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Mucignat-Caretta C, editor. Neurobiology of Chemical Communication. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Chapter 17Pheromones for Newborns

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17.1. INEXPERIENCED NEWBORNS’ QUEST FOR COLOSTRUM AND MILK

Newly born mammals have to reach the source of milk as promptly as possible to ensure uninterrupted mother-to-offspring transfer of hydration, nutrients, and energy. Colostrum and milk intake also warrants the neonates’ immediate exposure to micronutrients and antioxidants, passive immunization, innocuous bacterial strains, growth factors, and a range of bioactive peptides that control conservative behavioral functions (i.e., antinociception, sleep induction, learning). With these matters and commodities, mothers also pass on to their offspring different levels of chemosensory information that reveal her identity, the location of the mammae, and the composition of milk. Thus, lactation and sucking uniquely coevolved by mammalian females and newborns imply a puzzle of morphological, physiological, and behavioral arrangements (milk gland structure and location; lactational performance, nursing acceptance; neonate’s oral competence, absorptive abilities and development) that are all subject to natural selection.

Mammals are indeed exposed to an outstandingly powerful selective pressure while they are bottlenecked through birth and weaning. These windows in early development concentrate all types of challenges, and maladaptive responses to them in the female-offspring dyad are costly for neonatal viability (e.g., Clutton-Brock 2001). A well-documented case refers to primates, specifically humans, in which 27% of infants fail to survive their first year and 47% of children fail to survive to puberty in hunter-gatherer and historical societies (Volk and Atkinson 2013). The causes of such high mortality rates are not known precisely, but the first steps in infant-mother adjustment bear great momentum. The ability to initiate sucking is variable among human mother-infant dyads, leading to delays in establishing optimal colostrum/milk transfer in some infants. For example, a high rate of termborn infants display nonoptimal milk intake on the day of birth and on day 3 (i.e., 49% and 22%, respectively, in California [Dewey et al. 2003]; 43% and 8%, respectively, in France [Michel et al. 2006]). Such insufficient intake during the first feeds, if not handled rapidly, can lead to excessive weight loss, dehydration, and threat to viability when adequate care is lacking (Cooper et al. 1995; Neifert 2001). This is best emphasized in a study on homeborne infants in Ghana showing that a 1-day postponement to initiate breastfeeding explained 16% of neonatal losses and a postbirth delay of only 1 hour to engage breastfeeding explained 22% of neonatal mortality (Edmond et al. 2006). Early breast milk intake was associated with reduced mortality caused by infection, particularly in the gastrointestinal tract (e.g., Edmond et al. 2007; Huffman and Combest 1990).

Other mammalian species show the same trend. For example, piglets incur high mortality, especially when colostrum intake is lacking (Andersen et al. 2007). Another case is the European rabbit (Oryctolagus cuniculus), a species that has minimized direct maternal investment (although in the wild, indirect investment is high in excavating a burrow and lining it with an insulating vegetal material and hair). During the first 2 weeks postpartum, neonate rabbits can suck nipples only within the 3–5 minutes/day the female makes herself available (Rödel et al. 2012; Selzer et al. 2004; Zarrow et al. 1965). This limited access to milk must be added to an intense sibling rivalry (Drummond et al. 2000), and it is not rare that pups miss one feed and have to wait 24 hours to the next. While pups survive one sucking failure, they are jeopardized after two such failures. But as they do interchange nipples over a same nursing episode (Bautista et al. 2005; Drewett et al. 1982), pups can in principle get milk, and rapidly improve their localizatory and sucking skills from day to day (Hudson and Distel 1983; Müller 1978). Despite generally successful suckling, pups incur notable mortality in the days following birth (days 0–7) and around weaning (days 21–28), especially when females are primiparous (Coureaud et al. 2000).

Thus, mammalian mother-infant dyads are exposed to strong selective pressure in the days and weeks following delivery. Accordingly, any sensory, behavioral, or cognitive means in females or newborns that can speed up neonatal nipple localization and milk ingestion is beneficial to current mother-offspring dyads, and should have been beneficial to the mother’s inclusive fitness in the environment of evolutionary adaptation. In this chapter, we will consider how females and neonates coevolved chemosensory means for mutual adaptive ends at the start of their postnatal relationship. We will first outline the interface structures for milk transfer (nipples), which were shaped by females to match the sensory/motor skills of their offspring. Second, we will survey newborns’ perceptual and cognitive sophistication in the context of the nursing relationship. Third, some rodent, lagomorph, and primate cases will be analyzed in more detail to evaluate the nature of the cues and signals that neonates use in their quest for milk. Finally, we will present mammalian newborns’ pheromones as ontogenetic adaptations; that is, as perceptual mechanisms dedicated to orient and synchronize infant behavior in relation with the mother, and hence increase survival and stimulate adaptive learning.

17.2. NIPPLES AS SCENT ORGANS EVOLUTIONARILY TAILORED FOR NEWBORNS

Mother-neonate exchanges are diversely organized among mammals (Clutton-Brock 1991; Gubernick and Klopfer 1981; Numan et al. 2006), but this diversity is underlain by common mechanisms. First, at the same time as they procure various substances and realize numerous nurturing actions toward their offspring, maternal females unavoidably transmit information about the environment (including themselves) they create around them during fetal and postnatal development and this information transfer is a significant part of the “maternal effects” (Maestripieri and Mateo 2009). Second, the sensory resource that is mobilized in mediating maternal information transfer to the neonate depends on the receiver, precisely the neonate and its most advanced receptive and reactive abilities. In theory, females could exploit the whole range of their neonates’ sensory systems in these earliest exchanges, but the most basic, and hence most conserved ways, rely on somesthesis and chemoreception. While some species give birth to altricial neonates whose sensorium is restricted to these modalities (e.g., sightless newborns in monotremes, marsupials, altricial rodents, or carnivores), other species bear precocial or semiprecocial newborns whose behavior is controlled by all the senses, including hearing and vision (e.g., ungulates, some rodents or primates). Thus, touch and olfaction appear to be the common sensory denominator of neonatal mammals and the most universally exploitable channels to shape infant-directed information. Third, mammaries are the only structures of the maternal body that newborns have to obligatorily contact in order to survive. More specifically, the offspring contact with the mammary gland involves a specialized cutaneous interface, the papilla mammae, commonly called nipple or teat (surrounded by an areola in certain primate species). According to the point above, the most efficient strategy of females to increase the localizability and graspability of nipples in their newborns should have been to shape tactilely and olfactorily conspicuous structures. This evolutionary coadjustment between mothers and neonates has worked directly by affecting anatomical features on or around mammaries that release chemostimuli. Mammary chemosignalization has also followed indirect ways, females in many species and newborns in all species spreading extramammary substrates on their nipples when they groom or suck.

These various sources of chemical cues or messages emerged on or around nipples under different functional forces. While some of them may convey exclusive communicative functions (e.g., the inguinal glands of ungulates), others may be secondary to local requirements to preserve nipple functionality against the heavy stress that offspring wield on it. The evolutionary specialization of nipples has indeed co-opted exocrine structures to protect cutaneous and ductal entries from bacterial invasion, create the airtight seal necessary for the efficacy of suction, and relieve the strong friction of the lips of sucking neonates (Schaal et al. 2008b, 2009; see below). Thus, mammary structures aggregate a variety of secretory/excretory sources giving off potentially odorous substrates.

The most obvious and profuse sources of mammary odorants are colostrum and milk, which odor properties depend on the female’s lactational stage, dietary and aerial ecology, stress, and physical activity. Other mammary substrates are secreted or excreted by glands distributed in, on, or adjacent to, the mammary structure. The whole range of elementary skin glands is represented in the areola-nipple region, including eccrine, apocrine, and sebaceous glands. In some species, the mammary area is additionally endowed with sophisticated glandular specializations, working either in close functional link with lactation (e.g., human Montgomery’s glands or the structure producing the rabbit mammary pheromone) or throughout reproductive life (e.g., ovine inguinal glands).

The substrates released onto the nipple-areolar skin can be mingled with those brought here from extramammary sources. These exogenous substrates vary according to the species considered: in some rodents and carnivores, parturient females actively lick their nipple-lines, labeling them with a mix of urogenital and amniotic fluids, blood, saliva, and all kinds of secretions from oral or facial glands. Nursing females also often alternate licking their offspring and their own ventral fur, spreading on themselves infant-specific odor traces (excretions or secretions from anal or urogenital sources) mingled with own substrates (saliva). Further, while sucking, newborns stain nipples with mixed amniotic fluid and saliva, and later with mixed saliva, milk and other facial substrates (from lachrymal, nasal, facial, or ear glands). To further expand this biochemical puzzle, both mammary and extramammary substrates certainly depend on surface processes involving salivary enzymes or the local commensal microflora. Finally, local conditions of heat, humidity, and texture of the mammary epidermis are an additional way to differentiate emitted odorants in terms of volatility (the dermis underlying mammary structures is highly vascularized, provoking higher surface temperature).

To sum up, multifarious biological substrates and processes make the chemistry that females present to their offspring on their mammaries and nipples complex. It should thus be a perceptual challenge for newborns to navigate through this chemosensory mosaic. However, although the first efforts of mammalian neonates to locate nipples are sometime diffident (often as a result of the inexperience of the female), most of them survive and therefore demonstrate their skills to localize and grasp them and obtain enough colostrum and milk to start life.

17.3. NEONATAL OLFACTORY COGNITION: LEARNING AND PREDISPOSITIONS

We do not fully understand how mammalian neonates perceive and analyze the olfactory scene that is associated with the mammary structure. But, by staying alive, the majority of them prove their competence to orient adequately from the very first exposure to a nipple. Neonates dispose of several ways to make sense of the chemosensory complexity of mammaries, some being shaped by exposure and learning effects, others working independently from learning. Opportunistic processes involving learning occur in all species examined so far, whereas unconditional processes have been evidenced in only some species. These differentiable perceptual mechanisms may be dedicated to the processing of different sets of compounds within the complex mixture composing mammary chemosignals (see below).

Neonatal mammals are outstandingly efficient learning machines. During a certain period after birth, they acquire as “positive” any stimulus associated with the mother’s body or nest. Positive means here that these stimuli tap into the approach system of behavior. This avid information intake in the context of nursing has chiefly been investigated in the rat and mouse, and related findings can be summarized as follows (for reviews, see Alberts 1981; Blass and Teicher 1980; Brake et al. 1986; Leon 1994; Rosenblatt 1983; Wilson and Sullivan 1994). (1) Rat and mouse pups easily acquire artificial odorants applied on the female’s mammary area, which suggests that natural odorants are learned in much the same way. (2) Odor learning is functional from birth (e.g., Miller and Spear 2008, 2010) and its efficiency increases as a function of maturation and experience; thus nipple grasping, already functional right at birth, ameliorates during the first days due to the establishment of sensory incentives and to neuromotor training (Armstrong et al. 2006; Bouslama et al. 2005; Dollinger et al. 1978; Rosenblatt 1983). (3) Neonatal olfactory abilities are largely premolded during fetal development in terms of sensitivity and preferences (Molina et al. 1995; Schaal and Orgeur 1992; Smotherman and Robinson 1987; Youngentob et al. 2007), and this fetal sensory imprint goes in parallel with a relative transnatal continuity of chemosensory cues (Mendez-Gallardo and Robinson, 2010; Pedersen and Blass 1982; Schaal 2005; Schaal and Orgeur 1992); specifically, in the case of the rat, amniotic fluid odor is made available onto the nipple-lines by maternal self-licking activity (Teicher and Blass 1977), and milk accumulates odor cues derived from the gestating female’s general metabolism and diet (Capretta and Rawls 1974; Galef and Henderson 1972; Galef and Sherry 1973). (4) The reinforcing agents that potentiate neonatal learning of odor cues are multiple and redundant. Maternal and infant behavior afford numerous reinforcers, such as warmth, soft contact or targeted stimulation (anogenital licking), vocalizations, exertion of sucking, and postingestive (taste) and postabsorptive factors (gastric filling, brain sensing of satiety). All these reinforcers act separately on the learning of any associated odor cue, but their normally additive operation is most efficient (Brake et al. 1986). Milk itself supports the establishment of learned odor associations (e.g., Brake 1981). Finally, compounds conveyed in biological secretions may instantly potentiate the learning of co-occurring odor cues (e.g., presenting simultaneously an aversive orange scent with the odor of maternal saliva reverses the value of the orange odor into attraction [Sullivan et al. 1986]). Thus, milk and other excretions/secretions emitted from, or conveyed to, the nipples (e.g., saliva, amniotic fluid [Arias and Chotro 2007]) may alter the meaning of incidental odor cues in neonatal rodents.

The learning abilities of neonate rodents are certainly generalizable to all mammalian neonates, although only a handful of species has been investigated in detail. For example, rabbit pups can learn from the first day after birth any nonspecific odorant associated with nursing (Allingham et al. 1999; Coureaud et al. 2006; Hudson 1985, 1993; Ivanistkii 1962; Kindermann et al. 1994). After single odor-nursing pairing, such pups express the typical sequence of nipple searching and grasping on an unfamiliar female painted with the same odor (Hudson 1985). But the one-session learning of an odor associated with sucking appears only effective during the first 4 postnatal days (Kindermann et al. 1994); after day 5, nursing-induced odor learning vanishes completely, raising the possibility of a sensitive period for odor learning. Thus, the timing and the act itself of sucking are efficient promoters of odor learning in rabbit newborns, and any arbitrary odor cue sticking on a nipple can be assigned incentive value for the next suckling episodes (Hudson et al. 2002).

Sucking can also instigate learning of odorants associated with the breast or milk in human newborns (e.g., Delaunay-El Allam et al. 2006, 2010; Schleidt and Genzel 1990). But sucking is not a necessary condition as mere exposure or contingence with touch-induced arousal suffices to change the incentive value of initially irrelevant stimuli (Balogh and Porter 1986; Sullivan et al. 1990). Such acquisition of odor cues in human infants seems also subject to modulation by the birth process or the timing of its occurrence relative to birth (Romantshik et al. 2007).

Neonate mammals respond more intensely to, or learn more easily, certain stimuli than others before they were directly exposed to them. When responses to given odorants emerge without obvious reliance on previous exposure (even prenatal) and are resistant to deprivation from the specific stimulus or to its reassignment by other stimuli, the term “predisposed” may be used (Bolhuis 1996; Horn 2004). Such predisposed processes designate perceptual-motor loops generalized at the species level that are released from birth by stimuli that did not appear to occur in the prior developmental environment. Predisposed responses to odor substrates have rarely been investigated in mammalian neonates, but these rare cases are of particular interest. In general, odor stimuli recruit different response levels in neonates. When presented for the first time, novel odorants elicit sniffing or increased respiration, generally followed by withdrawal. In contrast, certain odorants do release appetitive oronasal investigation in absence of prior direct exposure to them. Such immediate oral grasping response is observed with fresh milk or its odor. It can be elicited at or before gestational term, before any contact with a lactating female or her milk. For example, human newborns respond to the odors of the lactating breast or milk by positive head orientation and appetitive mouthing regardless of the rate of prior exposure to the breast (Delaunay-El Allam et al. 2006; Makin and Porter 1989; Marlier and Schaal 2005; Porter et al. 1991; Russell 1976). Further, premature neonates react by increased mouthing and sucking movements to conspecific milk odor (Bingham et al. 2003a; Raimbault et al. 2007).

These responses of newborns to conspecific milk odor are not easily overcome by newly learned odorants. Indeed, when tested for relative preference between human milk odor and an artificial chamomile odor spread on the areolae at each feed since birth, breastfed newborns display equivalent orientation to either stimulus (Delaunay-El Allam et al. 2006). In addition, when simultaneously presented with human milk odor (from a nonfamiliar mother) and the odor of their cow’s milk-based formula, infants who were exclusively bottle-fed since birth demonstrate more appetence for the unfamiliar conspecific milk than for the familiar artificial milk (Marlier and Schaal 2005). Thus, odor chemostimuli carried in human milk are more reinforcing to human newborns than nonspecific odorants that were rewarded by sucking or satiety for several days.

In summary, the behavior of mammalian neonates appears to be driven by multiple olfactory mechanisms underlain either by plastic, experience-dependent processes or by predisposed processes. Since learning processes are easier to apprehend experimentally, they have received much more empirical attention than predisposed processes, and are thought to predominate in the control of neonatal adaptive behavior. It is clear that the extrafast odor learning abilities of newborn mammals make it difficult to characterize predisposed perceptual processes, as would be required if pheromones were involved, such compounds being operationally defined to imply no or minimal experiential induction of their biological activity (see next section).

17.4. ETHOCHEMICAL LOGIC TO DECONSTRUCT MAMMARY ODORS

As noted in Section 17.2, nipples and the areas of maternal skin harboring them are biologically complex with overlapping sources of multiple secretions and excretions. In Section 17.3, mammalian neonates were shown to address this “blooming, buzzing” confusion of chemical cues apparently without great trouble or need for training, which suggests that their chemosensory skills are somehow tailored to make sense of odors, and specifically of mammary odors.

The first ways for the neonatal brain to segregate this complexity of mammary chemostimuli may be based on physicochemical phenomena that affect ligand-receptor interactions constituting nasal and oral chemoreception, such as volatility, polarity, solubility, functional moieties, stability, and multicomponentiality. For example, volatile and involatile fractions of mammary secretions may lead, respectively, to detection from a distance or to the need for direct contact for perception to occur. Involatile proteins, lipids, or hydrocarbon may in this way act as carriers or precursors of volatile ligands, or they can protract the emission duration of associated volatile compounds. Differences in volatility may be linked to contrastive sensory impact, such as transient alarmlike effects depending on volatile/diffusible compounds, while heavier polar compounds may end in long-lasting attractant effects (Alberts 1992; Müller-Schwarze 2006). But involatile compounds do also work as chemosignals as recently shown in murine main urinary proteins (MUPs) that encode individual identity (Hurst et al. 2001) and induce learning of associated volatile fractions (Roberts et al. 2010).

Another potential perceptual split of complex mammary odors may separate individual-specific from species-specific components. Some odor compounds reflect idiosyncratic traits of the female (e.g., her atmospheric environment, diet, level of stress, physiological state, health and parasite load, and lactational age) or of the young (diet, physiological state, sex, age), while others carry higher-level categories of meanings (e.g., genus/species; population, group, or kin identity). Depending on the type of behavioral test used to assess responses, neonates’ ability to extract individual or supraindividual meanings can be evidenced from a same substrate. For example, rabbit or human newborns reveal that conspecific milk can carry odor cues related to the individual mother or to any lactating female of the species (Coureaud et al. 2002; Marlier and Schaal 2005; Schaal 2005). In the same way, lambs are strongly reactive to inguinal secretions from any ewes, but much more when they are from their own mother (Vince and Ward 1984).

A third divide in the perception of social odors in general and in mammary odors in particular concerns the notions of cue and signal. It has repeatedly been proposed (e.g., Dusenberry 1992; Hauser 1996; Maynard-Smith and Harper 2003; Wyatt 2010) to separate cues, taken as informative elements that derive from normal life sustenance processes in the emitter, from signals, taken as informative elements that “alter the behavior of other organisms, which evolved because of that effect, and which are effective because the receiver’s response has also evolved” (Maynard-Smith and Harper 2003, p. 3). While cues may be lastingly on, signals may be switched on-off according to the emitter’s behavior or condition (Hauser 1996). Mammary odor cues would include compounds derived from maternal physiology (diet, wastes, hormonal state, stress) without added cost involved to produce them. In contrast, mammary odor signals would designate compounds that may be released by specialized structures, exploit specific response biases in the receiver, and evolved for a specific signaling function (or were secondarily recycled for such a function). In the context of mammary odor mixtures, this would imply that rare signals are embedded in a system of abundant cues, and that looking for a signal is like seeking a needle in a haystack of cues. The task is even trickier when cues and signals, although they differ in the developmental process leading to their activity, release functionally equivalent responses. While odor cues are typically constituted of circumstantial and variable odorants, odor signals are relatable to the concept of the pheromone.

Once chemically identified, a behaviorally active odor compound can be screened to assess whether it can be construed as a pheromone. The initial definition of the concept (Karlson and Lüscher 1959) designated “substances, which are secreted outside by an individual and received by a second individual of the same species, in which they release a specific reaction, for example, a definite behavioral or developmental process”. Following this minimalist definition, almost every chemosensory signifier exchanged between conspecifics can be argued to act as a pheromone. To prevent latent confusion on the nature of the compounds involved as well as on the nature of elicited responses in mammals, Beauchamp et al. (1976) resized the concept of pheromone so that it better matches the cognitive complexity of mammalian behavior (see also Doty 2003; Johnston 2000). To name a candidate chemostimulus a pheromone, they proposed that the compound: (1) is chemically “simple” (being composed of a monomolecular compound or a very small set of chemicals in fixed ratio), (2) releases in a conspecific receiver an adaptive response that is morphologically invariant in a same context (or, better, in different contexts); (3) these responses should be elicited in a selective way by the considered compound that should thus be tested against several reference compounds, (4) their taxonomic specificity should be established, and (5) the coupling between the candidate chemostimulus and the response should not depend on previous exposure and learning; thus, prenatal exposure, facilitated learning during the natal process, or rapid learning immediately after birth should be eliminated as possible explanations of its behavioral activity.*

Mammary-related odorants have been mostly investigated in milk, the substrate that is most practical to handle with chemoanalytic techniques. Milk is nevertheless physicochemically and biochemically multifaceted, and the fraction(s) responsible for its chemosensory activity in newborns is (are) difficult to characterize. A first step in reducing the complexity of milk has been to analyze its volatile fraction. But even milk volatiles have a complex profile, leading to gas chromatographic (GC) tracings ranging from more than 150 peaks (e.g., in ovine milk [Moio et al. 1996], in rabbit milk [Schaal et al. 2003]) to 20–40 peaks (in human milk, e.g., [Büttner 2007; Shimoda et al. 2000]). In addition to volatile compounds, numerous nonvolatile lipids, proteins, or polysaccharides are chemosensorily active by themselves or act as carriers of volatile compounds (e.g., Murakami et al. 1998). Thus, the chemical dissection of the behaviorally-active components of milk is a complicated endeavor, and it has so far been carried out in only few mammalian species.

17.5. EVIDENCE FOR PHEROMONES IN MAMMARY CHEMOSTIMULI?

The contribution of nasal chemoreception to neonates’ response to mammary and extramammary substrates will be summarized here in the mammalian taxa which have received more attention so far, namely rodents, lagomorphs, and primates. For representative species of each of these groups, evidence for structures located in, on, or around the mammaries or for significant olfactory indices produced endogenously (in lacteal secretions) or exogenously (in extramammary substrates) will be surveyed. Further, we will consider whether mammary chemostimuli can be sampled for separate experimental restitution to neonates, whether chemically identified signals are embedded among these mammary odor mixtures and whether these can be categorized as pheromones (i.e., as signals distinct from ordinary, learned odor cues in following the operational criteria outlined in Section 17.4).

17.5.1. Rodents

17.5.1.1. Mammary Sources of Behaviorally Active Chemostimuli

Studies on the topic have been conducted in the laboratory rat and mouse which show altricial newborns rely mostly on olfaction in their interaction with the dam (reviews in (Alberts 1976, 1981; Blass 1990; Blass and Teicher 1980; Rosenblatt 1983). An odor factor from the ventral skin of lactating dams attracts rat or mouse pups. In mice, this substrate appears most active at short range, suggesting low volatility (Al Aïn et al. 2011; Hongo et al. 2000). The specific source of this odor factor is unknown, but nipples are important (although not exclusive; see Singh and Hofer 1978). When rat nipples are washed with organic solvents, the resulting solution distillated, and the distillate then applied on a nipple rendered inactive by prior washing, pups resume oral grasping of it (Teicher and Blass 1976, 1977). Rat and mouse nipples are endowed with apical sebaceous glands opening into the ductal ostia (Toyoshima et al. 1998a, b) whose size is maximal at the end of gestation and during lactation. The surface of the nipple changes drastically during lactation with increasing furrowy texture (Toyoshima et al. 1998a) that favors the accumulation of cutaneous secretions or milk, and of skin microflora.

Milk is expected to olfactorily tag nipples, although current data on this point is lacking. When rat milk was painted on olfactorily inactivated nipples, normal nipple grasping response was not restored in 8–9-day-old pups (Singh and Hofer 1978), but this experiment was too imprecisely reported to be conclusive. It is a paradox that most research on rat pup responses to milk has used cow’s milk or cow’s-milk-based formulas rather than conspecific milk (e.g, Ackerman and Shindledecker 1978; Cheslock et al. 2000; Koffman et al. 1998; Mendez-Gallardo and Robinson 2013; Petrov et al. 1997; Smotherman and Robinson 1994; Terry and Johanson 1987). Such responsiveness of newborn rats to heterospecific milk may not be generalizable to rat milk, implying that more research is needed here.

In contrast, recent investigation in the mouse indicates that neonatal pups respond to the odor of fresh murine milk (Al Aïn et al. 2012a, b; Logan et al. 2012). In an attempt to track odor-active substrates that elicit initial nipple seizing/sucking in newborn mice, Al Aïn et al. (2013) and Logan et al. (2012) coated olfactorily inactive nipples with murine amniotic fluid, milk, or maternal saliva. While pups were unresponsive when presented inactivated nipples, typical approach/sucking response was reinstated after painting these biological fluids on them. To control for earlier exposure effects possibly explaining this result (pups aged < 12 hours and hence, exposed to these stimuli while suckling), Logan et al. (2012) assayed pups delivered by Cesarean section and deprived of suckling prior to the test. When facing nipples coated with amniotic fluid, maternal saliva, or milk, these “premature” pups only grasped the nipples bearing amniotic cues, suggesting that the activity of the other substrates—specifically milk—was conditional on previous postnatal exposure. However, Logan et al.’s and Al Aïn et al.’s findings appear divergent. In Logan et al.’s conditions, milk was ineffective to trigger nipple grasping in pups deprived of prior suckling. In contrast, in Al Aïn et al.’s (2012b, 2013) conditions, unsuckled newly born pups displayed positive attraction toward milk or seizing/sucking of a nipple coated with fresh milk. These contradictory findings certainly reside in procedural and/or stimulus differences between studies (age of pups at testing: 1 hour postpartum vs. 4–6 hours; birth experience and perinatal exposure to anesthetics: vaginal delivery vs. Cesarean section; milk stimulus: fresh vs. aged). Regarding the stimulus, Al Aïn et al.’s studies took special care to use fresh murine milk no more than 15–20 minutes after ejection without freezing or deep-freezing (as both standing of milk after ejection and freezing do notably alter the profile of its headspace (Keil et al. 1990; Spitzer and Büttner 2013).

17.5.1.2. Extramammary Sources of Behaviorally Active Chemostimuli

Based on the fact that rat and mouse females self-lick during gestation, parturition, and lactation (Roth and Rosenblatt 1966), saliva, and amniotic fluid are presumably spread ventrally. Positive reactions to birth fluids are indeed observed in rat and mouse newborns (Hepper 1987; Kodama 1990, 2002; Kodama and Smotherman 1997; Mendez-Gallardo and Robinson 2012). The impact of amniotic odor has been assessed in the context of nursing (Logan et al. 2012; Teicher and Blass 1977): if nipples rendered inactive by prior washing are thereafter painted with amniotic fluid, oral seizing recovers at subnormal levels. In the normal course of events, newly born rat pups deposit amniotic fluid blended with saliva when they root in their mother’s abdominal fur, and saliva of a parturient or lactating dam elicits attraction in pups (Sullivan et al. 1986) and reinstates their grasping of a prewashed nipple (Teicher and Blass 1977). Pup saliva, as well as pup salivary gland extract, are also efficient in restoring grasping of prewashed nipples (Pedersen and Blass 1981). Finally, when rodent females self-groom, they spread a range of secretions of oral-facial (e.g., Harderian or lachrymal glands), anogenital, or pedal origins over their ventral fur (Thiessen et al. 1976). They lick then their pups’ anogenital area, consuming their urine (Friedman and Bruno 1976) and next lick their own ventrum, leaving there pup secretions/excretions, originating in urine or feces, and preputial or anal glands. Thus, the nipple-lines may receive a mixture of anogenital glandular or urinary volatile and involatile compounds (e.g., lipocalins such as MUP).* It may be noted that such involatile proteins are released in mammary, parotid, sublingual, submaxillary, and lachrymal glands (Shahan et al. 1987), so that all these secretions could carry common cues.

In sum, at least in the rat, current evidence indicates that the biological substrates that direct mammary localization and drive nipple grasping by pups may originate from extra-mammary sources conveyed by females and newborns themselves rather than from mammary sources. In contrast, recent research with mouse newborns indicates strong activity of both mammary and extramammary substrates in initial nipple searching/grasping. However, much more research is needed here.

17.5.1.3. Evidence for Pheromones?

Do newborn rodents respond to odor stimuli on nipples before direct exposure to them? So far this issue does not seem to have been directly addressed using conspecific stimuli (e.g., Cheslock et al. 2000, for cow’s milk). However, extramammary sources; that is, pup saliva, pup salivary gland extract, and suckled nipple wash extract, are reliable elicitors of newborn rat nipple grasping. These secretions were accordingly subjected to GC-MS with the goal to pinpoint dimethyl disulfide (DMDS), a compound that was a priori inferred to be active by extrapolation from its sexual attractant properties in male hamsters (Singer et al. 1976). Synthetic DMDS was indeed shown to be effective in eliciting nipple grasping in 3–5-day-old pups, but with a low releasing potency (approximately 50%) relative to that of olfactorily intact nipples (Pedersen and Blass 1981). Thus, unknown compounds from the natural mixture coating nipples do carry additional impact. In these studies, rat pups were aged 3–5 days, implying that the activity of DMDS may derive from prior exposure. Nevertheless, DMDS is behaviorally singular as it reduces aversive responses to noxious stimuli in the fetal rat (an effect mediated by opioidergic processes, suggesting unconditional reward properties [Smotherman and Robinson 1992]). DMDS is reported not to be detectable by GC in amniotic fluid (Blass 1990), leading to the logical conclusion that its behavioral activity does not depend on prenatal exposure. Thus, until the behavioral activity of DMDS is further assessed in newly born rats, it may be tentatively considered as a salivary signal for nipple attachment. But to be categorized as a pheromone, its species-specificity has to be proven and its action waits further testing for unspecific arousal effects against reference compounds.

Volatile amines that are abundantly excreted in rodent milk (Pollack et al. 1992) may constitute putative mammary chemostimuli for neonatal rodents. Although their behavioral activity remains as yet untested in neonatal rats and mice, they have strong affinity for a subclass of odorant receptors, the trace amine-associated receptors (TAARs) expressed in the main olfactory epithelium and in the Grueneberg ganglion of the mouse (Fleischer et al. 2007; Liberles and Buck 2006). Interestingly, the developmental course of TAAR expression in the Grueneberg ganglion is much higher in late fetal (embryonic day 17.5) and neonatal mice (postnatal day 0–1) than in week-old pups (postnatal day 7) and adults, suggesting a chemosensory role for the Grueneberg ganglion and amines in the earliest adaptive responses (Fleischer et al. 2007). This point is currently under scrutiny. Otherwise, sulfur-containing volatiles identified in adult rat breath (carbon disulphide and carbonyl sulfide) may also bear precocious behavioral activity. The former was shown to work as an attractant and a reinforcer in subadult rats and mice (Bean et al. 1989; Galef et al. 1988; Munger et al. 2010), but these compounds have not yet been assayed with neonates and nurslings.

Finally, it cannot be excluded that through their avid licking of pups’ anogenital area and consumption of their urine (Gubernick and Alberts 1983), lactating females spread on/around nipples traces of urinary and urinary tract glandular chemostimuli. This mammary distribution of extramammary substrates may concern, for example (1) dodecyl propionate, a compound emitted in neonatal rats’ preputial secretions known to release avid licking (Brouette-Lahlou et al. 1991a, b), (2) MUPs that themselves bear behavioral activity in adult mice (Roberts et al. 2010), and/or (3) active MUP-bound ligands known to carry pheromonal effects in young mice (Jemiolo et al. 1987, 1989). So far, these stimuli have not been assayed with newborns. Taken together, extant data does not clearly establish that rodent females emit infant-directed pheromones from their mammary structures. There is however some evidence that extramammary substrates applied on nipples operate as orientation and grasping cues.

17.5.2. Lagomorphs

In the mammalian order of lagomorphs, the most complete understanding of odor-based neonatal behavior stems from the European rabbit, Oryctolagus cuniculus. Rabbit newborns display a typical pattern of probing and searching in the female’s abdominal fur when she enters the nest, which generally ends in orally grasping a nipple in less than 15 seconds (Hudson and Distel 1983; Schley 1976). This swift response is mediated by olfaction (vision and audition being nonfunctional during the first week). When nasal chemoreception is suppressed, pups’ ability to locate nipples is lost (Schley 1977, 1979).

17.5.2.1. Mammary Sources of Behaviorally Active Chemostimuli

Female rabbits, particularly when lactating, release searching/oral grasping in pups exposed to their ventral fur (Coureaud and Schaal 2000; Hudson and Distel 1984, 1990; Schley 1976). When these cues are altered by washing the lactating female’s abdomen, the pups are delayed in finding nipples (Müller 1978). Covering nipples with an airtight film disrupts pup searching at various rates according to the degree and location of masking (Coureaud et al. 2001; Hudson and Distel 1983). Finally, pups are more reactive to nipples excised from lactating females than to nipples excised from nonlactating females (Moncomble et al. 2005). Thus, a major source of behaviorally active compounds on rabbit females’ ventrum is on the nipples. Currently, little is known on the histological origin of these chemostimuli, but several sources may be involved (Moncomble et al. 2005), including (1) intensified epidermal keratinization of the nipple during lactation, which induces higher release of surface lipids, (2) increased output from sebaceous glands located at the base of the nipple, which may be involved in intrinsic signaling function or in sequestering milk compounds; pup grasping responses are reduced or abolished by washing these surface cues away on excised nipples, and (3) minute oozing of milk, which volatiles release pups’ searching-grasping response (Coureaud et al. 2002; Keil et al. 1990; Müller 1978; Schaal et al. 2003). While the behavioral activity of rabbit milk fades away within 30 minutes after milking (Keil et al. 1990), the odor of nipples excised from lactating rabbits does not (Moncomble 2006), suggesting that surface compounds either bear intrinsic behavioral activity or do preserve the activity of remnant traces of milk.

The compounds that render rabbit milk behaviorally active to neonate pups can in principle originate from environmental sources (i.e., mother’s diet) transferred into milk and/or from compounds synthesized de novo in the mammary tract. The intramammary source of active compounds is attested by an experiment that compared the activity of milk sampled in either the alveoli, the ducts below the nipple or after ejection (Moncomble et al. 2005). Only ejected milk was behaviorally efficient, designating the terminal part of the milk ducts as the possible source of active compound(s). Histological analyses reveal indeed that the milk ducts in the terminal portion of the nipples form an enlarged, convoluted sinus lined with secretory epithelium (Moncomble 2006). Alternatively, some involatile or bound substances carried in milk might be oxidized at contact with air, leading to the instantaneous release of volatile compounds.

17.5.2.2. Evidence for Pheromones

As mentioned above, rabbit pups locate and grasp a nipple when put on the abdomen of any lactating doe or exposed to milk from any female (Coureaud et al. 2000; Keil et al. 1990). Since the behavioral activity of rabbit milk is fully conveyed in its headspace, gas chromatography was suitable. Using a gas chromatograph with a flow that was split between the mass spectrometer and an olfactory port to which pups were directly presented, the separative analysis of the headspace of fresh rabbit milk resulted in the identification of one compound among 21 candidates (Schaal et al. 2003). This compound, 2-methyl-but-2-enal (2MB2), being as efficient as fresh rabbit milk to elicit searching-grasping motions, it was considered as a putative signal, and therefore submitted to systematic tests verifying the five pheromone criteria specified in Section 17.4:

Criterion 1: 2MB2 is the chemically “simplest” possible stimulus as it is composed of a single molecular “species.” Its activity is extraordinarily strong in releasing searching-grasping actions, although it cannot be excluded that additional, not yet identified, milk or nipple compounds may act synergistically. However, such synergy will be difficult to assess as the effect of 2MB2 on the typical responses of pups is ceiling during the first 10 postnatal days.

Criterion 2: The macroscopic structure of rabbit pups’ responses to pure 2MB2 is not differentiable from that of entire fresh milk, indicating that a single key compound from rabbit milk can mimic the response elicited by milk itself. Further, during the first day 10 days after birth, 2MB2 is behaviorally efficient regardless of the context or mode of presentation (in individual tests presenting the stimulus on a glass rod or at the sniff port of a GC apparatus; in collective tests in the nest).

Criterion 3: The selective activity of 2MB2 was ascertained by comparing pup responsiveness to 40 odorants represented or not in rabbit milk or suspected to act as chemosignals in other species (among which DMDS shown to be behaviorally active in rat pups). These reference odorants were ineffective to release the criterion response in rabbit newborns at any tested concentration (Coureaud et al. 2003), so the behavioral activity of 2MB2 could not be explained in terms of novelty or nonspecific arousal effects. Further, the activity of 2MB2 was limited within a range of stimulus concentrations extending over 5 log units* (10–9–10–5 g/ml; Coureaud et al. 2004), suggesting some flexibility in 2MB2 intensity eliciting the typical response in pups.

Criterion 4: The species-level generality of the releasing potency of 2MB2 was established in showing its independence from maternal diet and genetic background (Coureaud et al. 2008; Schaal et al. 2003). Further, it was inactive in newborn rats, mice, cats, and humans (Contreras et al. 2013), and even in pups of phylogenetically related brown hares, Lepus europaeus (Schaal et al. 2003).

Criterion 5: Pup responsiveness to 2MB2 develops without need of previous direct exposure to it. To acquire its behavioral efficacy, 2MB2 does not require being contingent of labor-related arousal states, of suckling with or without ingestion of milk, or of contact with the mother: pups taken away from the mother immediately after birth display maximal response to it at very first presentation. Additionally, the 2MB2 stimulus-response loop remains functionally unaltered by long-term deprivation right after birth: separating pups from their mother and hand-feeding them with a cow’s-milk-based formula devoid of 2MB2 for 6 days left their high-level responsiveness to the 2MB2 unchanged on day 6 (Coureaud et al. 2000c). Furthermore, 2MB2 appears efficient in fetuses delivered 1–2 days before gestational term, and 2MB2-targeted GC-MS analyses in amniotic fluid and blood plasma of pregnant and lactating females failed to detect it. Although it cannot be excluded that 2MB2 is present in these fluids at concentrations below the detection level of the GC, this suggests that the behavioral activity of 2MB2 may not derive from prenatal experience (Schaal et al. 2003).

In sum, current data indicate that the 2MB2-behavior coupling requires neither prenatal nor postnatal direct exposure to become functionally specified. These findings allowed categorizing 2MB2 as a pheromone carried in rabbit milk, in the sense of Beauchamp et al.’s (1976) and Johnston’s (2000) operational redefinition of the concept. As 2MB2 appears to be produced somewhere in the mammary tract, presumably in the final portion of the nipple to be discharged into milk, it was named mammary pheromone (MP) (Schaal et al. 2003).

In addition to the completion of a set of physicochemical and biological criteria, any candidate pheromone awaits further demonstration for involvement in mutually beneficial functions between emitter and receiver. Participation of the MP in the reciprocal exchanges of the rabbit female and her offspring is clear on both proximate and ultimate levels of analysis. On the offspring side, it elicits immediate arousal and mobilization of directional actions when the female enters the nest, offers guidance, and favors searching/grasping of a nipple and ingestion of milk. On the female side, the MP may boost tactile stimulation from pups toward the abdomen, stimuli known to trigger and sustain lactational physiology. A critical consequence of pups’ reactiveness to the MP is highlighted by the fact that individual pups that do not respond to the MP on postnatal day 1 mostly die during the following 4 weeks (Coureaud et al. 2007). Thus, initial reactivity to the MP is predictive of long-term viability. Another point of functional interest is that the behavioral effectiveness of the MP closely matches the period when pups need to contact nipples to ingest milk (i.e., between birth and weaning), and more precisely during the 10-day period when they depend only on olfaction to satisfy their exclusive need of milk (Coureaud et al. 2008; Montigny 2008). Finally, the MP triggers automatic responses that ensure that pups are ready to grasp a nipple at any time during the first postnatal days; MP-induced oral grasping is then compulsory at each presentation of the mother, and it is only later that oral activity of pups comes to be modulated by circadian or metabolic factors (Montigny et al. 2006).

17.5.3. Primates

Our current knowledge about primate behavior in the nursing relationship stems essentially from human studies, nonhuman primates being more difficult to investigate in detail regarding the sensory processes that control mother-infant interactions. Darwin (1877) first intuited that human infants might use, among other cues, odors to orient to their mother’s breast. This was confirmed a century later by a boom of experiments assessing neonatal responses to odors emitted from the breasts of lactating women. Such odors were indeed shown to reduce arousal in active newborns (Nishitani et al. 2009; Schaal 1986; Schaal et al. 1980; Sullivan and Toubas 1998) and increase it in somnolent ones (Russell 1976; Soussignan et al. 1997; Sullivan and Toubas 1998); to elicit positive head turning (Macfarlane 1975; Makin and Porter 1989; Schaal et al. 1980), stimulate oral (Russell 1976; Soussignan et al. 1997) and respiratory activity (Doucet et al. 2009), favor directional crawling (Varendi and Porter 2001; Varendi et al. 1994) and the opening of the eyes (Doucet et al. 2007) with important consequences for the development of multimodal perception (Durand et al. 2013; Schaal and Durand 2012). Thus, Homo newborns are clearly affected by odor cues emitted from their mother’s breasts.

17.5.3.1. Mammary and Extramammary Sources of Behaviorally Active Chemostimuli

The human nipple/areolar region abounds in apocrine and sebaceous glands which ducts open on the tip of the nipple and give off secretions during lactation (Montagna and MacPherson 1974; Perkins and Miller 1926). Eccrine sweat glands and large sebaceous glands are also found on the areolae (Montagna and MacPherson 1974), where the surface is also dotted with small prominences (Morgagni’s corpuscles) that host Montgomery’s glands (MG) (Montgomery 1837), composed of sebaceous glands combined with miniature mammary acini (Montagna and Yun 1972; Smith et al. 1982). The quantitative assessment of MG prevalence, distribution, and patent activity in breastfeeding women (Doucet et al. 2012; Schaal et al. 2006) indicates that 97% of (Caucasian) women have more than 1 unit/areola, and 83%, from 1 to 20 units/areola. These MG can give off a latescent fluid (Doucet et al. 2012; Schaal et al. 2006). Colostrum and milk released from main lactiferous ducts add their intrinsic olfactory qualities to the areolae. The quality/intensity of lacteal secretions are in part influenced by odorous compounds transferred from the maternal diet (Hausner et al. 2008; Mennella and Beauchamp 1991a, b, 1996; Schaal 2005).

Extramammary substrates conveyed by the newborn or mother also contribute to the mammary odor in humans. Regarding the newly born infant’s contribution, such extraneous sources can be amniotic fluid, vernix caseosa, vaginal secretions, and blood, as well as tears, mucus, saliva, and saliva-milk coagulate spread on the breast during the first sucking attempts. Mothers may add some artificial scents as they often smear their areolae with locally prescribed emollients (e.g., Delaunay-El Allam et al. 2010).

Taken together, these varied sources of mammary and extramammary substrates create a multifaceted and dynamic areolar odor blend. Lipids issued from keratinizing epidermis, sebum from free sebaceous glands and MG, as well as fatty acids from milk, may all act as odor fixatives that improve the chemical and temporal stability of the odor mixture formed on the areolae. The intricate arrangement of sebaceous and lacteal sources within the MG favors the mingling of sebum with areolar milk. In addition, local biochemical and thermal processes may selectively release given compounds or categories of compounds from this mixture. Thus, salivary enzymes spread by the suckling infant may speed up the release of odor-active compounds (Büttner 2002), and areolar skin temperature fluctuations due to the vasoactivity of underlying Haller’s areolar plexus (see below) may segregate volatiles differing in vapor pressure (Schaal et al. 2009).

The complexity of the scent of the human areolar-nipple area and the difficulty in assaying human newborns makes analytic efforts uneasy. A study evaluated how far the morphologically differentiable areas of the breast could elicit distinct behavioral effects in newborns (Doucet et al. 2007). These areas were fractionated in applying an odor-free plastic film directly onto the breast of lactating women, various openings in it allowing to subtract the areolar contribution from the whole breast odor, and to separate the areolar contribution from those of the nipple or of oozing colostrum/milk. The behavioral impact of the areola was examined in approaching hungry newborns from the selectively unmasked breast regions of their mothers. Corresponding odor cues modulated infants’ arousal states and promoted appetitive oral activity, but the responses were not differentiable between the whole breast odor, the isolated areola or nipple odors, or separate milk odor, suggesting equivalent attractive potencies of all breast stimuli, with all being equivalent in activity with fresh human milk. Such behavioral uniformity of the breast regions may be due either to overlapping compounds resulting from shared exocrine sources or from cross-contamination, or to distinct compounds bearing similar attractiveness due to similar reward associations. In a finer-grained study, 3-day-old newborns were exposed to the fresh secretion from MG (Doucet et al. 2009). Neonatal reactivity to these areolar odors tested against several reference stimuli (e.g., human milk or sebum, solvent, vanilla, fresh cow’s milk, cow’s-milk-based formula) showed that pure MG secretion elicits more orofacial activity.

Colostrum and transitional milk were also tested separately as sources of active odor cues for infants ranging in age from minutes to weeks after birth. The odors of colostrum (from postpartum days 1–2) and milk (from postpartum days 3–4) were shown to elicit reliable positive head turns (Marlier and Schaal 2005; Marlier et al. 1998). They were also strong releasers of facial and oral responses (mouthing, protruding tongue, rooting, sucking) indicative of their attractive and appetitive value to infants born at gestational term (Mizuno and Ueda 2004; Russell 1976; Soussignan et al. 1997) or preterm (Bingham et al. 2003a, 2007). Finally, the odor of human milk has repeatedly been shown to attenuate pain responses in newborns (e.g., Mellier et al. 1997; Nishitani et al. 2009; Rattaz et al. 2005).

To sum up, the above results indicate that odors from human mammary secretions are clearly detectable to infants aged from about 2 months before term to more than 1 month postbirth, and that they have particular behavioral effects on arousal states, general attraction, appetitive actions, and self-regulatory responses.

17.5.3.2. Evidence for Pheromones?

So far no evidence for any chemostimulus that would qualify as a pheromone is at hand in primate, including human, mother-to-infant communication. In humans, two mammary-related substrates, colostrum/milk and the secretion from the areolar glands of Montgomery, are valuable candidates for systematic analyses. These substrates are emitted by any lactating females (i.e., postparturient women that are unrelated and unfamiliar to the tested infant), do elicit infants’ behavioral and psychophysiological responses that are species-specific (i.e., differentiable from heterospecific secretions), and are dissociable from nonspecific arousal effects caused by any odorant. In addition, the behavioral activity of these secretions does not derive from postnatal experience with breast-related stimuli, although the role of prenatal induction cannot be excluded. Clearly, further investigation is needed to confirm these first results and to substantiate whether mainstream milk and Montgomerian secretion convey redundant or distinct odor information to infants. These different mammary secretions wait to be subjected to chemical analyses to pin down volatile compounds that can then be brought under the nose of human newborns in repeatable bioassays.

17.6. MAMMARY CHEMOSTIMULI AS ONTOGENETIC ADAPTATIONS

Some authors have questioned whether the rabbit MP can be construed as a pheromone because rabbit pups responses to it “is not invariant, being influenced by age and degree of hunger” (Doty 2010, p. 91). Context independence of the response has indeed often been required for the development of reliable behavioral assays for pheromones (e.g., Beauchamp et al. 1976; Müller-Schwarze 1977; Thiessen 1977), the optimal response being a kind of reflex or a “fixed action pattern” with minimal intra- and interindividual variability. Rabbit pups provide indeed a high level of morphological stereotypy of their response to the MP when tested at a same age. But chemosignaling/reception devices cannot be conceived in independence of integrated biological systems, and hence, they can only fluctuate as a function of both external and internal conditions (e.g., Alberts 1987; Wyatt 2003, 2010).

17.6.1. Contextual Fluctuations in Mammary Chemosignaling

The emission rate or activity of mammary chemical signals fluctuates intraindividually along lactation and at each nursing episode. For example, the mixture of abdominal odor cues of lactating rabbits or cats is more efficient to release pup searching in early rather than late lactation (Coureaud et al. 2001; Hudson and Distel 1984; Raihini et al. 2009). Little is known about the endocrine control of such abdominal odor cues and whether it operates in anticipation of the engagement of nursing behavior, in response to the solicitation by offspring, or both. In rabbit females, sucking-related tactile stimulation of the nipples triggers prolactin and oxytocin release that controls milk production and ejection (Summerlee et al. 1986), and affects the tonic release of sebum (Wales and Ebling 1971). In rats, an injection of oxytocin reinstates the olfactory attractivity of lactating females’ abdomen after its disruption by washing (Singh and Hofer 1978). The endocrine effects of sucking-related somesthesis increase up to 15–20 days postpartum and then progressively drop with the inception of weaning (Summerlee et al. 1986), providing a basis for long-term variation in mammary-related chemoemission.

In the rabbit, pup reactivity to the complex odor of milk and to the pure MP follows fluctuations comparable to those noted with whole abdominal odor cues: when 2-day-old pups are exposed to the odor of fresh rabbit milk collected either on early or late lactation (postpartum days 2 and 23, respectively; weaning taking place on day 30 in domestic conditions), the behavioral activity of milk declines between both sampling points, in the same time as the MP concentration in the milk headspace decreases (Coureaud et al. 2006). Thus, the MP in milk or compounds in abdominal cues may be involved in the postnatal course of young-to-female interactions.

In human females, lactation-related variations in the olfactory attractiveness of the breast for infants remain poorly understood. Increased sebaceous productivity of the MG appears effective in late pregnancy and early lactation (Burton et al. 1973), leading to presumable variations in the amount/composition of areolar secretions. If MGs support communicative function, one may expect enhanced secretory output right after delivery and then before each ensuing nursing bout. The rate of women that have secretory MGs tend indeed to be higher on postpartum days 1–3 than on days 15 or 30 (Schaal et al. 2006), but more conclusive data are needed here.

Mammary odor varies also qualitatively and/or quantitatively along the nursing cycle. The abdominal odor of lactating rabbits is more efficient to release pup searching in prenursing than in postnursing condition (Coureaud et al. 2001). Nursing-related variations in lactogenic hormones may indeed favor milk emission at the nipple (and in humans in the lactiferous component of MGs) or the secretory activity of mammary-related skin glands. Infant attraction to the mammae may also be influenced by thermal changes due to changes in local metabolic activity or to vasoactive responses. For example, in humans the areolar dermis is underlain by Haller’s vascular plexus (Mitz and Lalardie 1977). An acute vasodilatation of this plexus may confer a higher temperature to the areolar surface relative to the adjacent skin and maximize evaporation of odorants oozing from the MG in synchrony with the infant’s presentation to the breast (Vuorenkoski et al. 1969).

To sum up, the best studied case of the rabbit highlights that the production and/or emission of the mammary odor is under the tonic control of gonadal steroids and lactogenic hormones. This leads to the externalization of odor cues at the very end of gestation and around birth, when pups’ reactivity to them is maximal. Then, the attractant potency of the mammary odor mixture appears to progressively drop, and the release of the MP is abolished near weaning. Thus, when the weaning process is engaged, rabbit females may control pup motivation to suckle in reducing MP emission. At peak lactation, the timely control of mammary chemosignalization is presumably modulated by rhythmic processes (e.g., Montigny et al. 2006) and by infant-related distal and proximal stimuli.

17.6.2. Contextual Fluctuations in Neonatal Chemoreception

The decrease in the female’s emission of mammary chemosignals is echoed in altered neonatal reactivity to them. The rabbit MP potency to release pup responses decreases progressively over the preweaning period, indicating regulation by endogenous and exogenous factors. The response rate of domestic rabbit pups to the MP goes indeed through several stages: (1) from birth to days 8–10 pups respond maximally to the MP when they exclusively depend on mother’s milk, (2) around postnatal days 8–11, a first drop from above 90% to ~80% of responding pups coincides with eye opening (~day 10–11) and the presumed reorganization of the pups’ perceptual balance (Montigny 2008), (3) between days 11–21 a second drop occurs from ~80% to ~40% responding pups who become mobile, localize the female visually, initiate suckling, and begin to ingest solid food, (4) after the third week the typical response to the MP vanishes completely (Coureaud et al. 2008; Montigny 2008).

In parallel to the progressive decline or releasing potency of the MP along the nursing cycle, rabbit pups’ response to mammary/milk signals comes gradually under circadian and metabolic modulation. On postnatal day 2, they react to the MP automatically at any time, without influence from prior milk intake or other emerging circadian factor (Montigny et al. 2006). But by postnatal day 5, and more so by day 10, this steady response to the MP restricts to prenursing hours.

Thus, with sensory reorganizations, cognitive development and changing metabolic needs, the sucking behavior of neonatal rabbits progressively escapes exclusive control by the MP. This shift in response to the MP from automatic to prandially-controlled is of particular significance in the context of the rare milk-resource access evolved by rabbit females. It warrants that rabbit pups are first bound to respond to the mammae in the rare minutes of milk availability; next, its decreasing strength (both in signal value and in evoked response) may contribute to the progressive disinvestment of the mammae when newborns can move by themselves and process nonmilk foods. This progressive shift of behavior control from chemosensation to other senses awaits investigations in rabbit newborns as well as in other mammalian newborns.

17.6.3. Chemosensory Ontogenetic Adaptations

The concept of ontogenetic adaptation implies a set of organismic responses to species-specific transformations of the environment during development (Alberts 1987). Each stage of development takes place in a given functional niche. In mammals, fetuses dwell in the uterus and amnion, where they are provisioned through the placenta; neonates are in a nest or within/against parent(s) and suck milk from their mother; while staying close to parent to ensure milk intake, weanlings acquire safe information about nonmilk foods and begin testing them; then come independent feeding and dispersion into extensive social networks. Each of these developmental niches correspond with exchanged substances or information between transitional phenotypes in both mothers and neonates (West-Eberhard 2003). These adaptive transitional phenotypes involve all levels of anatomical, physiological, and behavioral functioning. In the fetus, the placenta and related circulatory specificities are the most obvious adaptations, but numerous other subtle changes occur as labor sets on (e.g., Alberts and Ronca 2012). Neonatal mammals are behaviorally specialized to search, orally seize, and suck on a nipple or teat, their brain is engaged in (and dependent of) active sensory processing and integration, and their gastrointestinal tracts are designed to digest and absorb milk in symbiosis with the gut microflora passed on by the mother. As noted by Alberts (1987, p. 18), “stages of ontogenetic adaptation are composed of constellations of adaptive adjustments on multiple levels of organization… Successful stagewise transitions depend on coordinated and integrated readjustments, often drastic in extent.” In the perinatal period, the adaptive challenges are especially drastic, and “adaptive adjustments displayed by the infant are correspondingly stunning.” Thus, it should not be surprising that predisposed responsiveness to pheromones can change with age and age-related psychobiological readjustments.

The adaptive adjustments under scrutiny here concern sucking a nipple, and the sensory and cognitive means neonates engage to locate it and work on it to optimize milk intake. We have summarized how these achievements are conditional upon the perception of mammary-related odor cues, and in some species, of pheromones. When the dependence on milk declines as offspring grow up, it is expectable that the communicative value of these cues and signals changes or may completely vanish (as is the case in the rabbit MP). In this sense, nipple chemostimuli and their neonatal sensory processing can be seen as ontogenetic adaptations. They orchestrate the neonate-lactating female relationship, are vital for multiple proximate benefits to the neonate, and prepare the transition to the next developmental stage.

The rabbit MP not only serves to arouse and guide neonatal pups to the nipple, but also operates as a potent magnifier of odor learning. During a short window of early development (postnatal days 1–4), the MP promotes extrafast learning of any odor that is circumstantially associated with the mother or her milk (Coureaud et al. 2006; Montigny 2008). This MP-induced learning is a process by which newborns can update the changing odor properties of mammae and milk. More generally, the MP may speed up perceptual narrowing by accelerating glomerular refinement (Kerr and Belluscio 2006) and in this way rapidly assign meaning and reward value to some odorants beyond the sole MP that are salient in the individual odor profile of the mother (Patris et al. 2008), of the nest, and of littermates (Hudson et al. 2003; Montigny 2008; Serra and Nowak 2008), or of nonmilk foods (Montigny 2008). The strong arousal effect of the MP could also be involved in setting circadian rhythmicity of the coordinated activity by which neonate pups anticipate the brief daily nursing episode to increase their sucking success (Caldelas et al. 2009; Nolasco et al. 2012). It was indeed recently shown that the MP functions as a non photic zeitgeber for the central oscillators that contribute to regulate rhythms in body temperature and nursing-related anticipatory behavior in newborn rabbits (Montúfar-Chaveznava et al. 2013).

This pheromone-enforced learning process evidenced in the rabbit can presently guide us to question how mammalian neonates encode and decode chemosensory information from exceedingly complex and changing stimuli (e.g., Sinding et al. 2013). It should also stimulate future research to understand the precise nature and development of the molecular processes at the chemosensory periphery (perireceptor events (see Legendre et al., submitted); ligand-receptor interactions) and the neural pathways involved in the differential processing of the MP and conventional odorants (e.g., Charra et al. 2011, 2013). Dedicated neural pathways to process mammary chemosignals in the rabbit newborn, if any, would then prove informative about similar possibilities in other mammalian newborns.

17.7. CONCLUSION: MAMMALIAN NEONATES AS MODELS TO UNCOVER HOW AND WHEN CHEMORECEPTIVE SYSTEMS MAKE SENSE OF ODOR CUES AND SIGNALS

This review suggests that, at least in the mammalian species surveyed above, aspects of females’ morphology, physiology, and behavior were evolutionarily selected to render the mammary area conspicuous for their newborns. This strategy of mammalian females to advertise mammaries to their offspring relies on informative means that match the earliest developing perceptual and behavioral abilities of their newborns. Accordingly, emitting some chemical cues and/or signals from the mammae is a suitable pan-mammalian strategy to pilot neonatal arousal, motivation, and attraction to the mother, to provide assistance in localizing and orally seizing the mammae, and to boost up timely learning. However, as noted in the three mammalian orders surveyed above, the ways by which these chemical cues are produced and assembled on the mammary area are complex within species and diverse between species.

The above review also highlights that neonatal mammals can develop a repertoire of learned odor cues derived from intra- and extramammary sources, but it indicates only rare cases of pheromonal signals that control nursing. The most completely documented cases so far of such mammary-based pheromones are Oryctolagus, the European rabbit (Hudson and Distel 1994; Schaal et al. 2008a) and Rattus, the laboratory rat (Blass and Teicher 1980). This scarcity of studies appeals for more research in an area that bears great potential to advance our knowledge on mammalian communication and chemoreception. It is a vital imperative for mammalian neonates to detect sensory cues from mother, mammae, and milk, and it is accordingly expectable that they are designed to do it right at birth. Thus, testing neonatal animals with odor stimuli they may be evolutionarily canalized to detect may be a productive way to identify new pheromones as well as new strategies of females to produce odor signals and to facilitate their sensing by neonates. In fact, newborn mammals may allow the strongest corroboration of the concept of the pheromone in its renewed formulation (see Section 17.4). Newborns (especially those of the altricial type) have generally restricted sensory abilities, are specialized in motor responses, limited in their stores of odor memories, and they are highly motivated to approach the mother or salient sensory traits disembodied from her. Finally, in many species, newborns are relatively easy to handle (although it is not always the case of maternal females). In fact, probably the most complete demonstrations to date of mammalian pheromones have advantageously focused on the newborns of readily available species.

Empirical emphasis on newborns may also help to assess the validity of categorizing stimuli into evolved signals and developmentally-acquired cues (see Section 17.2). Both kinds of stimuli are often considered as functionally equivalent, bringing arguments to some authors who propose to clear any distinction between pheromonal signals and circumstantially learned odor cues (e.g., Doty 2010). However, under adequate experimental circumstances, there is evidence that this may not be the case. When both types of stimuli are presented concurrently, neonates do not treat them as equivalent. For example, human infants deprived from birth of direct exposure to mother’s breast/milk exhibit a clear preference for human milk odor over the odor of their formula milk that recurrently sated them (Marlier and Schaal 2005). In the same line, when paired with human milk odor, a chamomile odor sensed during nursing does not surpass milk for attractiveness in human newborns (Delaunay-El Allam et al. 2006), indicating that the most dominant or the most recent smell is not the most powerful in a choice test. Finally, when rabbit pups deprived of any exposure to the MP were conditioned to artificial odorants for 6 days, their response rate to the MP remained unaffectedly high and the releasing potency of the newly acquired odorant that recruited the same motor response system (oral grasping) never surpassed that of the MP (Coureaud et al. 2000). Thus, mammalian female-neonate units may be particularly suited models to uncover whether, when, why, and how the chemoreceptive system establishes the salience of social odor stimuli.

Finally, the paucity of our knowledge on the chemosensory regulation of mammalian nursing behavior is startling when one considers its absolute necessity for neonatal survival and initial development. Renewed interest in that topic, after the considerable work of developmental psychobiologists in the 1970s–1980s (e.g., Alberts 1976, 1981, 1987; Blass and Teicher 1980; Rosenblatt 1983), would certainly be rewarding to further understand the proximate mechanisms and development of chemoemission and chemoreception in readily accessible mammalian species (laboratory rodents, domestic ungulates and carnivores, humans). Such an approach should also encourage interest in more unusual species in which neonates are odor-guided in the nursing context (e.g., marsupials, insectivores, pinniped carnivores, nonhuman primates,) or in which such indications seem lacking (e.g., monotremes, proboscidians, cetaceans). Such knowledge would be interesting for comparative and phylogenetic analyzes of communication mechanisms that were seminal in the evolutionary success of mammals. In a different perspective, it would also be of interest to identify evolved odorant signals from maternal/lactating females to use them in promoting adaptive responsiveness and well-being in human neonates undergoing medical treatments and related prolonged separation from the mother.

ACKNOWLEDGMENTS

This chapter recapitulates and actualizes ideas developed in Schaal (2010). I gratefully thank my colleagues and students in Dijon and abroad, S. Al-Aïn, J.Y. Baudouin, A. Büttner, R. Charra, G. Coureaud, S. Doucet, K. Durand, C. Fenech, W. Francke, E. Hertling, A. Holley, R. Hudson, I. Jakob, T. Jiang, H. Loos, A.S. Moncomble, D. Montigny, P. Orgeur, B. Patris, H. Rödel, G. Sicard, C. Sinding, R. Soussignan, and F. Védrines for past and continued teamwork in investigating the behavioral biology of neonates. While writing this chapter, I was supported by grants from ANR (Colostrum program), the Regional Council of Burgundy (PARI) and the CNRS.

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Footnotes

*

Accordingly, to keep the pheromone concept meaningful, any candidate secretion, excretion, or fractions of them bearing repeatable behavioral and/or physiological effects on newborns (the excretion of a gland, abdominal skin secretions, milk, saliva, etc.) should not be termed pheromone. If such biological mixtures verify some of the above criteria, they might be named “candidate secretions for pheromonal mediation” (Doty 2003) before the long way to the chemical identification of the active compound(s). In any case, the term pheromone should be reserved for clearly identified chemicals that have undergone systematic screening of above operational criteria.

*

Although pure urine from lactating dams appears weakly effective (Teicher and Blass 1976, 1977).

*

The fact that these concentration values of 2MB2 in the stimuli were those in the experimental water solutions seems to have escaped some authors (Doty 2010; Hudson et al. 2008). The 2MB2 concentrations in the headspace of these solutions—to which rabbit pups were actually exposed—were not titrated, but can be expected to be lower than those in the aqueous solutions.

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