14.1. INTRODUCTION

Closely related Mus species Mus musculus and Mus domesticus are the most popular objects in the study of mammalian chemical communication. The understanding of pheromone influences on mammalian behavior has advanced dramatically since the term “pheromone” was introduced. The major advances in recent years have been based mainly on a single species—the mouse (laboratory form of Mus musculus domesticus). Genetic technologies have revealed a surprisingly large repertoire of chemosensory receptors in mice that potentially detect pheromones (Brennan 2010). However, interspecies chemical communication in the house mouse remains the least investigated area. Use of the laboratory inbred strains of mice makes understanding of the behavioral effects elicited by chemical signals from other species even more complicated.

Predator-prey relationships provide an excellent model for the study of interspecies chemical communication. Small mammals in general are frequently at risk to be caught by mammalian, avian, or reptilian predators. In turn their prey species developed a variety of specific adaptations to facilitate recognition, avoidance, and defense against predators. Such antipredator behavioral systems are critical for survival (see review Apfelbach et al. 2005). Chemosensory detection is a very important aspect for predator avoidance strategy for many mammals including the house mouse. Odors from carnivores may elicit fear-induced stereotypic behaviors, change activity patterns and feeding rate, and affect the neuroendocrine system, reproductive behavior, and reproductive output in potential prey (Apfelbach et al. 2005; Dielenberg and McGregor 2001; Harvell 1990; Hayes 2008; Hayes et al. 2006; Kats and Dill 1998; Müller-Schwarze 2006). A number of studies (see Table 14.1) showed effects of odors derived from different predators on behavior and physiology of the house mouse. It implies the existence of shared signal properties through a number of predator species. This idea about generalized “leitmotif” of predator odors was suggested even much earlier (Stoddart 1980).

TABLE 14.1

Examples of Studies on Responses to Predator Odors in the House Mouse (Mus domesticus, Mus musculus)

The idea about the existence of a common carnivore signal was experimentally tested for the first time by Nolte et al. (1994). Manipulations with predator diet as well as chemical removal from carnivore urine of the sulfurous compounds and amines revealed their key role in the effects of coyote urine (Canis latrans) on feeding rates in wild living Mus domesticus (Nolte et al. 1994). Berton et al. (1998) also demonstrated that the diet of a cat strongly affects the behavior of mice towards its feces. Using similar chemical manipulations with cat urine (Felis catus) and manipulating with the diet of urine donors, it has been shown that sulfurous compounds and amines are critical for reproductive inhibitory effects of the cat urine in rodents (Voznessenskaya et al. 2002). Another study (Fendt 2006) indicates that only exposure to urine of canids and felids but not of herbivores induces defensive behavior in laboratory rats (Fendt 2006). The term “kairomone” was widely adopted to name predator chemical signals: “kairomones, such as those that elicit fear behavior, are cues transmitted between species that selectively disadvantage the signaler and advantage the receiver” (Wyatt 2003). In search of the molecular nature of kairomones, Papes et al. (2010) isolated the salient molecules from two species (rat and cat) using a combination of behavioral assays in naïve laboratory mice, calcium imaging and c-Fos induction. The defensive behavior-promoting activity released by other animals is encoded by species-specific proteins belonging to the major urinary protein (MUP) family, homologs of aggression-promoting mouse pheromones and mediated through the vomeronasal organ (VNO) (Papes et al. 2010).

The trace-amine-associated receptors (TAARs) form a specific family of G protein-coupled receptors in vertebrates that was initially considered to be neurotransmitter receptors before it was discovered that mouse TAARs function as chemosensory receptors in the olfactory epithelium (Liberles and Buck 2006). Discovery of a new function of TAARs stimulated the search for the potential ligands. More recent studies (Liberles 2009) showed that ligands for mouse TAARs include a number of volatile amines, several of which are natural constituents of mouse urine. One chemical, 2-phenylethylamine, is reported to be enriched in the urine of stressed animals, and two others, trimethylamine and isoamylamine, are enriched in male versus female urine. These findings raised the possibility that some TAARs are pheromone receptors (Liberles 2009). Further studies (Ferrero et al. 2011) revealed that 2-phenylethylamine is a key component of a predator odor blend that triggers hardwired aversion circuits in the rodent brain. Neurons expressing TAARs project to discrete glomeruli predominantly localized to a confined bulb region (Johnson et al. 2012). TAARs expression involves different regulatory logic than OR expression. Moreover, the epigenetic signature of OR gene choice is absent from TAAR genes. The unique molecular and anatomical features of the TAAR neurons suggest that they constitute a distinct olfactory subsystem (Johnson et al. 2012). Initially 2-phenylethylamine was purified from bobcat urine; quantitative HPLC analysis across 38 mammalian species indicated enriched 2-phenylethylamine production by numerous carnivores. Rats and mice avoid a 2-phenylethylamine odor source; enzymatic depletion of 2-phenylethylamine from a carnivore odor showed that it is required for full avoidance behavior (Ferrero et al. 2011). This study clearly demonstrated that rodent olfactory sensory neurons have the capacity for recognizing interspecies odors.

Findings of universal carnivore signals may explain why potential prey respond to odors from allopatric predators with which they do not have evolutionary links and never encountered in their lives, on one hand. On the other hand, the ability of predator odors to produce profound effects on the behavior of prey in general and especially on the reproductive behavior and neuroendocrine system is associated with natural predators only, which suggests an essential role of the evolutionary link between signaling predator and potential prey. First of all, it means that potential prey (in our case, mice) are able to distinguish predator species on a chemosensory basis. Numerous studies (Table 14.1) support this observation (also see review in Apfelbach et al. 2005). It raises a question about the multicompound nature of the kairomones as well as about the existence of species-specific predator chemical cues. One of the most specialized predators toward the house mouse is the domestic cat Felis catus. A long history of coexistence in the same environments led to the development of mutual adaptations at the genetic level. These two species provide a perfect model for the study of innate responses to predator odors.

Felinine is a unique sulfur-containing amino acid found in the urine of domestic cats (Rutherfurd et al. 2002). Sulfur-containing volatile compounds 3-mercapto-3-methyl-1-butanol, 3-mercapto-3-methylbutyl formate, 3-methyl-3-methylthio-1-butanol, and 3-methyl-3-(2-methyl-disulfanyl)-1-butanol are identified as species-specific odorants and candidates of felinine derivatives from the cat urine. The levels of these compounds were found to be sex- and age-dependent (Miyazaki et al. 2006a, b). These cat-specific volatile compounds may represent pheromones used as territorial markers for conspecific recognition or reproductive purposes by mature cats (Miyazaki et al. 2008). Species-specific compounds may be used also by other species to recognize potential predators and their physiological status. We now present evidence to support bioactivity of L-felinine and its derivates with the house mouse (Mus musculus).

14.2. METHODS AND MATERIALS

14.3. RESULTS AND DISCUSSION

We observed a block of pregnancy in experimental groups of mice exposed after mating to intact cat urine. The percentage of females with pregnancy block ranged from 31.25% to 68.75% depending on the season (Figure 14.1) with the largest effect in the autumn-winter period. This reflects the seasonal dynamics of reproduction in the house mouse. Even in the laboratory, numbers of cycling and accordingly breeding females are lower in the autumn-winter period. Hormonal status also experiences seasonal changes, making females more vulnerable to any stress event during the autumn-winter season. In control groups of mice we also observed some seasonal variation in the percentage of pregnancy block: from 12.5% in spring-summer to 18.75% in autumn-winter, but differences were not significant. We did not observe such robust seasonal differences in sensitivity to potential active ingredient from cat urine the unique Felidae family amino acid L-felinine. Exposures of mated females to L-felinine (0.05% in water) provoked pregnancy block in 67.85% female mice while in the control group we observed only 17.86% (n = 28, p < 0.01, Fisher test). For the remaining females we counted the total number of pups to compare litter sizes for experimental and control animals. Differences in litter size in the control and experimental groups were not significant; we only observed a tendency for lower litter size in the felinine treatment group. This may be explained by a considerable percentage (67.8%) of females with pregnancy block in the felinine treatment group. We used the total number of pups per fertile female as a cumulative indicator that takes into consideration both effects: block of pregnancy and litter size reductions. In the felinine treatment group the total number of pups per fertile female was 2.5 ± 1 while in the control group it was 5.70 ± 1.00 (n = 28, p = 0.046 Mann-Whitney U test). This clearly indicates significant suppression of reproduction. Another significant effect was observed under cat urine exposures: skewed sex ratios in favor of males (p < 0.001) (Figure 14.2a). A similar effect was observed for the L-felinine exposure group (p < 0.05) (Figure 14.2b). A skewed sex ratio in favor of males was interpreted as an adaptive response. A high concentration of felinine provides information about the high population density of a very specialized predator, Felis catus. Cushing (1985) was the first who proposed that females in a reproductive condition are more vulnerable to predation than nonreproductive females, and thus he suggested that it would be adaptive for them to suppress reproduction in case of high predation risk. The generation time of rodents is relatively short; complete reproductive inhibition may not be adaptive. However, reduced reproduction may be beneficial. Reduced reproduction would relieve energetic constraints on lactating females that might otherwise jeopardize survival if a full litter size was attempted. In accordance with theory on reproductive value, the probability to succeed reproductively under deteriorating environmental conditions is higher for males. First, males are more mobile and cover longer distances escaping from unfavorable territory. Even with reduced litter size, females may still experience lower survival probabilities during reproduction and lactation in food-limiting or predator-overpopulated environments because of energetic constraints. However, males would be less constrained by such energetic considerations. Thus, their survivorship probabilities may be higher than females, and by implication their value in contributing to fitness would also be higher.

FIGURE 14.1

The influence of exposures of cat (Felis catus) urine during first week of gestation on the percent of pregnancy block in the house mouse Mus musculus; exp.1 = autumn-winter season; exp.2 = spring-summer season; control = autumn-winter season. p < (more...)

FIGURE 14.2

(a) The influence of cat (Felis catus) urine exposures during gestation on sex ratio in house mouse Mus musculus (***p ≤ 0.001, n (cat urine) = 52, n (water) = 118, Fisher test). (b) The influence of the L-felinine (0.05%) exposures during gestation (more...)

Such indicators like litter size or number of pups per fertile female prior to weaning characterizes fecundity rates rather than reproductive success. To assess reproductive success we used such indicators as survivorship of pups after weaning. In another set of experiments we compared the reproductive output of Mus musculus musculus during two spring-summer months (mid-May–mid-July) in four fully covered small enclosures (1.5 m × 2.0 m). We placed nest building material and wood shavings in each module. In two of them (exp. 1, exp. 2) we placed plastic containers with a cotton swab soaked with cat urine. Additionally we placed a wooden box (0.3 × 0.3 m) that served as a shelter in one control (contr. 2) and one experimental (exp. 2) module. Taking into consideration frequency of scent marking in Felis catus under natural conditions, we renewed cotton swabs once a week. We placed equal numbers of cycling females of the same age and the same weight in each module. We also placed two males of the same age and weight in each enclosure. By the end of experiment we counted the number of live pups and the number of adult live females for each enclosure (Figure 14.3a, b). Cat urine significantly affected reproductive output in the house mouse. In experimental module 2 (no shelter inside) we did not find any live pups, while in control 1 the number of pups per fertile female was 2.9 (p < 0.001, n = 10). In experimental module 2 (shelter inside), the number of pups per fertile female was 1.64 while in the control group it was 2–3.36. By the end of the experiment, the age of pups ranged from 3 to 5 weeks. This data indicated that responses to predator odors even under seminatural conditions may be significantly modified by the availability of shelter. Early field studies on the effectiveness of predator odors as natural repellents revealed the importance of characteristics of habitat such as availability of cover (Epple et al. 1993).

FIGURE 14.3

(a) The influence of cat (Felis catus) urine on reproductive output of the house mouse (Mus musculus musculus) under seminatural conditions. Y-axis indicates number of live pups by the end of the experiment (7 weeks). (b) The influence of cat (Felis catus (more...)

In natural environments mice frequently undergo long-lasting and chronic exposures to predator odors. Taking these circumstances into account we evaluated chemosensory behavior of mice exposed to cat odor for extended periods. Male mice were exposed to cat urine for 10 days; 24 hours after completion of the exposures they were tested in a number of tests. Those animals discriminated female odor from water but did not show preference for receptive female odor versus diestrus female odor in a standard odor preference test (Figure 14.4a, b). Striking similarity was observed in the same test when mice were exposed for 10 days to L-felinine (0.05%). Male mice discriminated female urine versus male urine but not estrus female urine versus diestrus female urine. We compared the sexual behavior of males before long-lasting exposure to cat urine and after exposure in a standard pairing test with a receptive female. Exposure to cat urine significantly (p < 0.05) diminished the number of nasal-nasal contacts, attempted mountings, and mountings with intromissions (Figure 14.5). Our results indicate that extended exposures to cat odor suppresses sexual behavior in male mice.

FIGURE 14.4

(a) Performance of males in standard odor preference test in the house mouse (Mus musculus). (b) Performance of males in standard odor preference test in the house mouse (Mus musculus) after 10 days of exposure to cat urine (Felis catus). *p ≤ (more...)

FIGURE 14.5

The influence of long-lasting (10 days) exposure of cat urine on sexual behavior of males Mus musculus in standard pairing test with receptive female. *p ≤ 0.05 Wilcoxon matched pairs test, T-SD; n = 10; t = 60 min.

To study possible mechanisms underlying suppressed sexual behavior and reduced reproduction effort we monitored plasma corticosterone, the major glucocorticoid in mice. We observed clear elevation of plasma corticosterone (p < 0.001, n = 8, Tukey test) in response to cat urine in female mice (Figure 14.6a, d). As a positive control we used an open arena test with added stress (Figure 14.6c). Mice responded to this kind of treatment with elevated corticosterone but we observed habituation during the course of consecutive placements (days 1–7). At the same time mice did not habituate to consecutive exposures to cat urine (Figure 14.6a). We also observed such a habituation in mice introduced to another novel stimulus: guinea pig urine (Figure 14.6b). To explore for how long predator chemical cues may provoke elevated corticosterone we exposed male mice to L-felinine (0.05% in water) for 2 weeks. On completion of the exposures, feces from each animal were collected over 24 hours and glucocorticoid metabolites were measured for each animal. In the control group of male mice, the concentration of corticosterone metabolites was 203.85 ± 47.74 ng/0.2g feces; in the felinine treatment group, 702.15 ± 122.24 ng/0.2 g feces (n = 13, p < 0.001, t-test). The response of laboratory naive animals to predator scents and failure to habituate to the stimulus indicate the innate nature of the response. Chronically elevated plasma corticosterone in response to cat odor exposure, especially at early stages of pregnancy, may be a reason for the induction of pregnancy block. Early studies by McNiven and de Catanzaro (1990) showed that diverse psychological stressors, including exposures to predator odor (rat), correlated with elevated plasma corticosterone, provoke pregnancy block in the house mouse.

FIGURE 14.6

(a) The influence of short-term exposures (15 min) to cat urine on plasma corticosterone in the house mouse (Mus musculus). X-axis indicates days of treatment during one week. Mean ± SD; n = 8. (b) The influence of short-term exposures (15 min) (more...)

There have been a number of studies investigating the effects of cat odor exposure on the glucocorticoid and ACTH production of the potential prey (Blanchard et al. 1998; Cohen et al. 2000; Figueiredo et al. 2003; Papes et al. 2010; Sullivan and Gratton 1998; Voznessenskaya et al. 2002). The first study, performed in rats (File et al. 1993), showed that a cloth that had been rubbed on a cat caused an increase in circulating corticosterone. However, with repeated exposure to the cat odor stimulus this endocrine response habituated, indicating the role of learning. In our studies using cat urine as a source of odor, we also observed habituation to cat odor at the level of plasma coticosterone response in Wistar rats (Voznessenskaya et al. 2002). In contrast, mice did not habituate to repeated exposures of the cat odor. It may imply a hardwired processing of a cat odor as a pheromone in the house mouse. It seems likely that a profound and aversive effect of predator odors and lack of habituation under repeated exposures might only exist “if predator and prey have a long evolutionary history in parallel so that a prey species becomes genetically pre-disposed to avoid the odors of sympatric predators” (Stoddart 1980b); another important condition of such a response: an extremely high risk of fatal outcome for the direct interactions of predator and prey. Obviously, rats are less vulnerable to such predators as cats (Felis catus) compared with mice (Mus musculus, Mus domesticus).

The well-known Bruce effect (Bruce 1959)—a pregnancy block in rodents caused by exposure to a strange male after mating—requires an intact VNO. This phenomenon relies on an olfactory memory formed in the accessory olfactory bulb (Bellringer et al. 1980; Brennan 2004). We performed a VNX to test a hypothesis about the involvement of VNO in suppression of reproduction in mice under cat odor exposures. The results of the experiment are presented in Figure 14.7. Female mice with VNO removal did not show significant reductions in litter size under cat odor exposures while in sham-operated animals we observed significant reductions in litter size (p < 0.05, n = 12, Mann-Whitney test). Our findings are in good agreement with other studies on involvement of VNO in reception and analysis of predator odors. Papes et al. (2010) showed that VNO function is necessary for the display of innate behavior induced by odors from the cat, rat, and snake. Our earlier research also showed the involvement of the VNO in reproductive inhibitory effects elicited by cat odor in rats and mice (Kassesinova and Voznessenskaya 2009; Voznessenskaya et al. 1992, 2006). To explore further whether potential active ingredient from the cat urine L-felinine could be analyzed by VNO, we performed Fos immunohistochemistry. Exposure of L-felinine (0.05% in water) intermittently (1 minute on, 1 minute off) for 40 minutes to male mice as well as to female mice (n = 4, two independent experiments) resulted in elevated Fos immunoreactivity in the caudal part of the accessory olfactory bulb (AOB). We also observed a variable pattern of activation in the main olfactory bulb (MOB). More prolonged exposures of L-felinine (90 minutes) stimulated Fos immunoreactivity mainly in the basal part of VNO epithelial tissue. VNO neuroepithelial tissue is subdivided into two anatomically and functionally distinct subpopulations of neurons (Rodriguez et al. 2002). Apical sensory neurons are located closer to the lumen and express V1Rs. Basal neurons are located more peripherally and express V2Rs. V1Rs are mainly activated by volatile compounds and V2Rs by substances of higher molecular weight and peptides (Halpern and Martinez-Marcos 2003). Neuroanatomical projections of V1R and V2R neurons also differ. V2R neurons project to the caudal part of the AOB, which sends its projections to the vomeronasal amygdala where myriad steroid receptors are located (Halem et al. 2001). V1R neurons send their projections to the rostral part of the AOB, which in turn projects to the rostral amygdala (Rodriguez et al. 1999). Activation in the caudal part of the AOB may indicate that L-felinine is analyzed rather as a pheromone. Felinine in the presence of water is quite unstable and exists in the form of a mixture of felinine and sulfur-containing volatile compounds; 3-mercapto-3-methyl-1-butanol is one of the candidates for the pheromone role in cats for which behavioral response was observed, although the significance of the response is still unclear (Miyazaki et al. 2008). As far as volatile compounds are released eventually, this may explain the variable pattern of activation in MOB.

FIGURE 14.7

The influence of vomeronasal organ removal (VNX) on litter size in the house mouse under cat (Felis catus) urine exposures. SHAM = sham-operated animals; *p ≤ 0.05, n = 12.

Our data supports the hypothesis that species-specific molecules in cats involved in communication between conspecifics may play the role of kairomones for potential prey—the house mouse. On the basis of the cat scent marks, gender, age, physiological status, location, and population density of the predator could be detected which provides essential information for the adaptive response in mice. In conclusion it should be noted that we are at the very beginning of identifying species-specific molecules from different predators. A paper that was just recently published presents evidence that wolf (Canis lupus) urinary volatiles can engender aversive and fear-related responses in mice and pyrazine analogues were identified as the predominant active components among these volatiles to induce avoidance and freezing behaviors via stimulation of the murine AOB (Osada et al. 2013). More discoveries on the signals of particular predators are expected in the near future.

14.4. CONCLUSIONS

Accumulated up-to-date research shows a complex nature of predator odors that elicit adaptive responses in prey species. An evolutionary link between predator and prey is essential for full defensive response in the potential prey. Only sympatric species develop a full set of adaptations against a predator. Another important aspect is the ecology of the predator and the potential prey. Even if sympatric, predator and prey may have different ecological niches. Though predator odors induce innate responses, learning is still important. Rodents, though slowly, still habituate to predator odors at the level of the behavior, which is the major limitation of using predator odors as natural repellents. Recent studies revealed a multicompound nature of predator odors that characterize them rather than as a pheromonal blend. Defensive responses in prey also depend on presentation context, gender, age, social status, and the physiological state of the signal recipient. None of the known molecules may produce a full set of defensive behaviors. The hardwired nature of the predator-prey responses is a laboratory phenomenon rather than what is observed under natural conditions. Nevertheless, laboratory research is a very important stage in identifying active ingredients to be tested in the field.

ACKNOWLEDGMENTS

Supported by the Russian Foundation for basic research 10-04-01599a and by a project from the RAS Program “Zhivaya priroda” (Live Nature).

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