) and its metabolites, toproduce aversive odor (Knapp et al., 2006).

3.5.1. Steroid hormone modulation of illness-associated odorSince males often show lower levels of testosterone during

infection (Hillgarth and Wingfield, 1997; Barnard et al., 1998; Kleinand Nelson, 1999; Wingfield et al., 2001; Barthelemy et al., 2004),those lower levels of testosterone might influence conspecific odorsignaling and ultimately approach/avoidance tendencies towardthe odor cues by conspecifics. Urine from intact adults appearsto have an aversive property since males usually decrease theirinvestigation toward urine from intact males when compared tourine from castrated males (Jones and Nowell, 1973a, 1973b).Testosterone replacement in castrated males restores these aver-sive properties (Jones and Nowell, 1973a; Sawyer, 1980), indicatingthat the aversive properties of urinary signals are likely to be asso-

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ciated with an increase in testosterone concentration (Jones andNowell, 1973a, 1973b; Evans and Brain, 1978). Accordingly, urinefrom dominant males, which display higher testosterone level thansubordinate males (Blanchard et al., 1993; Barnard et al., 1996),provokes avoidance tendencies in adult males when compared tothose from subordinate males (Jones and Nowell, 1989; Novotnyet al., 1990; Hurst, 1993).

From a slightly different perspective, it is important to note thattestosterone metabolites (including estradiol) play an inhibitoryrole on the LPS-stimulated inflammatory response (Folstad andKarter, 1992; Gaillard and Spinedi, 1998; Barreto et al., 2007). Ithas been reported that central injection of IL-1! (Turnbull andRivier, 1997) or systemic injection of LPS (Arakawa et al., 2010a)significantly decreased circulating testosterone levels. Conversely,testosterone treatment reduced the inflammatory responses pro-duced by LPS administration (Litvinova et al., 2005; Barreto et al.,2007). Estradiol also reduced expression of inflammatory cytokinesin adult male rats that were administered a systemic LPS infu-sion (Blanco-Rodríguez and Martínez-García, 1998; Baker et al.,2004; Barreto et al., 2007). The over-arching picture that emerges,therefore, is a trade-off in adult males between testosterone con-centration, which is associated with sexual attractiveness andterritoriality, versus immune defense, which is associated withinflammatory activity, aversive odor signaling, and suppressedtestosterone release (Barnard et al., 1998; Klein, 2000). In theapproach/avoidance paradigm, testosterone treatment to intactmales had little effect on the aversive property of their urinaryodor, while the testosterone or estradiol treatment into LPS treatedmales caused a decrease in avoidance of their bedding by healthyconspecifics (Arakawa et al., 2010a). This aversive property of theairborne odor was not associated with circulating testosteroneor corticosterone levels, but with circulating IL-1! level in theodor donors (Arakawa et al., 2010a). Therefore, testosterone andits metabolites appear to have an inhibitory effect on the releaseof aversive odor cues from LPS-treated rats, which appears tooccur through interaction with inflammatory processes rather thanthrough traditional gonadal steroid-dependent mechanisms.

Traditionally, corticosterone has been considered as a candidatefor odor mediation (Mackay-Sim and Laing, 1980, 1981; Fanselow,1985; Barnard et al., 1994), because stressed animals release air-borne odor cues that signal alarm to conspecifics (Mykytowycz andGoodrich, 1974; Novotny et al., 1985; Blumstein, 1999; Schaal et al.,2003). Because stress increases corticosterone levels, it is possiblethat the alarm-related chemosignals released from stressed ani-mals originate from products of the HPA axis or corticosteronesecretion itself (Cocke and Thiessen, 1990). Corticosterone alsohas potent anti-inflammatory effects (Guyre et al., 1984; Barnumet al., 2008) and is associated with aggression in rats (Blanchardet al., 1993; Mikics et al., 2007). However, not all chemosignaleffects require the involvement of adrenal steroids (Abel et al.,1992; Abel and Bilitzke, 1992), since adrenalectomized rats do notdiffer from sham controls in production or secretion of aversivechemosignals (Abel and Bilitzke, 1992). Corticosterone infusionsinto rats produced little if any impact on investigatory behavior ofodor recipients (Arakawa et al., 2011), and the avoidance responseof male rats to scent odor was not correlated with plasma corti-costerone concentration of the odor stimulus animals (Arakawaet al., 2010a). This may support the hypothesis that corticosteronesecretion resulting from HPA axis activation may be indepen-dent from the mechanism for releasing illness-associated aversiveodors. Alternatively, it is possible that illness-related odor cuesare more salient than alarm-related cues. Regardless, emergingevidence supports the view that illness state is associated with aunique odor bouquet that appears to be distinct from other knownodor-signaling mechanisms such as gonadal steroids and stresshormones.

3.5.2. Immune cascade mediation in odor: MHC class I moleculeshypothesis

Based on the above discussion, it is conceivable that activa-tion of the inflammatory response leads to changes in body odorbecause of the metabolic alterations induced by immunologicalactivity. IL-1! is considered to be one of the central mediators ofinflammatory reactions (Dinarello, 1988; Dantzer, 2001, 2004). Ofthe many roles that IL-1! plays in the inflammatory response, theone most relevant in the present context is its ability to upregulateMHC class I expression on various cells (Wicks et al., 1992; Nagarajuet al., 1998). Interestingly, the highly polymorphic genes of MHC areknown in the immune response to pathogens (Klein and Figueroa,1986) and in odor regulation for mate recognition, in which femalemice are able to recognize familiar mates through dissimilarities inodor from mice having different MHC types (Yamazaki et al., 1976,2002; Beauchamp and Yamazaki, 2003). Female rodents show preg-nancy failure when they detect male odor involving different MHCtypes from that previously mated males possess (Yamazaki et al.,1976; Yamaguchi et al., 1981; Singh et al., 1987). This pregnancyblock may occur through the detection of MHC-ligand peptidesthat are likely signals of genetic individuality (Milinski et al., 2005;Restrepo et al., 2006). A number of studies have shown that theMHC-dependent odors are volatile compounds (Beauchamp et al.,1985; Penn and Potts, 1998b), indicating that MHC-related compo-nents could play a role in the release of chemosignals, or serve asodor cues themselves. Although the exact nature of the chemosen-sory cues involved has remained elusive (Boehm and Zufall, 2005;Spehr et al., 2006a), the most common hypothesis for volatile trans-mission of MHC-related odor is that MHC class I molecules aredegraded into waste products small enough to become evaporatingmolecules in urine and feces (Pearse-Pratt et al., 1992; Singer et al.,1997; Knapp et al., 2006; Kwak et al., 2010), and/or result in MHC-specific communities of microbial flora (Howard, 1977; Schellincket al., 1991; Beauchamp and Yamazaki, 2003). Fragments of theMHC class I molecules are found in serum, saliva, sweat and urine,although the peptides bound to the MHC class I molecules are alsoreleased intact (Knapp et al., 2006). It is thus hypothesized that MHCclass I molecules that are activated by IL-1! can be excreted througha variety of metabolic mechanisms, and that the related moleculesreleased will be degraded into specific volatile molecules that serveto signal illness-related conditions (Fig. 3).

Recently, some of the specific odor molecule receptors havebeen identified and agonists of each are molecules associated withwaste products of inflammation, wounds, and disease reactions(Migeotte et al., 2006; Le et al., 2007; Riviere et al., 2009). Inaddition, Leinders-Zufall et al. (2000, 2004) found that moleculesderived from MHC class I peptides are detected by both theolfactory receptors in the main olfactory epithelium and thevomeronasal organ (see also Spehr et al., 2006b). The vomeronasalorgan plays a critical role in mediation of kinship recognitionthrough MHC gene types (Yamaguchi et al., 1981; Li et al., 1989,1990; Ehman and Scott, 2001; Brennan, 2004), yet little is knownabout the role of the main olfactory epithelium with respect tochemoreception of MHC peptide compounds (Spehr et al., 2006a;Kwak et al., 2010). Nevertheless, this suggests that MHC-relatedmolecules are degraded and separated into volatile and non-volatile molecules, which may be processed through differentsensory organs, thereby serving multiple different functions. Itmay be noteworthy that the presence of the MHC-ligand peptidesalone is not sufficient to induce pregnancy failure in females, butinstead must be combined with a male odorant signal (Leinders-Zufall et al., 2004; Milinski et al., 2009). Notably, females are notlikely to produce such MHC-associated signals (Milinski et al.,2009). These recent findings seem to be consistent with the find-ings for illness-associated odors, in which only males show anassociation of inflammatory responses with the release of the

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Fig. 3. Proposed dual function of inflammation in regulation of social behavior. Par-asites and pathogens induce an inflammatory response in the host as an immunedefense. The induction of IL-1! as part of the inflammatory response may acti-vate the expression of MHC class I molecules in various cells of the host. The wastemolecules such as degraded MHC-related peptides are metabolized and excretedthrough exocrine glands and urine/feces. These molecules are released into the airas an airborne odor signal and detected by conspecifics, which in turn induces sup-pression of social contact from the odor recipients. At the same time, IL-1! expressedin the CNS induces sickness behavior in the host animals, which manifests as reducedsocial motivation on the part of the sick animal.

aversive odor. Further studies are needed to identify specific path-ways that release inflammation driven volatile odors, as well asthe neural mechanisms for detecting and processing these odorcues that integrate into innate, adaptive behavioral responses(e.g., Arakawa et al., 2010b). Regardless of the identification ofspecific illness signaling molecules, the fact that these odors areinflammation-dependent illustrates the significance of inflamma-tion for understanding olfactory-based communication in socialspecies.

4. Conclusion

A distance-based process of social behavior provides a usefulview to describe and understand the complex nature of social inter-actions. When at a distance to a social situation, animals pursuedetection of social cues then assess those social cues to form asubsequent strategy, culminating in approach or avoidance behav-ior. The behavior is determined based on attractant and alarmcomponents contained in airborne odor that have been investi-gated, which may prevent direct contact to a potential danger. Anapproach to the source of the social cues results in a subsequentcontact-based investigation that allows for additional gathering ofinformation about a specific individual. In this manner, odor cuesoften become the definitive cue for the nature of the social interac-tion experience that ensues.

Airborne alarm odors appear to reflect a wide range of physio-logical states that include bacterial, viral or parasitic infections, aswell as more general states of distress that do not directly involveinfectious processes (Mykytowycz and Goodrich, 1974; Wheeler,1976; Kavaliers et al., 2005b; Arakawa et al., 2011). Studies about

inflammation-dependent odor cues indicate that the induction ofproinflammatory cytokines, but not steroid hormones, is a keymediator for releasing aversive odors. It is hypothesized that IL-1!expression may play a particularly important role, perhaps in partby activating MHC class I molecules and/or gut microflora prod-ucts to be released from exocrine glands or through the urine andfeces (Fig. 3). The odorant signaling molecules that are releasedas airborne compounds induce the suppression of social contactfrom odor recipient conspecifics without direct contact to the odorsource. On the other hand, IL-1! has another well-known func-tion in regulating social behavior, which induces sickness behaviorincluding the suppression of social motivation and behavior inthe hosts (Bluthé et al., 1991; Dantzer, 2001, 2004). The adaptivefunction of proinflammatory cytokines suggests that IL-1!, accom-panied by other aspects of the inflammatory response, plays a dualrole in regulating social behavior. The release of illness-related odorcues has important implications for our understanding of chemicalcommunication of social species.

Acknowledgements

This work was supported by grants from the National ScienceFoundation (NSF; 0822129), Hope for Depression Research Foun-dation (HDRF; 10-005), and Center for Development and BehavioralNeuroscience at Binghamton University to TD. H. Arakawa is sup-ported by a grant from the National Institute on Deafness and OtherCommunication Disorders (DC005633). Any opinions, findings, andconclusions or recommendations expressed in this material arethose of the author(s) and do not necessarily reflect the views ofthe above stated funding agencies.

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