15.1. INTRODUCTION

Although olfaction is generally assumed to play a minor role in humans compared to vision or audition, it is also commonly accepted that odors have a rather unique status for eliciting memories. Indeed, one of the most striking features of odor memory in humans resides in the amazing power of odors to vividly trigger the evocation of autobiographical experiences. This property has been referred to as the “Proust phenomenon” by some authors (Chu and Downes 2000, 2002) because of the well-known literary anecdote reported by Proust (1919) at the beginning of his novel, Swann’s Way, wherein the flavor of a madeleine cake dipped into a cup of tea unwillingly caused the remembrance of an old detailed memory.

“The memory suddenly appears before my mind. The taste was that of the little piece of madeleine which on Sunday mornings at Combray (because on those mornings I did not go out before church-time) my aunt Leonie used to give to me, dipping it first in her own cup of real or lime-flower tea’, leading him to the conclusion that ’When from a long-distant past nothing subsists … the smell and taste of things remain poised for a long time … and bear unfaltering, in the tiny and almost impalpable drop of their essence, the vast structure of recollection.”

A number of psychological studies have experimentally investigated the so-called Proust phenomenon in human subjects. Different works have shown that odor-cued memories are more emotional than memories triggered by visual or verbal cues (Chu and Downes 2000; Herz and Cupchik 1995; Herz 1998; Herz and Schooler 2002; Willander and Larsson 2007). Odor-cued memories have also been described as more vivid than memories evoked by corresponding words (Chu and Downes 2002). In addition, the feeling of being brought back in time to the occurrence of the event is experienced as stronger for odor-cued memories than memories evoked by words and pictures (Herz and Schooler 2002; Willander and Larsson 2006). Interestingly, it was also shown that autobiographical memories evoked by olfactory information were older than memories associated with verbal information (Chu and Downes 2000; Willander and Larsson 2006). Specifically, most odor-cued memories were located to the first decade of life (<10 years), whereas memories associated with verbal and visual cues peaked in early adulthood (11–20 years). This observation is in agreement with the fact that olfaction emerges very early in ontogeny and with research showing that associative odor learning begins very early in life (Schaal et al. 2000; Van Toller and Kendal-Reed 1995). Taken together, these studies suggest that human olfaction is unique in its ability to cue the emotional aspects of autobiographical memory, including experiences formed early in life.

In animals, memory for environmental odors plays a vital role because it regulates many behaviors that are crucial for their survival. Highly emotional or at least particularly ethologically relevant olfactory learning occurs during an animal’s major life events. For instance, and as will be developed in Section 15.3, during the early postnatal (PN) period when altricial pups are crucially dependent on their mother for feeding and maternal care, unusually rapid and strong olfactory learning occurs. The newly learned odor becomes preferred and is approached to bring the infant in contact with the mother, although the odor also controls the complex sequencing of motor patterns to support nipple attachment in rats (Cheslock et al. 2000; Hofer and Sullivan 2001; Pedersen et al. 1982) and rabbits (Distel and Hudson 1985; Coureaud et al. 2006; Schaal et al. 2003). At adulthood, two types of powerful ethological olfactory learning have been described in the literature. The first occurs in the postpartum period, when the mother learns the odor of the newborn and is critical for the mother to accept and nurse the young. This has been eloquently described in the postpartum sheep (Levy et al. 2004; Nowak et al. 2007; Keller et al. 2004, 2005; Brennan and Kendrick 2006) and rat (Fleming et al. 1999; Levy et al. 2004), and is the first step in the establishment of mother-young bonding. The second example of ecologically significant odor learning involves chemosensory individuality (Brennan 2004) and mate recognition (Brennan and Keverne 1997), which regulate reproductive behavior in mice (see also Chapter 6). Thus, particularly robust and rapid odor learning occurs throughout the life span during life transitions critical for survival and reproductive success.

Rapid, emotional learning is also necessary during threatening situations, to avoid that danger in the future. This type of learning is modeled by fear conditioning, where a temporal association of a neutral stimulus (i.e., tone or odor) is made with a noxious stimulus (i.e., shock) after only a few pairings. The formerly neutral stimulus acquires the ability to elicit defensive or escape responses critical in avoiding the danger and is dependent upon plasticity in the basolateral complex of the amygdala (LeDoux 2000; Fanselow and Gale 2003; Davis and Whalen 2001; Maren 2003; Otto et al. 2000). This paradigm has permitted enormous progress in our understanding of emotional learning in a controlled laboratory environment. More recently, this approach has been extended to humans with remarkable convergence in the underlying neural circuitry during acquisition, expression, and extinction, suggesting some homologous control of emotional learning in rats and humans (LaBar et al. 1998).

The aim of the present chapter is not to present an exhaustive review of the neurobiology of these different olfactory learning tasks, but rather to concentrate on those inducing emotional olfactory memory in rats, both at early PN ages and at adulthood. The vast majority of the existing studies on fear conditioning have been carried out using auditory or visual modalities. However, odors are at least as potent as auditory or visual cues in sustaining learned fear. Therefore, we specifically review the literature describing the neural circuit involved in odor fear conditioning in adult and infant rats, but we begin by presenting a brief review of the olfactory pathways within the brain.

15.1.1. Neuroanatomy of the Olfactory Pathways

Olfactory sensory neurons lie in the olfactory epithelium, which covers the back of the nasal cavity. The axons of the olfactory sensory neurons travel through the cribriform plate to the olfactory bulb, which is the first relay of olfactory information (Figure 15.1). The olfactory bulb output neurons send direct projections to the olfactory cortex, including the anterior olfactory nucleus, the olfactory tubercle, and the piriform or olfactory cortex (Shipley and Ennis 1996; Haberly and Price 1977; Carmichael et al. 1994). The first unusual characteristic of the mammalian olfactory pathways is that, unlike other sensory systems, it does not need to pass through the thalamus to reach cortical areas. Indeed, there is no thalamic relay between the first relay of sensory information, namely the olfactory bulb, and the primary olfactory cortex, as is the case for other sensory modalities (Figure 15.1). Similarly, there is no obligatory thalamic relay for olfactory information to reach the orbitofrontal cortex. Indeed, although the piriform cortex sends sparse projections to the mediodorsal thalamus, thereby disynaptically targeting the orbitofrontal cortex, it establishes direct monosynaptic connections with the orbitofrontal cortex (Datiche and Cattarelli 1996; Tanabe et al. 1975; Yarita et al. 1980; Ray and Price 1992; Carmichael et al. 1994). These observations suggest that the thalamus might be less relevant for olfaction than for the other senses (Shepherd 2005; Wilson and Stevenson 2006), but see Plailly et al. (2008) for an alternative view.

FIGURE 15.1

Schematic representation of the main components of the olfactory pathways. Diagram illustrates the intimate link between the olfactory bulb and the limbic areas (amygdala and hippocampus).

Another unique feature of the olfactory pathways is the olfactory bulb’s output neurons rapid connections to structures crucially implicated in emotion and memory, namely the amygdala and the hippocampus. Indeed, the main olfactory bulb makes dense monosynaptic contacts with nuclei of the corticomedial amygdaloid group, including the nucleus of the lateral olfactory tract, the cortical nucleus of the amygdala, and the periamygdaloid cortex (Price 1973; McDonald 1998). These observations led Swanson and Petrovich (1998) to suggest that the corticomedial amygdala is an integral component of the olfactory system. These superficial nuclei are a major source of the projections from the amygdala to the hypothalamus (Price et al. 1991). In contrast, the deeper amygdaloid nuclei, including the basolateral nuclear group, do not receive projections from the olfactory bulb and receive relatively weak projections from the olfactory piriform cortex (Krettek and Price 1978; Luskin and Price 1983; Ottersen 1982). However, they receive fairly dense projections from the corticomedial nuclei within the amygdala (Savander et al. 1996). Taken together, these anatomical data suggest that compared to the other sensory modalities, olfactory information has a unique direct access to the amygdala.

In addition, both anatomical (Price 1973; Haberly and Price 1977) and electrophysiological (Biella and de Curtis 2000; Wilson and Steward 1978; Boeijinga and Van Groen 1984; Mouly et al. 1998, 2001; Mouly and Di Scala 2006; Biella et al. 2003) studies have shown that the olfactory bulb and the piriform cortex also send direct projections to the lateral entorhinal cortex via the lateral olfactory tract. The lateral entorhinal cortex, in turn, has been shown to project to the hippocampus via the lateral perforant path (Witter and Amaral 1991). Furthermore, in addition to providing a gateway to the hippocampus, the lateral entorhinal cortex sends monosynaptic projections to the amygdala. The primary targets of the entorhinal cortex are the basolateral amygdala and the cortical nuclear complex (Brothers and Finch 1985; McDonald and Mascagni 1997). The lateral entorhinal cortex is, therefore, in a position to transmit information from olfactory cortical areas to two major telencephalic components, the amygdala and the hippocampus, and back to olfactory areas through reciprocal connections (Swanson and Kohler 1986; Insausti et al. 1997).

15.2. EMOTIONAL ODOR MEMORY IN ADULT RATS

15.2.2. Neurobiology of Olfactory Fear Conditioning in Rats

Behavioral researches have shown that olfactory fear conditioning induces robust emotional responses. Otto et al. (1997, 2000), measuring freezing behavior as an index of learned fear, reported that olfactory fear conditioning resulted in robust and long-lasting associations between an odor and a foot-shock. Richardson et al. (1999) and later, Paschall and Davis (2002), using fear-potentiated startle as another measure of learned fear, showed that an odor previously paired with shock was a particularly effective stimulus for potentiating the startle response in rats. Moreover, in a subsequent study, Richardson et al. (2002) reported that extinction of learned fear potentiation of startle occurs more slowly with an olfactory CS than with auditory or visual cues. Thus, odors are at least as efficient as other types of sensory stimuli to induce learned fear responses.

15.2.2.1. The Role of the Amygdala

Concerning the neural basis of olfactory fear conditioning, there is a consensus in the existing literature that the amygdala plays a crucial role. Indeed, Cousens and Otto (1998) first showed that pre- and posttraining excitotoxic lesions of the basolateral amygdala abolished the acquisition and expression of olfactory fear conditioning in rats. In another study, Walker et al. (2005) evaluated the respective contribution of the basolateral and medial amygdala to olfactory fear conditioning by infusing antagonists of glutamate receptors into these areas prior to either odor-shock pairings or retention test using fear-potentiated startle. Pretraining blockade of N-methyl D-aspartate (NMDA) receptors into the basolateral amygdala disrupted fear conditioning to the odor, while pretest blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptors disrupted fear-potentiated startle to the learned odor. Neither compound blocked fear conditioning when infused into the medial amygdala prior to training, but pretest AMPA/kainate receptors antagonist infusion did block fear-potentiated startle. Using an electrophysiological approach, Rosenkranz and Grace (2002) performed in vivo intracellular recordings in the lateral nucleus of the basolateral amygdala during acquisition of an odor fear conditioning under anaesthesia, in rats. Their data revealed that repeated pairing of an odor with foot-shock induced enhanced postsynaptic potential responses in neurons of the basolateral amygdala, and that this modification resulted from local changes in synaptic efficacy, and was dependant on dopamine.

Another set of studies has investigated more specifically the involvement of the amygdala in the consolidation of odor fear conditioning. Specifically, Killpatrick and Cahill (2003) used reversible inactivation of the basolateral amygdala with tetrodotoxin following paired odor-shock presentation in rats. This treatment resulted in a deficit in learning, thus suggesting that the basolateral amygdala plays a role in consolidation of odor fear conditioning. Similarly, Rattiner et al. (2004) measured the expression of brain-derived neurotrophic factor (BDNF) mRNA in the amygdala after olfactory as well as visual fear conditioning. BDNF is known to play a critical role in activity-dependent synaptic plasticity and has been implicated as mediator of hippocampal-dependent learning and memory (Hall et al. 2000; Kesslak et al. 1998). The authors showed that BDNF expression was increased in the basolateral amygdala two hours after fear conditioning and that this increase occurs independently of the sensory modality of the CS.

Taken together, these data suggest that the basolateral amygdala plays a major role in the acquisition, consolidation, and retention of olfactory fear conditioning, thus extending to odor cues the previous observations obtained with auditory and visual CS.

15.2.2.2. The Role of Extra-Amygdala Structures

Beside the above studies specifically addressing the role of the basolateral amygdala, sparse studies have investigated the potential involvement of other target structures in this learning. Among them, Ressler et al. (2002) used genes identified in a kainic acid model of synaptic plasticity, as in situ hybridization probes during the consolidation period after odor fear conditioning. They found that following odor-shock pairings, these genes (such as immediate early genes like c-Fos and Zif 268) were transcriptionally regulated in several brain areas, including the basolateral and medial amygdala, the piriform, perirhinal, and insular cortices, along with the endopiriform nucleus and the habenula. These data suggest that plasticity after odor fear conditioning may depend on a broad neural circuit that includes the amygdala.

Other studies have investigated more precisely the role of extra-amygdala areas in odor fear conditioning. Laviolette et al. (2005) examined the possible role of the medial prefrontal cortex (mPFC) in the acquisition and encoding of odor fear learning at the behavioral and single-neuron level. A subpopulation of neurons in the mPFC that received monosynaptic inputs from the basolateral amygdala demonstrated strong associative responding to odors paired previously with foot-shock by increasing spontaneous activity and bursting activity. In addition, systemic or intra-mPFC blockade of dopamine receptors prevented this emotional associative learning in neurons of the mPFC and blocked the expression of olfactory conditioned fear. These results demonstrate that mPFC neurons that receive a functional input from the basolateral amygdala actively encode emotional learning and that this process is under the dependence of dopamine.

In another study using aspirative or excitotoxic lesions, Herzog and Otto (1997, 1998) investigated the role of the perirhinal cortex. They reported that rats with perirhinal cortex lesions presented a robust attenuation of fear conditioning to olfactory stimulus, thus, suggesting that the perirhinal cortex is an important component of the neural circuit supporting the association between olfactory cues and foot-shock. Later, Schettino and Otto (2001), measuring c-Fos expression related to the acquisition and expression of olfactory fear conditioning, reported that the anterior region of the medial nucleus of the amygdala, as well as the ventral perirhinal cortex, could be critically involved in this learning. Using the same technique, Funk and Amir (2000) also showed that presentation of the aversive conditioned odor stimulus induced an enhanced increase in levels of Fos expression in the main and accessory olfactory bulbs and in the anterior olfactory nucleus, as well as in the infralimbic and orbital cortices.

15.2.2.2.1. The Role of the Hippocampus

In the literature, there is widespread agreement that the hippocampus is not critically involved in the acquisition of discrete CS-US associations (Anagnostaras et al. 2001; Lopez-Fernandez et al. 2007; Maren et al. 1997; Phillips and LeDoux 1992; Schafe et al. 2001), and this also stands for odor-shock pairings (Otto and Poon 2006). Interestingly however, when the odor is presented as a contextual cue instead of an elemental discrete cue, the hippocampus seems to be engaged in the learning of the association. Specifically, Parsons and Otto (2008) examined the effects of temporary inactivation of the dorsal hippocampus on fear behavior in an explicitly nonspatial contextual fear conditioning paradigm, in which olfactory stimuli served as temporally and spatially diffuse contexts. They found that the transient lesion of the dorsal hippocampus produced both anterograde and retrograde deficits in olfactory contextual conditioning, while sparing the acquisition and expression of freezing to a discrete auditory or olfactory CS. These data suggest that the dorsal hippocampus participates in both the acquisition and retention of unimodal olfactory contextual fear conditioning.

15.2.2.2.2. The Role of the Piriform Cortex

Among the other candidate structures for participating in the neural network sustaining odor fear learning, the piriform cortex has been the core of particular attention. The piriform cortex is the largest of the olfactory areas and is usually divided into anterior and posterior parts. Olfactory bulb output neurons synapse primarily on pyramidal cells in the anterior piriform cortex and only send lighter, more distributed inputs to the posterior piriform cortex (de Olmos et al. 1978; Haberly and Price 1978; Haberly 2001). Furthermore, the ratio of associative to afferent input is higher in more posterior regions of the piriform cortex (Haberly and Price 1978; Luskin and Price 1983; Datiche et al. 1996). Moreover, whereas the anterior piriform cortex receives input from the orbitofrontal cortex (Datiche and Cattarelli 1996; Illig 2005), the posterior piriform cortex receives afferents from the basolateral amygdala (Johnson et al. 2000; Majak et al. 2004). In addition, electrophysiological studies have further emphasized this dissociation. Indeed, Litaudon and Cattarelli (1996), using optical recording of the whole piriform cortex activity, showed that following repetitive electrical stimulation of the olfactory bulb, a higher degree of inhibition was observed in the ventromedial anterior part of the piriform cortex than in the posterior part. Using the same technique, Litaudon and Cattarelli (1995) also found that the amplitude of a late component of the evoked activity was larger in the posterior than in the anterior piriform cortex, a result which was confirmed by Mouly et al. (1998) on classical evoked field potential signals. In the domain of synaptic plasticity, Jung et al. (1990) showed that the induction of long-term potentiation in vitro was easier in posterior piriform cortex slices than in the anterior slices. Taken together, the anatomical and functional differences observed between anterior and posterior piriform cortices suggest that these two parts of the olfactory cortex could play differential roles in odor fear conditioning.

Jones et al. (2007) examined BDNF mRNA expression across the olfactory system following fear conditioning in mice. They found a specific increase in BDNF mRNA in animals receiving paired foot-shocks in the posterior piriform cortex and the basolateral amygdala. This was in contrast to the unpaired and odor-alone treatments, where BDNF mRNA was increased in the olfactory bulb and the anterior piriform cortex only, but not the higher olfactory areas. Thus, BDNF mRNA in the olfactory bulb and the anterior piriform cortex seems to be induced simply by exposure to olfactory stimuli, regardless of whether the odor is associated with the shock. In contrast, BDNF mRNA is only induced in the posterior piriform cortex and the basolateral amygdala when there is an association between odor and shock to support learning.

These data complement previous observations reported in our group. Indeed, using an electrophysiological approach, we investigated whether olfactory fear conditioning induces synaptic changes within the olfactory pathways, mainly focusing on olfactory cortical areas, namely the piriform cortex and the amygdala cortical and basolateral nuclei (Sevelinges et al. 2004). For this, evoked field potential signals induced in behaving animals by electrical stimulation of the olfactory bulb were collected simultaneously at the level of the anterior piriform cortex, the posterior piriform cortex, the cortical nucleus of the amygdala, and the basolateral nucleus of the amygdala. Recordings were made before learning and during a retention test carried out 24 h after acquisition of odor fear conditioning. The data showed that learning was accompanied by a lasting increase in signal amplitude in the cortical amygdala, i.e., an increase observed before CS presentation (Figure 15.2A). In addition, introduction of the learned CS odor induced a transient facilitation in the basolateral amygdala, as well as in the cortical amygdala and the posterior piriform cortex (Figure 15.2B). These data suggest that the posterior piriform cortex and the amygdala are key structures in the neural circuit underlying odor fear conditioning.

FIGURE 15.2

Evoked field potentials were induced in the anterior piriform cortex (aPC), the posterior piriform cortex (pPC), the cortical (CoA) and basolateral nucleus of the amygdala (BLA) in response to stimulation of the olfactory bulb, either before (plain line) (more...)

In a recent study (Hegoburu et al. In preparation), we used high temporal resolution (1 min sampling rate) intracerebral microdialysis, in order to study the accurate temporal dynamic of neurotransmitter release in these two structures during the course of learning acquisition. Simultaneous monitoring of GABA and glutamate was performed in both the basolateral amygdala and the posterior piriform cortex, during the odor fear acquisition session including six odor-shock pairings. A transient increase in glutamate was observed in the amygdala for the two first CS-US pairings, whereas a significant increase in GABA levels was shown for the second pairing only. In contrast, in the posterior piriform cortex, transient increases in both GABA and glutamate levels were found after each odor-shock pairing. Interestingly, for both neurotransmitters, the increase observed in the amygdala occurred earlier in time (1–2 min) than the increase in the posterior piriform cortex. High temporal resolution microdialysis, therefore, allowed us to show a temporal dynamic of activation of these two structures during the course of successive pairings, with the involvement of the amygdala during the first odor-shock associations preceding neurotransmitter release in the posterior piriform cortex, after which the latter alone supports pairing-induced modifications. This led us to suggest that the amygdala has a crucial, but temporally limited, role in signaling changes during a potentially dangerous situation, while the posterior piriform cortex may contribute to higher mnemonic processes, including storage of the detailed attributes of the learned stimulus

Taken together, these data bring further support to the growing body of evidence showing that the anterior and posterior piriform cortices play different complementary roles in memory processes. Specifically, the anterior piriform cortex would be mainly involved in coding the sensory features of the odor (Roesch et al. 2007), and in simple forms of short-term memory like habituation (Kadohisa and Wilson 2006; Wilson 1998, 2000) or perceptual learning (Barnes et al. 2008; Wilson and Stevenson 2003), whereas the posterior piriform cortex would be involved in the learning and recall of associations between odorants and information from other sensory modalities (Chabaud et al. 1999, 2000; Mouly et al. 2001; Mouly and Gervais 2002; Kadohisa and Wilson 2006; Haberly 2001; Litaudon et al. 2003; Sevelinges et al. 2004, 2008; Calu et al. 2007; Martin et al. 2004).

15.3. DEVELOPMENT OF ODOR LEARNING MEMORY

The importance of emotional olfactory learning is evident in the rat pups’ first learning experience, when pups must learn the mother’s odor to attach to their caregiver. However, pup learning is strikingly different from adult learning and appears to accommodate pups’ unique environmental demands. Pups are born immature and completely dependent upon their mother for survival, yet become independent only three weeks later. During this time, the rat pups’ world repeatedly changes as they transition from intrauterine life, to nest life, and finally to independence. As will be illustrated in this chapter, different forms of learning emerge, disappear, and sometimes coexist as pups mature. Here, we will review the relationship between a few forms of olfactory learning that change as the demands and importance of attachment learning to the mother and more “adultlike” learning interplay. We will review three types of infant learning: (1) attachment learning that involves learning the maternal odor and expressing the complex behaviors controlled by that odor; (2) olfactory fear learning that emerges as pups begin to venture outside the nest; and (3) malaise learning that enables pups to avoid odors paired with gastrointestinal distress, learning that occurs throughout development but with a changing neural circuit.

15.3.1. Attachment Learning and Maternal Odor

Perhaps the most dramatic transition occurs at birth when infant rats face the daunting cognitive task of transitioning from intrauterine life to nest life. Not only do pups need to learn their mother’s odor within minutes of birth, but also they must rapidly express this learning with approach to their mother and nipple attachment for their first nursing bout. While the mother does assist pups in maintaining contact with her, and prenatal learning supports the PN learning, the PN learning and expression are essential (Pedersen and Blass 1982; Polan and Hofer 1999). If pups do not learn the maternal odor or their olfactory function is disrupted, they have little chance of survival (Singh et al. 1976). Furthermore, since the maternal odor is dependent on the maternal diet, pups must continue to learn the maternal odor throughout the preweanling period.

The maternal odor guides pups to the mother and controls social interactions with the mother, including nipple attachment. During the first week and a half of life, this attachment learning shows very rapid and robust acquisition, as well as some intriguing unique characteristics similar to imprinting. This sensitive period for pups’ rapid learning appears well adapted for the unique demands of life within the nest and the transition to independence that occurs a few weeks later. For most of the sensitive period, the motorically immature pups remain in the nest nursing. However, the mother entering and leaving the nest is sometimes associated with distress to pups when the mother drags still-attached pups out of the nest and steps on others. Thus, pups’ exposure to the maternal odor occurs during nursing and grooming by the mother, but with occasional painful stimuli from the mother. Importantly, pups feel pain (Fitzgerald 2005; Collier and Bolles 1980; Barr 1995; Emerich et al. 1985; Shair et al. 1997; Stehouwer and Campbell 1978). As illustrated in Figure 15.3, one of the most strikingly unique learning characteristics of pups, is the ability of both painful stimuli (0.5 mA shock, tailpinch) and presumably pleasant stimuli (milk, warmth, stroking that mimics maternal grooming) to both support learning of approach responses and nipple attachment. Specifically, pairing a novel odor (CS) with either a painful or presumably pleasant reward, results in pups showing subsequent approach responses to that odor. Indeed, this learning occurs within the nest with a mother nursing her pups, but also when pain is induced by a stressed mother (Gilles et al. 1996), who exhibits rough handling and transporting of pups without nursing (Roth and Sullivan 2005). This attenuated odor-aversion or fear learning during pups’ early life is not the only learning restriction for pups, since inhibitory conditioning and passive avoidance are also attenuated (Blozovski and Cudennec 1980; Collier and Mast 1979). Finally, these early life learned odors are not just approached as a preferred odor, but appear to take on characteristics of maternal odor and also support nipple attachment when the natural maternal odor is removed (Pedersen and Blass 1982; Raineki et al. in progress; Hofer et al. 1976). Thus, this learning is unique both in its expression and acquisition and has been characterized as mammalian imprinting (Hofer and Sullivan 2001).

FIGURE 15.3

Y-maze test in sensitive-period PN8 pups using the CS odor or the maternal odor vs clean home cage bedding (response to bedding not shown). Infant rat pups can be classically conditioned to approach a novel odor with previous pairings with either painful (more...)

The early life odor learning that supports acquisition of the maternal odor is also potentiated by other unique learning features in infancy. Specifically, exposure to the odor CS before classical conditioning (latent inhibition) and uncorrelated presentations of the CS and reward (learned irrelevance), both of which retard/inhibit learning in adults, either enhance or have no effect on the young infant rat’s learning (Stanton 2000; Stanton et al. 1998; Campbell and Spear 1972; Hoffmann and Spear 1988; Rescorla 1967, 1988; Rush et al. 2001; Siegel and Domjan 1971; Spear and Rudy 1991). Finally, while sequential presentation of the CS and the reward optimizes learning in adults, simultaneous presentation of stimuli enhances associations in young pups (Barr et al. 2003; Cheslock et al. 2003).

Thus, rat pups have myriad unique learning characteristics that potentiate the odor learning required for pups to maintain proximity to their mother. While one normally thinks of early life learning as providing enhancement of learning, such as in imprinting, limitations on aversive learning in early life are actually widespread. For example, shocking a chick while it is following the surrogate caregiver during imprinting, enhances following of the surrogate caregiver. Just hours after the imprinting critical period ends, a similar shocking procedure causes the chick to avoid the surrogate (Salzen 1967). An analogous situation has been demonstrated in young dogs (Stanley 1962). Indeed, mistreating a puppy with shock or rough handling by a human caregiver results in a strong attachment to that caregiver. A similar phenomenon has been repeatedly documented in nonhuman primate colonies, where the young of abusive mothers still form and maintain strong attachments to their caregiver (Harlow and Harlow 1965; Maestripieri et al. 1999; Sanchez et al. 2001; Suomi 2003; Nemeroff 2004). Finally, clinical and epidemiological studies on children indicate that “abuse” results in children forming and maintaining strong attachments to their caregiver (Bowlby 1965; Helfer et al. 1997). Indeed, the wide phylogenetic representation of tolerance of pain during attachment learning and its maintenance suggests a phylogenetically preserved system for attachment (Hofer and Sullivan 2008).

15.3.3. Emergence of Olfactory Fear Learning

At around PN10, crawling transition to walking, and the probability of pups leaving the nest increases. Pup odor attachment learning is not appropriate for outside the nest, where learning needs to reflect the consequences of pain or pleasure to ensure pups survival in preparation for independent life. Indeed, the sensitive-period attachment learning ends at this time, at least when pups are outside the nest. Furthermore, new learning emerges and pups begin to exhibit olfactory fear conditioning from odor-pain pairings (0.5 mA shock, tailpinch), with pups avoiding the odor in a two-odor choice Y-maze and freezing to CS odor presentation in a glass jar (Roth and Sullivan 2005; Haroutunian and Campbell 1979; Moriceau and Sullivan 2006; Moriceau et al. 2006; Sullivan and Leon 1986; Sullivan et al. 2000) (Figure 15.4).

FIGURE 15.4

The graphic on the left illustrates the neural basis of the attachment learning that occurs when an odor is paired with myriad stimuli (stroking, warmth, milk, 0.5 mA shock). Without the mother present, this learning occurs in pups younger than PN10. (more...)

15.3.6. Development of Malaise Olfactory Learning

The developmental delay in pups’ emotional learning and amygdala-dependent fear conditioning is not due to pups’ inability to learn an odor avoidance. Indeed, young pups can learn to avoid odors, although malaise and introceptive distress rather than exteroceptive pain is responsible for this learning (Haroutunian and Campbell 1979). Specifically, rat pups can learn to avoid odors paired with malaise throughout ontogeny, including before birth (Shionoya et al. 2006; Smotherman 1982; Miller et al. 1990; Rudy and Cheatle 1983; Coopersmith and Leon 1986; Hoffmann et al. 1987). We have recently assessed the neurobiology of malaise learning. Since this learning occurs during the prenatal period, which is prior to the maturation of brain structures critical for adult odor-malaise learning (i.e., amygdala) (Touzani and Sclafani 2005; Berdel and Morys 2000; Berdel et al. 1997; Morys et al. 1998), we searched for a unique circuit for learning. We used two means of inducing malaise in pups, odor-LiCl and 1 mA high shock (Haroutunian and Campbell 1979), both of which also produce gastrointestinal distress in pups (Davenport 1950; Stern et al. 1969; Raineki et al. 2008). In sharp contrast to the important role of the amygdala in adult odor-malaise learning, young pups use the olfactory bulb and the piriform cortex to support learning (Shionoya et al. 2006). Indeed, it is not until pups are close to weaning that the amygdala is used in odor-malaise learning, which is almost a week later than the emergence of amygdala-dependent fear conditioning (Sullivan et al. 2000; Roth and Sullivan 2005; Moriceau and Sullivan 2006; Moriceau et al. 2006). Thus, despite the similar appearance in the odor-aversion learning produced by odor-0.5 mA fear conditioning and the odor-malaise learning, the neural circuitry supporting this learning differs, indicating caution is required when assuming that similar appearing behaviors in development use the same neural structures.

Maternal presence also modifies pups odor-malaise learning. Specifically, if pups are nursing while conditioned with odor-LiCl pairings, pups fail to learn the aversion and learn to prefer the odor (Shionoya et al. 2006). These data complement pups conditioning with taste-LiCl, which is blocked if pups are nursing (Martin and Alberts 1979; Gubernick and Alberts 1984; Melcer et al. 1985; Kehoe and Blass 1986).

As illustrated in Table 15.1, pups show remarkable odor learning abilities, which are uniquely adapted to the pups’ ecological demands as the transition from complete dependence changes to complete independence. Indeed, pups transition from unique neural circuits supporting their unique learning to circuits consistent with that documented in the adult. More remarkable is the dramatic effect of maternal presence on pup learning, which provides pups to “switch” to attachment learning in the mother’s presence. It is important to note that the similarity in behavior between fear and malaise learning (odor avoidance) suggests that similar behaviors across development may be an unreliable tool to assess brain development. Indeed, the age at which the amygdala supports pups’ emotional learning from odor-shock conditioning differs from the age the amygdala supports malaise learning, suggesting caution when extrapolating functional brain development from one behavior to another. Additionally, while this odor-0.5 mA shock conditioning begins to produce fear conditioning at PN10, fear conditioning is blocked and the early life odor preference learning is extended via suppression of the amygdala or if the mother is present (Moriceau and Sullivan 2006). A similar learning constraint exists with odor-LiCl and taste-LiCl learning. Specifically, if pups nurse during odor-LiCl conditioning, they develop a preference for the odor (Shionoya et al. 2006), while taste-LiCl avoidance learning is blocked (Martin and Alberts 1979; Gubernick and Alberts 1984; Melcer et al. 1985; Kehoe and Blass 1986).

TABLE 15.1

Infant Rats Show at Least Three Types of Learning in Early Life and Each Type of Learning Is Influenced by Maternal Presence, Albeit in Unique Ways.

15.4. IMPACT OF EARLY LIFE EVENTS ON ADULT ODOR MEMORY

Early life experiences have a profound effect on later life sensory, cognitive, and emotional processing. While a wide range of manipulations has been used to manipulate early life experiences (maternal deprivation, handling, maternal licking, odor-shock), there is remarkable convergence concerning mediating factors to induce enduring adult effects. Indeed, long-term effects have been documented in the hypothalamic-pituitary-adrenal (HPA) axis and the extended limbic system, including the LC, hippocampus, amygdala, and prefrontal cortex (Plotsky et al. 2005; Francis et al. 1999; Dent et al. 2001). While olfactory learning has not received much attention, adult cognitive function is well documented to be increased or decreased based on the type and age of infant manipulations (Fleming et al. 1999; Pryce et al. 2003; Denenberg and Bell 1960; Caldji et al. 1998, 2000; Coplan et al. 1996; Denenberg 1963, 1999; Kosten et al. 2005, 2006; Levine 1962, 1967, 2001; Lindholm 1962; Sevelinges et al. 2007, 2008; Seckl and Meaney 2004; Romeo et al. 2009).

We have been assessing the effects of infant odor learning on adult odor learning. However, as we assess the enduring effects of infant odor learning, it is important to remember that odor attachment learning differs from adult learning in that it involves social learning and attachment that occurs within the unique functioning of the infant brain. Specifically, the novel odor paired with either stroking or 0.5 mA shock takes on characteristics of maternal odor to support approach responses and complex motor responses such as nipple attachment. This odor produces a profound effect in infancy, which is retained into adulthood where the odor enhances male and female sexual behavior (Moore et al. 1996; Raineki et al. In progress; Coopersmith and Leon 1986; Fillion and Blass 1986; Sevelinges et al. 2007).

The attachment odor learned in infancy also modifies odor learning in adulthood (Sevelinges et al. 2007, 2008). Specifically, early life paired odor-shock conditioning attenuates adult fear conditioning and alters the functioning of olfactory sensory cortical areas, such as the piriform cortex and the basolateral amygdala. However, other changes were found even when the conditioned odor was not present. Specifically, using field potentials induced in the piriform cortex and the basolateral amygdala in response to paired-pulse stimulation of the olfactory bulb revealed that in these sites, the level of inhibition was significantly reduced in adult rats, but only if they had received infant paired odor-shock conditioning and not unpaired. These results suggest that the contingency or predictability of early life experience are important variables for an enduring effect of early life experience on adult cognition. Thus, infant experiences enduring effects are due, at least in part, to learning effects that interact with neural changes induced through experience to alter the trajectory of brain development.

15.5. CONCLUSION

This review of the neurobiology of emotional olfactory memory has focused on rat odor fear conditioning and highlights the fact that the olfactory modality might be particularly appropriate for understanding the interplay between limbic and cortical areas for the acquisition and storage of learned associations. Indeed, the existence of rapid direct anatomical connections between early sensory areas (i.e., the olfactory bulb and the piriform cortex) and the amygdala seems to favor the implication of olfactory cortical areas at early stages of learning acquisition. Together, these properties might endow the sense of smell with the capacity to automatically trigger emotional odor memories.

The developmental research reviewed here also illustrates the remarkable functional changes that occur in learning as an animal makes the transition from one developmental phase to the next. During early life, when infant rats are confined to the nest, they rapidly learn to prefer an odor when it is paired with myriad stimuli that appears dependent upon their ability to raise NE levels within the bulb rather than their hedonic value. This unique early life learning system may have evolved because of the critical survival value of odor learning: pups must learn the maternal odor to approach the mother and nipple attachment (Polan and Hofer 1999; Pedersen and Blass 1982; Leon 1992). Therefore, pups’ survival is dependent on odor approach learning, suggesting that evolutionary pressure may have developed a neural circuit to ensure pups only learn to approach their caregiver regardless of the quality of care received (Bowlby 1965; Hofer and Sullivan 2001). The development of odor learning provides insight into at least a few basic principles concerning the development of the neurobiology of learning: (1) learning that appears similar throughout development can be supported by neural systems showing very robust developmental changes; (2) the functional emergence of the amygdala, or perhaps any brain structure, during ontogeny depends upon which function of the brain area is being assessed; and (3) the context of learning (maternal presence) dramatically modifies the neural circuitry pups use for odor learning, and hence the behaviors learned.

The olfactory system is an evolutionarily old sensory system with a simplistic neural circuitry, at least compared to other sensory systems, that has direct access to the emotional centers of the brain. This suggests that the sense of smell has a critical role in controlling emotional behavior that has been maintained through evolution. Environmental odors control emotions and behavioral responses that enable avoidance of danger but approach in social situations, both of which enhance survival of the individual and the species. Importantly, the olfactory system is remarkably flexible and eloquently designed for emotional learning and memory, which is reflected in odors’ direct access to brain areas critical for emotional learning. Finally, the remarkable flexibility of the olfactory system to adapt to divergent learning demands at different developmental periods during the life span underscores the critical role of this sensory system in emotional and social attachment.

ACKNOWLEDGMENT

This work was funded by grants NICHD-HD33402, NSF IOB-0544406, NIDCD-CD009910, NIMH-MH086952, and Oklahoma Center for Science and Technology OCAST to RMS, and by grants ANR-05-PNRA-1.E7 AROMALIM to AMM.

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