The main olfactory system and social learning in mammals

Behavioural Brain Research 200 (2009) 323–335

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Review

The main olfactory system and social learning in mammals Gabriela Sanchez-Andrade, Keith M. Kendrick ∗ The Babraham Institute, Cognitive and Behavioural Neuroscience, Babraham, Cambridge CB2 4AT, UK

a r t i c l e

i n f o

Article history: Received 24 September 2008 Received in revised form 11 December 2008 Accepted 12 December 2008 Available online 25 December 2008 Keywords: Social recognition Olfactory learning Olfactory bulb Maternal recognition Oestrogen receptor Social learning

a b s t r a c t There is increasing evidence for specialised processing of social cues in the brain. This review considers how the main olfactory system of mammals is designed to process social odours and the effects of learning in a social context. It focuses mainly on extensive research carried out on offspring, mate or conspecific learning carried out in sheep and rodents. Detailing the roles of the olfactory bulb and its projections, classical neurotransmitters, nitric oxide, oestrogen and neuropeptides such as oxytocin and vasopressin in mediating plasticity changes in the olfactory system arising from these different social learning contexts. The relative simplicity of the organisation of the olfactory system, the speed and robustness of these forms of social learning together with the similarity in brain regions and neurochemical contributions across the different learning paradigms make them important and useful models for investigating general principles of learning and memory in the brain. © 2009 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of social chemosignals in mammals by the olfactory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The main olfactory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Social olfactory recognition paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Lamb-odour recognition in sheep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Social recognition in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Other forms of social olfactory learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Neonatal odour learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Social transmission of food preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Learning in the main olfactory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Social olfactory recognition and the MOB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Social olfactory learning, gonadal hormones and vaginocervical stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Social recognition and oestrogen receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. The OB plays a primary role in odour-guided behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Social interactions and bonds are of paramount importance for humans as well as for many other animal species. It is, thus, not surprising that the brain has evolved sophisticated specialisations for the control of social behaviour, recognition, attraction and bonding. For many, it is the complex demands

∗ Corresponding author. Tel.: +44 1223 496385 fax: +44 1223 496028. E-mail address: [email protected] (K.M. Kendrick). 0166-4328/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2008.12.021

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of a social environment which have driven the evolution of the brain and of cognitive functions [38–40]. A major function of animals’ cognitive abilities being to recognise, manipulate and behave appropriately with respect to socially relevant information. The study of this “social brain” helps us understand the nature and regulation of social interactions between individuals and groups in a particular species. It also allows us to recognise the wide variety of affective and personality disorders where key aspects of normal social behaviour are dysfunctional, making it difficult for such individuals to cope with everyday social demands.

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How are social signals perceived and processed? Are these systems exclusive to social stimuli? Different animals rely on different sensory systems to interact with the world. Some sensory systems appear even to have evolved specially for social behaviour. The most notable example of this is the system used for detecting pheromones, the chemosignal compound used for communication between conspecifics (reviewed in [36]). Most social signals, however, are not processed by a specialised sensory system but by common systems adapted for multimodal processing of complex stimuli such as social ones. There are increasing examples of situations where the brain has evolved specialisations for processing key sensory cues for social recognition or where specific aspects of social behaviour are controlled by particular genes [21,44]. Many studies have now shown that the brain often processes social cues differently than non-social ones. Neuropsychological and neuroimaging studies in humans for example have shown different brain processes for social visual stimuli than for non-social ones. For example, the lateral fusiform gyrus is involved in the recognition of faces and is activated to a greater degree when subjects view faces than other non-face objects [70]. This general region is also involved in recognition of faces in monkeys and sheep [152]. There is also evidence for specialised processing of vocal cues for social communication in humans and other animal species [5]. Finally, while there are obviously a number of different genes involved in different aspects of social behaviour there has been considerable recent interest in those that are involved in social bonds and social recognition memory. In rodents, sheep and humans for example there is also increasing evidence showing that the neuropeptides oxytocin (OT) and vasopressin and their respective receptors play a key role in the control of social recognition memory and in partner and offspring bonding as well as in aspects of social trust and anxiety [45,56,60,88]. Animals in many species rely heavily on the emission and detection of olfactory cues for social recognition; and have developed incredible sensitivity in discriminating between and remembering the chemosignals secreted by conspecifics [167,168]. This has developed to the point where the inclusion of non-biological odours has little or no effect on learning and recognition of social cues. In a social context, social odours are the prominent cues for social recognition, with artificial odours perhaps adding only motivational or attention value to a social stimulus [67,126]. The ability to recognise, use and behave according to socially relevant information requires neural systems that process perception of social cues and also those that connect such perception to motivation, emotion and adaptive behaviour. The olfactory bulb is also a simple and easily accessible structure with a well-defined olfactory system and these features make it ideal for studying how sensory

cues drive even complex behavioural responses such as social ones. It is, therefore, possible to study the involvement of the different neural substrates at all levels in the system, from the initial sensory detection of odour molecules by the olfactory receptors through to limbic and higher cortical processing. This review will consider in detail the neural systems and transmitter and hormonal substances involved in the mediation of a number of different examples of olfactory guided social recognition and learning models in mammals and focussing on odours processed by the main olfactory system.

2. Detection of social chemosignals in mammals by the olfactory system The mammalian olfactory system has the ability to detect volatile molecules as well as non-volatile ones (peptides and proteins). The nasal cavity of rodents contains two sets of chemosensory neurones located in the vomeronasal organ (VNO) and in the main olfactory epithelium (MOE) (Fig. 1). The MOE neurones project a single axon into a glomerulus and synapse with mitral cells of the main olfactory bulb (MOB) and those in the VNO to mitral cells in the accessory olfactory bulb (AOB). Olfactory information is then processed further by each bulb’s associated networks, the main and the accessory olfactory systems (MOS and AOS respectively). Both neuronal populations from the VNO and MOE, have distinct locations in nasal cavity, segregating their access to odourant stimuli. The MOE lines the posterior recess of the nasal cavity, favouring access to volatile stimuli in the nasal airstream. The VNO is encased in bony capsules on each side of the ventral nasal septum and is connected to it by a narrow duct. It mainly has access to non-volatile molecules (like the ones in urine and in skin, scent and reproductive secretions) by direct contact with the stimulus source [12]. This led to the idea that each neuronal population has a specific and distinct function: the detection of numerous airborne odour molecules by the MOE and of pheromones by the VNO. Although this is largely true, recent findings on the workings of both olfactory systems suggest that the distinction between volatile and non-volatile natures of olfactory and vomeronasal cues is not quite as clear cut as this. Although the MOE responds mainly to volatile odour molecules, there is evidence that non-volatile stimuli can reach the MOE after direct contact with a stimulus [140]. As for the VNO, it is still debatable whether it can detect volatiles without direct contact. While a study presenting volatile odours with a cotton swab near the nostrils failed to detect any responses made by VNO neurones [98], functional magnetic resonance imaging (fMRI) in anaesthetised

Fig. 1. Schematic diagram of rodent main olfactory system. The main olfactory bulb receives input from the main olfactory epithelium and projects to the anterior olfactory nucleus (AON), tenia tecta (TT), olfactory tubercle (OT), the piriform cortex olfactory cortex (PIR), entorhinal cortex (ENT) and anterior cortical nucleus (ACo) and posterior lateral cortical nucleus (PLCo) of the amygdala. Some second order connections to the amygdala (shaded region), the hypothalamus, bed nucleus of the stria terminalis (BNST) and hippocampus are shown to highlight how olfactory information reaches cortical as well as limbic parts of the brain. Adapted from Refs. [37,12]. Abbreviations: BAOT, bed nucleus of the accessory olfactory tract; Me, medial nucleus; PMCo, posteriomedial cortical nucleus of the amygdala.

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mice did show activity change in the AOB (and also the MOB) when urine odours were delivered via the airstream [169]. The detection and processing of pheromonal information is more complex and (to some extent) both olfactory structures seem to be involved in pheromone-mediated responses. Chemicals carrying pheromonal information are typically small organic molecules that could likely reach equally well both olfactory and vomeronasal systems. Mammals release an enormous variety of molecules into the environment, either as specific chemosignals or as products of metabolic processes [12]. These range from small volatile molecules to large proteins [131,139]. They provide a great amount of information about their producer, such as sex, reproductive state, age, health and individuality [6,9,14,64,65]. Some of these volatile molecules can act independently as classical pheromones eliciting a specific behavioural response; such as androstenone the male sex pheromone in pigs [34,35], the “nipple pheromone” (2MB2) in rabbits [130] and methanethiol in mice (MTMT), a male urine component that mediates attraction of female mice toward males [97]. These single pheromone molecules act via the MOB. Chemosignals like the ones signalling individuality are components of complex mixtures of molecules and both olfactory systems seem to be needed for their processing. Traditional views focused on the specific role each olfactory system had in detecting specific social cues. However, recent findings have shown that in mice both the main and accessory olfactory systems can detect, at least in part, overlapping sets of social chemosignals. There is, then, parallel processing of the same molecules in both olfactory systems [141], For example, an fMRI study has shown that 2-heptatone, a known mouse pheromone, elicits strong signals in both MOB and AOB [169]. The differences in the neural organization of the main and accessory olfactory systems [12] (Fig. 1) suggest that the contribution of the olfactory and the vomeronasal system in socially-mediated responses lies not only in the nature of the odourants but also on how the chemical information is processed by them. We can then say that both systems can detect and process social chemosignals of non-volatile and volatile nature (as well as pheromones and non-pheromone cues) and that the MOE and the VNO detect in part overlapping sets of chemosignals. Behavioural tests using mice with genetic ablation or surgical lesions have also shown stimulation of each system by the same social signal can lead to distinct behavioural outcomes [91,140]. For example, processing of major histocompatibility complex (MHC) peptides by the MOS in male mice is required for decision making in the context of a social preference test [140]. On the other hand, processing of the same peptides by the AOS was a crucial signal in the pregnancy block effect in female mice (Bruce effect) [91]. Therefore, it appears that the same chemosignal can mediate different sexual and social behaviours through differential activation of each olfactory system [141].

3. The main olfactory system Classical anterograde and retrograde tracing studies have provided evidence for two distinct neural networks forming the projections of the vomeronasal and olfactory systems. In the MOS, odours are detected in the MOE by olfactory sensory neurones (OSN) which express one of 1000 different odourant receptor types [19,99]. The OSN send their axons into the MOB where they synapse with glutamatergic mitral cells which are the output neurones of this region and send projections to different areas of the paleocortex, also known as the primary olfactory cortex, that include the piriform cortex (Pir), entorhinal cortex (Ent), anterior olfactory nucleus, olfactory tubercle and anterior cortical amygdala (ACo). These structures are in turn connected to regions of the

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hypothalamus, limbic system and neocortex involved in a variety of motivated behaviours as well as in emotional and cognitive responses. Thus the MOS is potentially involved in the olfactory mediated regulation of a wide range of important social as well as other behaviours [37]. A summary of these pathways is shown in Fig. 1. 4. Social olfactory recognition paradigms Social olfactory recognition involving the MOS has been studied in a number of different animal species although mainly in rodents and ungulates. The behavioural models are based on ethologically important events where learning usually leads to reproductive success or survival. These include maternal recognition of offspring in sheep [79,116] and social recognition in rats and mice [45,153]. Offspring recognition ensures the mother will preserve her own genes by limiting maternal investment to her own progeny. The importance of social recognition is self-evident, it is the fundamental requisite for development and maintenance of social structure. These animal models offer many advantages in studying learning and memory in the brain since learning is rapid and robust creating long-lasting memories that are simple to test experimentally. 4.1. Lamb-odour recognition in sheep Sheep are seasonal breeders, so a large number of lambs are born in the same short period each year. Lambs are precocial young and within a few hours after birth they are capable of standing up, moving around and suckling their mothers. Therefore it is important for them to be able to identify their mother and vice versa. It can take maternal ewes several weeks to distinguish their small and highly homogeneous in appearance lambs from others and the lambs themselves take even longer to recognise their mothers this way [77]. So the maternal ewe needs a more efficient method to be able to recognise its own lambs [116] and it does this mainly by using olfactory cues from the lambs skin and wool. This recognition is dependent on the MOS since interfering with the olfactory epithelium affects the selectivity of maternal behaviour but sectioning of the vomeronasal nerve does not [95]. The ewe forms a selective olfactory memory in a sensitive period of around 2–4 h after parturition and will consequently reject the approach of any strange lamb [82]. Both the sensitive period for odour learning and the maternal acceptance behaviour are dependent on the hormonal environment of late gestation and are triggered by feedback to the brain from mechanical stimulation of the vagina and cervix that occurs during parturition. A post-partum ewe can even be induced to accept, and form a new recognition memory for a strange lamb by being given a few minutes of vaginocervical stimulation, mimicking the birth process, up to 3 days after giving birth [83]. Maternal experience and lamb–ewe bonding can also have enduring effects on subsequent lamb-odour selectivity. Ewes are more efficient in establishing individual recognition of their own lamb in successive births [74,77,85]. This is due to long-lasting changes in the MOB, involving up-regulation of OT receptors and increased sensitivity of the system to vaginocervical stimulation [17,94]. The duration of this social recognition memory is subject to the usual consolidation effects, with separation of mother and lamb within the first 12 h leading to the selective maternal recognition bond being broken within 4–24 h (the shorter the period after memory formation the shorter period of separation being required), whereas after that time it requires many days (Kendrick, unpublished observations). The individual recognition memory of offspring lasts far longer than this, but what is disrupted is the

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ability of the recognition to elicit a selective maternal response [123].

another animal or its products’ [61], is in fact one of the most common and important forms of learning in animals.

4.2. Social recognition in rodents

4.4. Neonatal odour learning

Tests of social recognition in rodents rely on the intrinsic motivation of animals to investigate other individuals in a social context and particularly novel ones. Rodents investigate novel, “strange”, conspecifics more than familiar ones [20]. During a brief encounter, a mouse or rat will intensely investigate a novel conspecific by sniffing the head and anogenital region. On a second encounter, after a given time interval, it will investigate the animal significantly less. However, if a fresh new animal is presented, the investigation duration goes back up to initial levels. The reduced investigation following repeated encounters is taken as measure of a social recognition memory having been formed. That is, a social memory was stored during the initial encounter and retrieved during the second encounter. Information on the identity of the conspecific comes from olfactory cues from urine or secretions from skin, reproductive tract or specialised scent glands [108,109,143]. The recognition of olfactory cues for identity is dependent on the MOS since lesions of the olfactory bulb or chemically induced anosmia impairs individual recognition in rodents [7,28,100,118]. This paradigm was classically used as a model for short-term olfactory memory, since it was thought that it lasted no more than 1 h in singly housed animals [2,8,153]. However, a more recent study showed that housing conditions and isolation can affect the duration of social recognition memories. Group-housed, but not singly-housed, mice can show retention of this form of social recognition for up to 7 days after a single encounter with another individual lasting only a few minutes [87]. The protocol for social recognition has been modified in different ways to test either habituation–dishabituation or discrimination of a social stimulus. Diverse protocols exist using different exposure times, inter-trial intervals and stimulus animals [8,87,148]. For the habituation–dishabituation test, the animal is repetitively exposed to the same stimulus conspecific for (usually) four trials with a variable inter-trial interval (habituation trials) although usually less than 10 min [148]. On a last, 5th trial, the animal is exposed to a fresh new stimulus animal (dishabituation trial) [31,163]. This protocol results in a progressive general reduction of investigation time of the stimulus animal during the habituation trials which is then restored to original high levels on the dishabituation trials. For the discrimination test, the animal is given a simultaneous choice of two stimulus animals; the previously encountered familiar and an unfamiliar novel animal [41]. In our laboratory, for example, we have combined both of these protocols to test for habituation–discrimination (with 1 min trials and 10 min inter-trial intervals) initially and then after a 24 h interval we test long-term retention with a further discrimination test between the familiar animal and another unfamiliar one [127]. A powerful additional model of social recognition is also that of mate recognition in pair-bonding voles. Here the act of mating in conjunction with odour stimuli from the partner leads to a recognition memory for the partner as well as promoting the formation of a pair bond. This has also been shown to involve the MOS and has been reviewed in detail elsewhere [56].

Rodent pups have the ability to recognise their familial environment; from an early age they show a preference to approach maternal odours [162]. This happens regardless of whether they have been nursed by their biological or a foster mother, i.e. the preference can be changed by experience and is not hard-wired [170]. Early learning of the familial environment is important for survival not only to help the pups get back to their nest, but also by assuring maternal protection. It also has long-term effects on their adult behaviour in terms of mate preference by promoting optimal outbreeding. Mate preference, associated with the major histocompatibility complex (MHC), can be reversed by cross-fostering newborn mice to a mother of a different MHC type [113,171]. The preference, however, is not completely reversed by cross-fostering suggesting that there is still some influence of very early perinatal or even prenatal learning [117] or self-referral (recognising your own odour) [69]. The somatosensory stimulation from maternal licking and grooming acts as a strong unconditioned stimulus for learning nest odours (maternal and sibling odours). By mimicking the conditions of natural olfactory learning of nest odours, neonatal pups can be conditioned to non-biological artificial odours [162]. In the laboratory, temporally pairing an odour used as conditioned stimulus with a potential unconditioned stimulus (e.g. milk, tactile stimulation, tail pinch or electric-shock) produces a conditioned response to it. For example, rat pups can be placed in a beaker with peppermintscented (conditioned stimulus) wood shavings and then stroked with a paintbrush to mimic maternal licking and grooming for a few minutes (unconditioned stimulus). When given a choice between peppermint-scented versus unscented wood shavings the neonates spend more time over the conditioned peppermint scent compared to naive animals [165]. This form of learning happens during a sensitive period in early neonatal development and does not normally extend beyond postnatal day 10. After this period stroking looses its ability to act as unconditioned stimulus [164]. At this early age many brain structures associated with olfactory learning in adults are not yet anatomically mature or appropriately interconnected and will not be effectively activated by odours. Therefore, early olfactory learning is heavily dependent on changes occurring within the olfactory bulb (for a review see [145]). These changes require noradrenergic (NA) input from the locus coeruleus for their acquisition [144,147] but not for recall [146]. Tactile stimulation (unconditioned stimulus) increases NA release in the MOB of neonatal rats by centrifugal projections from the locus coeruleus [119]. Pairing the NA release from an unconditioned stimulus with an odour brings odourspecific and long-term morphological and functional changes in MOB at the level of the glomerulus and mitral cells [68,164]. As a result, the activity of mitral cells is more likely to be inhibited by the learned odour; while mitral cells of control animals are usually excited by the presence of the same odour [161]. Changes in the bulb’s output suggest that lateral and feedback inhibition of mitral cells by local inhibitory interneurones is increased after learning in response to the conditioned odour [162]. The sensitive period for olfactory learning is delineated by developmental changes including an increase in the ratio of ␣2–␣1 noradrenergic receptors in the locus coeruleus. This limits the duration of the locus coeruleus activity in response to tactile stimulation, consequently reducing the amount of NA released into the MOB by stroking [107]. These developmental changes also mark the difference between preference and avoidance of a conditioned odour. Adult animals will avoid an odour if it has been paired with an aver-

4.3. Other forms of social olfactory learning Social olfactory learning is not limited to recognition of odour cues signalling individuality; it can also involve non-biological odours in a social context. Social learning, ‘when an individual’s behaviour is influenced by observation of, or interaction with,

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sive stimulus like a mild electric shock. However, the same pairing of odour and shock in neonatal rats younger than 10 days leads to a lasting odour preference. Since newborn rats depend completely on their mother for survival, they cannot afford to develop an aversion to her or her odours at this stage. The developmental changes in the neonatal brain also include the onset of a fully functional amygdala and the appearance of fear responses and conditioning [144]. 4.5. Social transmission of food preference Social transmission of food preference is a model for olfactory learning that uses a combination of social and non-social odours. Rodents are capable of passing on information regarding safe food (mice [51,157]; rats [47]; gerbils [156]); they can learn which foods are safe to eat merely by smelling that food on another animal’s breath (demonstrator animal). As a result, they will overcome their natural neophobia to novel foods and develop a preference for food associated with the odour detected on the demonstrator’s breath over other equally novel food [48]. A single brief interaction between two mice or rats is enough to induce a food preference that lasts for at least 6 days [26,125,166]. This olfactory learning is believed to involve a combination of two odours present on the demonstrator’s breath; the odour of the recently eaten food and carbon disulfide (CS2 ), which is naturally carried in the exhaled breath of rodents. When an animal is presented with CS2 in combination with food odour it will subsequently eat more of that food than it would have done otherwise. The exposure to both odours, food odour and CS2 , is both necessary and sufficient to develop a food preference [4,49]. 5. Learning in the main olfactory system Olfactory recognition memory involves a distributed neural network in the MOS, including secondary and tertiary odour processing regions. The participation of each brain area partly depends on the nature and parameters of the learning task as well as on temporal configurations [73,114,127]. There is therefore an anatomical as well as a temporal configuration for the consolidation of memories, similar to other memory models [101]. Valuable information has come from sheep studies on brain structure activation (by measuring the change in expression of immediately–early genes c-fos and zif/268) [27,73] and reversible inactivation (by bilaterally infusion of either the local anaesthetics, lidocaine or tetracaine, or the GABAa receptor agonist, muscimol) [75] as well as electrophysiological recordings [82] (for review see [79]). Initial memory formation and short-term retention involve a wide neural system formed by the MOB, piriform and entorhinal cortices, medial and cortical amygdala [75] and probably the hippocampus. Activation of the MOB, piriform, entorhinal and orbitofrontal cortices, cortical amygdala (CoA) and dentate gyrus is evident in post-parturient ewes exposed to their own lamb [27,73]. This activation was not seen in anosmic post-parturient ewes that showed maternal behaviour but no individual lamb recognition [73]. To date electrophysiological recordings have only been carried out in the sheep MOB. These have shown a remarkable change in the encoding of lamb odours by maternal ewes following birth and bonding with their lambs. Whereas mitral cells show no preferential response to lamb odours before birth, around 60% of them do so afterwards and a small number of these even show selective responses to own lamb odours [82]. This indicates wide-spread plasticity changes have occurred within MOB networks. The fact that some mitral cells showed high level encoding at the level of specific individuals (lambs) distinguishes the olfactory system from the visual and auditory ones since such high level encoding in the

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latter for faces and voices is only found in association neocortical areas in the visual and auditory projection systems [5,152]. In mice, a brief period of social exposure also leads to increased c-fos expression in the MOS-granular and mitral cells in the MOB and in the piriform cortex. It also activates the AOB, septum (dorsolateral and lateral) and the medial amygdala—together with downstream projections, the bed nucleus of the stria terminalis (BNST) and medial preoptic area [44,120]. Neurones in the entorhinal cortex of hamsters have been shown to be responsive to individual social odours [114]. And there is strong evidence suggesting that the medial amygdala and OT are key for social recognition in rodents [46]. Oxytocin knock-out mice are incapable of recognising a previously encountered animal as “familiar” [45] and OT infusion in to the medial amygdala rescues this social recognition learning [44]. The anterior medial amygdala can respond to both conspecific and heterospecific chemosensory stimuli, but the posterior medial amygdala responds only to socially relevant conspecific ones [103]. In the maternal recognition of lambs model it has also been suggested that the cortical and medial amygdala are important for the formation of a selective olfactory recognition memory [73]. Although OT action in the medial amygdala is crucial for social recognition, it also plays an important role in the MOB in maintaining or facilitating olfactory memories in rats [32]. In female rats and sheep, for example, OT is released in the MOB in response to vaginocervical stimulation. In both of these species vaginocervical stimulation promotes or facilitates olfactory recognition of individuals and this is disrupted by the infusions of OT antagonists into the MOB rats [79,89]. The corticomedial amygdala, which is of key importance for social recognition, is interconnected with both the main and accessory olfactory systems. As a result it is a major site for integration of vomeronasal and main olfactory information [12]. Output neurons of the MOB synapse in the posterio-lateral CoA, which in turn sends projections to the medial amygdala and BNST (Fig. 1). Studies on sexually experienced male hamsters exposed to females’ vaginal secretions have shown that the MOB, and not the AOB, is responsible for the activation of the medial amygdala, BNST and medial preoptic nucleus [149]. This is most likely through participation of the CoA. The AOB is the key player for mediating the copulatory response of naïve males to oestrous vaginal secretions [29,138], but following sexual experience, mating behaviour can be sustained by the MOS alone. Thus, odours transmitted by the MOS may become associated with vomeronasal stimuli at the level of the medial amygdala and may subsequently become sufficient to drive the same behavioural response [102]. Retrieval of memories involves time-dependent participation of brain areas due to the consolidation process [47,122]. It seems that distinct neural processes occur for short- and long-term olfactory memory recall. The timescale for olfactory memory consolidation can vary depending on the behavioural model. As olfactory memory consolidates (after ca. 8 h), the neural system involved in maintaining it appears to become less extensive than the one that is required for it to be formed. After consolidation it seems that only the MOB and piriform cortex are responsible for maintaining the memory trace. There is strong evidence that the participation of the olfactory bulb is central for the formation and recall of olfactory social recognition memory [73,100,118]. Permanent [73] or reversible (using tetracaine or muscimol. Kendrick, unpublished observations) inactivation of the sheep olfactory bulb disrupts memory formation and recall (short- and long-term). This is not surprising since the animals are effectively anosmic. However, selective infusions into this region of drugs targeting the glutamatergic or nitric oxide signalling, without producing a general anosmia, also disrupt social recognition memory formation [79] or post-consolidation recall [84]. Likewise, the piriform cortex is activated during recall of both

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Fig. 2. Percentage of post-partum ewes showing selective recognition of their lambs following a 4 h bilateral administration of 2% tetracaine into the entorhinal cortex via four microdialysis probes (5 mm membrane length CMA-10, 2 probes per hemisphere). (A) Control vs tetracaine infusions for the first 4 h post-partum, sheep remained nonselective even after the tetracaine was stopped (N = 8 per group). (B) Same as (A) but tetracaine infusions were given between 6 and 9 days post-partum when post-partum ewes were fully selective and the memory for their lambs consolidated. Here the tetracaine infusions had no effect (N = 10 per group). • P < 0.001 compared to control animals, Fisher’s exact test with adjusted P vales for repeated measures. Selectivity was assessed at each time point with three 10 min tests where the ewes were exposed to their own lamb, or a strange lamb of the same breed or of a different breed. Selectivity was confirmed if only the own lamb was accepted for suckling and only strange lambs had any rejection or aggressive behaviours shown towards them. Testing/treatment protocol was as in Broad et al. [18].

short-term (ca. 4 h) and long-term (ca. 16 h post-partum or 7 days of contact) olfactory memories in sheep [72]. Inactivation of sheep entorhinal cortex, on the other hand only prevents short-term memory formation and has no effect on (longterm) recall once the memory is established (Fig. 2). Similarly, in rodents, lesions of the entorhinal cortex result in deficits of shortterm odour memory [71,142]. It seems likely that these memory formation effects are mediated via the entorhinal cortex projections to the hippocampus, which is also activated during memory formation and short-term recall of lamb odours [18]. Thus memory formation may involve an extensive network including the olfactory bulb, piriform cortex, medial amygdala, entorhinal cortex and the hippocampus whereas postconsolidation maintenance of it may reside primarily just the olfactory bulb and piriform cortex. The specific role of other central projections of the MOS in social recognition memory has still to be defined. The frontal cortex, for example, has been implicated in olfactory mediated social recognition. Post-consolidation maintenance of social recognition memories seems to depend not only on the olfactory bulb and piriform cortex, but also on the links between the frontal cortex and systems controlling motor and motivational response. Maternal ewes show enhanced activation of the frontal cortex in response to their lamb following long-term memory consolidation [73,72]. However, the frontal cortex in the context of this type of social recognition memory appears to be mainly responsible for mediating executive responses to the learned odour stimulus. While reversible inactivation with tetracaine during the period of memory formation results in a non-selective acceptance of both own and strange lambs, once the anaesthetic is removed a fully intact selective memory is revealed and only the own lamb is accepted [16]. Lamb recognition is initially based on olfactory but as the memory consolidates (over a 12 h recognition period) it progressively extends to incorporate visual cues [18,74]. Therefore, it is also possible that the frontal cortex, a multisensory integration region [121], might be activated by other sensory modalities in this context. Dynamic changes occur in neural substrates and also in the molecular involvement in formation and consolidation of memory traces [66,101]. Long-term consolidation of social recognition memory requires multiple waves of protein synthesis and cyclic AMP responsive element binding protein (CREB) function [87,120]. Anisomycin administered just before learning blocks long-term (24 h) but not short-term social recognition in male mice [120]. The time

course of memory related protein-synthesis that lead to consolidation is divided in two, similar to other memory systems [66,101]. The first phase is relatively short beginning immediately after learning and lasting up to 3 h. This phase is paralleled by activation of specific brain areas including the MOB, piriform cortex and medial preoptic area [120]. The second phase is long-lasting starting 6 h after learning and lasting approx 12 h [159]. 6. Social olfactory recognition and the MOB Regardless of the type of task at question, odour learning involves long-lasting neurochemical changes in the olfactory bulb. Similar plasticity changes have been observed in post-partum ewes [80] and in mice following olfactory conditioning [15] social recognition or social transmission of food preference [126,127]. These changes are caused by a reorganisation of information processing in the OB. The MOB has a simple structure formed by three main cell layers; periglomerular, mitral/tufted and granule cells (see Fig. 3). The main output neurones, mitral and tufted cells (using glutamate and possibly aspartate), receive olfactory inputs via their primary dendritic connections within the glomeruli which in turn receive converging inputs from odourant receptors via the olfactory nerve. The mitral and tufted cells also have their secondary dendrites in the external plexiform layer where they form reciprocal dendrodentritic synapses with granule cells (GABA-containing inhibitory interneurones). These granule cells are likely to be responsible for mitral cell output control and lateral inhibitory interactions with surrounding mitral cells [172]. It is changes in these mitral-granule cells reciprocal synapses which are of crucial importance during learning [10,155]. A common feature of olfactory learning in the MOB is the increased inhibitory feedback control of MOB mitral cells in response to the learned odour stimulus [13]. The plasticity changes required for olfactory learning involve both centrifugal (noradrenergic and cholinergic) and intrinsic pathways in the olfactory bulb (Fig. 3). Attention, arousal or somatosensory stimulation, such as vaginocervical stimulation during mating or giving birth, trigger noradrenaline (NA) or acetylcholine (ACh) release via centrifugal projections to the bulb synapsing with GABAergic granule interneurones [12] (Fig. 3). Lesions of the noradrenergic centrifugal projections significantly impair memory formation in sheep [92]. Treatment with cholinergic antagonists, such as scopolamine, has similar effects [96]. Activation of ␣-noradrenergic receptors is associated with memory formation in rodents [32], while ␤-receptor activity is in other

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Fig. 3. Memory related changes in the main olfactory bulb (Left: intrinsic cell organisation, and main neurotransmitters; right; mitral-to-granulle cell dendro-dendritic reciprocal synapse). Enhanced release (due to attention, tactile or vaginocervical stimulation) of acetylcholine (ACh) or noradrenaline (NA) from the centrifugal projections ( ) reduces GABA release onto mitral cells ( ). Olfactory receptor activation stimulates glutamate release inducing nitric oxide/cGMP release ( ). These will potentiate the release of glutamate from mitral cells and subsequent GABA release from granule and periglomerular cells. Abbreviations: GLU, glutamate; l-arg, l-arginine; l-cit, l-citrulline; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NMDA-R, NMDA receptor; AMPA/Kainate-R, AMPA/Kainate receptor; mGluR, metabotropic glutamate receptor.

species such as sheep [93]. The release of NA (or ACh) via these centrifugal projections reduces GABA release by granule cells onto the mitral cells (Fig. 3) and consequently disinhibits them [82]. The disinhibited state paired with incoming odour-induced activation of olfactory receptors make mitral cells increase their activity and consequent glutamate release at their reciprocal synapses [154]. Glutamate acting on ionotropic receptors (AMPA and NMDA) in turn activate an intracellular molecular cascade that ultimately releases nitric oxide from the granule cells (Fig. 3). Nitric oxide acts as a retrograde messenger at the mitral cells to stimulate guanylyl cyclase activity and the formation of cyclic GMP, which then facilitates further glutamate release. All this glutamate release promotes enhanced GABA release from the granule cells thus increasing feedback inhibition onto the mitral cells [12]. At the same time, autoreceptors on the mitral presynaptic site are also activated resulting in enhanced glutamate release following exposure to the learned odour [80]. Therefore, learning results in increased sensitivity to glutamate in both mitral cells and at the mitral–granule cell dendrodendritic synapses. This leads to greater excitability of the mitral cells and tighter excitatory/inhibitory coupling between them and their associated granule cells so that learned odours evoke both a stronger activation of the mitral cells which are tuned to them and a sharpening of their phasic firing discharge pattern caused by a more robust inhibitory feedback response from the granule cells that follow from each excitatory burst [15,79]. This is expressed as a significant increase in the release of both excitatory (glutamate) and inhibitory (GABA) amino acids in response to the learned odour [82]. What is more, the ratio of glutamate to GABA is significantly lower in response to the learned odour compared to a novel one, suggesting that there is up-regulation of the mitral to granule cell synapses following learning and which results in greater inhibitory feedback onto the mitral cells following exposure to the learned odours [15]. Formation of olfactory recognition memories requires glutamate acting on ionotropic receptors and promoting NO release,

since blocking either NMDA or AMPA receptor activation (with an ionotropic receptor antagonist) or preventing NO release (using the non-selective NOS inhibitor, l-nitroarginine) during learning can disrupt long-term olfactory recognition. However, once the memory has been formed, disruption of NMDA or NO signalling has no effect on recall [67]. Nor does it interfere with the potentiated release of glutamate and GABA associated with it. Therefore, these signalling pathways are not involved in recall of a consolidated recognition memory [50]. Following consolidation then, there must be an alternative signalling pathway involved. A possible candidate are class 1-metabotropic glutamate receptors (mGluR1 ) in mitral and granule cells. Agonists of these receptors are able to release more potently glutamate and GABA within the OB [11,155] and there is some preliminary evidence of its role on olfactory recognition memory in sheep. Infusion into the OB of mGluR1 , but not mGluR5 antagonists, has no effect on recognition memory formation although it does prevent recall after consolidation (tested at 12–24 h post-partum in ewes [15,78]. It is possible therefore that as olfactory recognition memory consolidates there is a shift away from the dependence on glutamate acting on NMDA/AMPA-NO signalling pathways to a dependence on its actions on mGluR1 receptors. This would then release the NMDA/AMPA-NO signalling pathway to be utilised for formation of new memory associations. However this remains to be confirmed. 7. Social olfactory learning, gonadal hormones and vaginocervical stimulation Many behavioural models of social recognition are based on ethologically relevant behaviours occurring in critical periods of reproduction. This suggests sex hormones play a role in social olfactory memory and that somatosensory stimulation, such as of the vagina and cervix during mating or parturition, might also have a facilitatory effect. For the sheep model, memory formation occurs following the post-partum induction of maternal behaviour

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resulting from vaginocervical stimulation and high levels of hormones, particularly of oestrogen. Indeed, both maternal behaviour and olfactory recognition memory can be induced by artificial vaginocervical stimulation (VCS) in non-pregnant animals treated exogenously with oestrogen and progesterone [83] with oestrogen treatment appearing to be critical in this respect [81]. In mice, when females engage in sexual activities they need to remember not only their sexual partner [11], but also their social environment. Females need to assess the environment for danger and its suitability for reproductive activities (mating, birth and offspring rearing) and they must be prepared to either engage in sexual behaviour when the environment is favourable, a familiar social environment will improve reproductive and rearing success, or suspend resourcecostly reproductive behaviours until they are more likely to succeed [105]. It seems olfactory memory formation is facilitated in females when they are reproductively active, having high oestrogen levels (in particular), and when underging VCS from mating. Therefore both hormonal priming and VCS-induced changes are important for olfactory memory formation. Recent studies have attempted to elucidate the way gonadal hormones affect the olfactory system and in particular with respect to social olfactory learning. Early studies in male rats showed that gonadal hormones acted at the level of the OB. For example, testosterone can increase Fos immunoreactivity induced by female chemosignals in the MOB in both rats [115] and ferrets [76]. Castration reduces noradrenaline (NA) levels and potassium-evoked release of NA in the OB [25,52], but not in the olfactory cortex [134]. This is translated behaviourally as a substantially impaired social recognition memory which can be restored by l-DOPA treatment [133]. Oestrogen and progestins can also regulate olfactory bulb functions by modulating the expression of key proteins, like glutamic acid decarboxylase (GAD), the GABA A receptor ␣-2 subunit (GABAA R ␣-2), glutamate receptors 2/3 (GlutR 2/3) and tyrosine hydroxylase [53]. In females, stimulation of the vagina and cervix (VCS) produces morphological, neurochemical and electrophysiological changes in various reproduction-related brain areas including the OB [57,90]. These effects are mediated by ovarian hormones. VCS stimulates mitral cell activity in the OB during the proestrous/oestrous stage of the cycle and decreases it during dioestrous [55]. The oestrous cycle has no effect on basal extracellular levels of classical neurotransmitters and nitric oxide (NO) in the olfactory bulb, as measured by microdialysis [54,129]. However, VCS significantly increases concentrations of glutamate, aspartate, GABA, NA, dopamine and NO in females during proestrous/oestrous but not during metaoestrous/dioestrous or following ovariectomy (OVX). It appears though that there may be a general increased sensitivity of OB circuits to stimulation, and not just to VCS, since potassiumevoked release of NA, GABA and NO in the OB was also increased in proestrous/oestrous females [54]. In a more recent microdialysis study, we found that three consecutive NMDA challenges into the OB, mimicking memory formation, resulted in potentiated release of NA, aspartate, glycine, glutamate, GABA and NO (citrulline) only when females where in the proestrous stage of the cycle [129]. These NMDA challenges to the OB also potentiated release of glutamate and glycine in the ipsilateral piriform cortex of proestrous females but not at other stages of the cycle (Fig. 4). Therefore, signal transmission downstream of the olfactory system pathway is also affected by ovarian hormones. Interestingly, there was a disproportionately higher release of GABA in the OB of dioestrous females resulting from the first NMDA challenge. So, any likely enhancement of glutamate and NO release in dioestrous females could have been blocked by the elevated feedback inhibition caused by high levels of evoked GABA. This suggests that ovarian hormones act to decrease feedback inhibition from inhibitory interneurones [112]

and therefore oestrogen-induced disinhibition may be associated with a decreased probability of GABA release at granule to mitral cell synapses [124]. Further evidence for oestrogen acting on OB GABAergic cells in mice, is that oestrogen receptors (ER) have been found in glomerular and granule cells. While ␤ER is present in moderate amounts in glomerular and granule cells, ␣ER is found in large amounts in scattered GABAergic granule cells [104]. Therefore, sex hormones can act at the level of the OB and this action might influence olfactory memory related plasticity changes. Early studies on the effects of ovarian hormones on social recognition showed enhanced memory retention in female rats following oestradiol (E2 ) treatment. While OVX females showed memory retention for only 30 min, in oestradiol-treated ones it was maintained up to 120 min [62]. Memory retention, in female mice, can also be extended to 24 h by treatment with E2 but only when using high doses (0.72 mg of 17␤-oestradiol) [150]. This dose-dependent effect suggests that natural fluctuations in ovarian hormone levels during oestrous cycles or pregnancy may have facilitatory effects on a female’s social recognition memory retention. Indeed, social recognition memory retention is improved if learning occurs during proestrous but not during dioestrous or oestrous. Female mice show similar habituation–dishabituation behaviour across the oestrous cycle, however, when tested for retention at 24 h, only females that were in proestrous during learning showed maintenance of the social recognition memory [127,129]. Therefore, olfactory memory formation and retention, it seems, are facilitated in females when they are reproductively active. Olfactory perception and motivation do not seem to contribute to this since they are not affected by the oestrous cycle [127]. Since the OB is necessary for long-term retention of olfactory memories, it is possible that oestrogen promotes the preservation of these memories by acting in the OB. It is most likely however, that oestrogen is also acting at secondary and tertiary processing levels in the olfactory system. 8. Social recognition and oestrogen receptors Recent studies have focussed on establishing the role of oestrogen in neural plasticity associated with social recognition through the activation of it’s ␣ or ␤ receptors (␣ER and ␤ER). We have investigated the involvement of both receptors in olfactory learning by studying short- and long-term social recognition in mice lacking functional ␣ER or ␤ER genes (␣ERKO and ␤ERKO mice respectively). Our findings show that social recognition memories require a functional ␣ER activated by oestrogen. Male and female ␣ERKO mice showed impaired long-term (24 h) social recognition compared with wildtype controls, while ␤ERKO mice were unaffected [128]. Interestingly, habituation–dishabituation behaviour was also affected by the lack of ␣ER but in a gender specific manner. Female ␣ERKO mice showed an attenuated habituation to the presentation of a sedated adult wildtype female suggesting impaired memory formation. Therefore, oestrogen is not only acting on the preservation of long-term olfactory memories, it is also acting on the formation and/or short-term retention of those memories. Oestrogen, also potentially acts at other brain regions to control social behaviour and recognition memory. Other studies have shown that female mice lacking either ␣ER, ␤ER or OT genes have impaired short-term social recognition [21]; although in general agreement with our findings, deleting ␤ER has a milder effect [23]. This has been proposed to occur through the interaction of four genes coding for OT, OT receptor (OTR), ␣ER and ␤ER [21,22]. Oestrogen, through activation of ␣ER and ␤ER, modulates the OT system that in turn controls social recognition [21]. Oestrogens through ␤ER regulate OT production in the hypothalamic paraventricular nucleus (PVN) [63,110,136], while activation of ␣ER drives the transcription of OTR in the amygdala [135,137,173] and probably the OB

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Fig. 4. In vivo microdialysis (15 min) sampling in the main olfactory bulb and piriform cortex of females across the oestrous cycle. (A) Three consecutive 15 min-NMDAchallenges, with 2 h inter-challenge interval, were delivered into the main olfactory bulb, samples were also taken from the ipsilateral piriform cortex. (B) NMDA-evoked neurotransmitter release in the olfactory bulb (OB) and (C) piriform cortex (PC). * P < 0.05, P < 0.06, ** P < 0.01 compared with NMDA challenge-3. ♦ P < 0.05, ♦♦ P < 0.01 compared with proestrous females’ challenge-3.  P < 0.05 compared with proestrous and oestrous females’ (+++)P < 0.001 compared with NMDA challenge-1. Overall analysis of logtransformed data was done using two-way ANOVA with repeated measures for NMDA challenge and oeatrous cycle stage as factor, followed by a Tukey’s multiple comparison test.

as well. Therefore, in the olfactory pathway for social recognition, the signals from odour stimuli detected by OB reach the cortical and medial amygdala and OT actions via the OTR can modulate social recognition but only when there is appropriate oestrogen priming [44]. 9. The OB plays a primary role in odour-guided behaviour Olfaction in mammals can strongly mediate diverse behaviours from fear responses to predators and aversive behaviour to avoidance/approach toxic/palatable foods, mate preferences and offspring or maternal recognition. Rodents, for example, show avoidance behaviours towards the odours of predators’ and the smell of spoiled food [58,59,158]. They can also show attraction behaviours to specific food or conspecific odours [97,111]. Some of these behaviours are learned and others are innate. Recent studies have found that many of these behaviours are controlled, in the first instance, by the MOB. The MOB is divided in different olfactory receptors, with each glomerulus representing a single species of odour receptor [106]. A single odourant can interact with several different receptor species and the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the OB. Little is known about how the OB map is decoded in the brain and if different odours activate different neural systems. A recent study trying to address this used mutant

mice that had ablated olfactory sensory neurones in a specific area of the olfactory epithelium (by targeted expression of the diphtheria toxin gene) [86]. These animals showed OB regions lacking glomerular structures but preserved second-order neurons. They were capable of detecting fox (trimethyl-tiazoline, TMT) “aversive” odours but lacked the innate aversive and fear responses to them. In rats, TMT activates the BNST which leads in turn to the stimulation of the hypothalamic–pituitary–adrenal axis [30] and raises plasma adrenocorticotropic hormone (ACTH) levels (i.e. a stress response). Interestingly, the amygdala was also involved in the TMTinduced fear processing [43]. In the mutant mice, the BNST—innate fear pathway—failed to be activated by TMT. On the other hand, spoiled food odours that evoke aversive behaviour do not activate the BNST or raise ACTH levels. These results therefore show that fear responses induced by TMT and aversive responses to spoiled food odour are separately processed in the brain with different neural circuits and that this might be caused by differential processing of innate and learned odours within the MOB Innate aversive/fear responses probably involve genetically programmed neural circuits. As in the immune system, the mouse olfactory system seems to have maintained both innate odour responses with hard-wired neural circuits, in parallel with adaptive ones for newly acquired information. In the olfactory system, the OB may not simply be a topographic projection target to form a glomerular map, but may, instead, have area-specific functions that are predetermined genetically before the development of the olfactory sensory neu-

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rone projections. Thus the MOB can evoke different behavioural responses through relaying information to different downstream targets depending upon the odour in question. Another role of the MOB in mediating behaviour may be through differential control of olfactory perception. Dopaminergic neurones (juxtaglomerular dopaminergic neurones, JDN) exclusive to the MOB [3], modulate odour detection and the discrimination between odours [160]. They modulate sensory input from olfactory sensory neurones to mitral cells through dopamine D2 receptor (D2R)-mediated pre-synaptic inhibition [42]. What is more, tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine, is modulated in the MOB by oestrogen [33]. Vaginocervical stimulation can also modulate tyrosine hydroxylase synthesis and dopamine release in the brain, including the MOB [1,151]. A recent study has shown that these JDNs play a fundamental role in the timing of the Bruce effect [132], a form of olfactory learning that was thought to be restricted to the AOB. In the Bruce effect, implantation of the embryo can be blocked between 0 and 3 days of pregnancy in female mice when they are exposed to the scent of a strange male, but not to the stud male that had originally mated with her. This is caused by the inhibition of prolactin secretion resulting in a decrease of progesterone, termination of pregnancy support and a return to ovulation. However, on days 4–6 of pregnancy (the implantation stage) females become resistant to the Bruce effect [24]. The exact mechanisms of this pregnancy protection are still not fully known, however it is thought to be by impairing the perception of social odours contained in male urine. Females can usually distinguish male urine from oestrous female urine, but they fail to do so when in the implantation stage of pregnancy spending similar amount of time investigating the two urine samples. This happens as a result of increased dopamine in the MOB and activation of D2R shortly after mating. Treatment with a D2R antagonist 6 days after mating restores perception of social odours and promotes pregnancy block by inhibiting prolactin release when females are exposed to the strange male urine [132]. The above examples further support the notion of the MOB as being a major player in the control of behaviour and physiological responsesy by social odours [20]. 10. Conclusions From this review it is clear that many different aspects of social recognition and social learning involve relevant odour cues being processed by the MOS and that while a distributed system of primary, secondary and tertiary processing regions is involved in associated memory formation, plasticity changes within the olfactory bulb and piriform cortex maintain it post-consolidation. The neurotransmitter systems involved in these plasticity changes are the same as those reported in the hippocampus and elsewhere making olfactory memory a tractable model for the study of general mnemonic processes. Furthermore the robust modulatory actions of oestrogen and OT within this system make it an important model for studying how these substances influence both social and nonsocial recognition memory systems in the brain. Our increasing knowledge of the organisation of the olfactory projection system together with the range of different learning models make it extremely tractable for more detailed studies of how the whole processing network encodes and organises behavioural responses to odours and lead to the development of in silico (computer simulation) models of the whole system. References [1] Arbogast LA, Voogt JL. Progesterone reverses the estradiol-induced decrease in tyrosine-hydroxylase messenger-RNA levels in the arcuate nucleus. Neuroendocrinology 1993;58:501–10.

[2] Axelson JF, Smith M, Duarte M. Prenatal flutamide treatment eliminates the adult male rat’s dependency upon vasopressin when forming social-olfactory memories. Horm Behav 1999;36:109–18. [3] Baker H. Dopamine and substance-P are contained in different populations of tufted cells in the Syrian and Chinese-Hamster main olfactory-bulb. Chem Senses 1986;11:578–9. [4] Bean NJ, Galef BG, Mason JR. The effect of carbon-disulfide on foodconsumption by house mice. J Wildlife Manage 1988;52:502–7. [5] Belin P. Voice processing in human and non-human primates. Philos Trans R Soc Lon B Biol Sci 2006;361:2091–107. [6] Blissitt MJ, Bland KP, Cottrell DF. Detection of oestrous-related odour in ewe urine by rams. J Reprod Fertil 1994;101:189–91. [7] Bluthe RM, Dantzer R. Chronic intracerebral infusion of vassopressin antagonist modulates social recognition in rat. Brain Res 1992;572:261–4. [8] Bluthe RM, Dantzer R. Social recognition does not involve vasopressinergic neurotransmission in female rats. Brain Res 1990;535:301–4. [9] Boehm T, Zufall F. MHC peptides and the sensory evaluation of genotype. Trends Neurosc 2006;29:100–7. [10] Brennan PA, Friedrich RW. Something in the air: new vistas on olfaction. Trends Neurosci 1998;21:1–2. [11] Brennan PA, Kaba H, Keverne EB. Olfactory recognition: a simple memory system. Science 1990:1223–6. [12] Brennan PA, Kendrick KM. Mammalian social odours: attraction and individual recognition. Philos Trans R Soc Lon B Biol Sci 2006;361:2061–78. [13] Brennan PA, Keverne EB. Neural mechanisms of olfactory recognition memory. In: Bolhuis JJ, editor. Brain, perception, memory. Advances in cognitive neuroscience. Oxford, UK: Oxford University Press; 2000. p. 93–112. [14] Brennan PA, Keverne EB. Something in the air? New insights into mammalian pheromones. Curr Biol 2004;14:R81–9. [15] Brennan PA, Schellinck HM, de la Riva C, Kendrick KM, Keverne EB. Changes in neurotransmitter release in the main olfactory bulb following an olfactory conditioning procedure in mice. Neuroscience 1998;87:583–90. [16] Broad KD, Hinton MR, Keverne EB, Kendrick KM. Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory. Neuroscience 2002;114:715–29. [17] Broad KD, Levy F, Evans G, Kimura T, Keverne EB, Kendrick KM. Previous maternal experience potentiates the effect of parturition on oxytocin receptor mRNA expression in the paraventricular nucleus. Eur J Neurosci 1999;11:3725–37. [18] Broad KD, Mimmack ML, Keverne EB, Kendrick KM. Increased BDNF and trk-B mRNA expression in cortical and limbic regions following formation of a social recognition memory. Eur J Neurosci 2002;16:2166–74. [19] Buck L, Axel R. A novel multigene family may encode odorant receptors—a molecular-basis for odor recognition. Cell 1991;65:175–87. [20] Carr WF, Yee L, Gable D, Marasco E. Olfactory recognition of conspecifics by domestic Norway rats. J Comp Physiol Psycol 1976;90:821–8. [21] Choleris E, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW, Ogawa S. An estrogendependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice. Proc Natl Acad Sci USA 2003;100:6192–7. [22] Choleris E, Kavaliers M, Pfaff DW. Functional genomics of social recognition. J Neuroendocrinol 2004;16:383–9. [23] Choleris E, Ogawa S, Kavaliers M, Gustafsson JA, Korach KS, Muglia LJ, et al. Involvement of estrogen receptor alpha, beta and oxytocin in social discrimination: a detailed behavioral analysis with knockout female mice. Genes Brain Behav 2006;5:528–39. [24] Chung HJ, Reyes ABV, Watanabe K, Tomogane H, Wakasugi N. Embryonic abnormality caused by male pheromonal effect in pregnancy block in mice. Biol Reprod 1997;57:312–9. [25] Cornwell-Jones CA, Marasco EM. Castration decreases olfactory bulb norepinephrine in male rats but not in hamsters. Brain Res 1980;183:377–82. [26] Countryman RA, Gold PE. Rapid forgetting of social transmission of food preferences in aged rats: relationship to hippocampal CREB activation. Learn Mem 2007;14:350–8. [27] da Costa APC, Broad KD, Kendrick KM. Olfactory memory and maternal behaviour-induced changes in c- fos and zif/268 mRNA expression in the sheep brain. Brain Res Mol Brain Res 1997;46:63–76. [28] Dantzer R, Tazi A, Bluthe RM. Cerebral lateralization of olfactory-mediated affective processes in rats. Behav Brain Res 1990;40:53–60. [29] Darby EM, Devor M, Chorover SL. Presumptive sex-pheromone in hamsters—some behavioral-effects. J Comp Physiol Psycol 1975;88:496–502. [30] Day HEW, Masini CV, Campeau S. The pattern of brain c-fos mRNA induced by a component of fox odor, 2.5-dihydro-2,4,5-trimethylthiazoline (TMT), in rats, suggests both systemic and processive stress characteristics. Brain Res 2004;1025:139–51. [31] Dluzen DE, Kreutzberg JD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Mptp) disrupts social memory recognition processes in the male-mouse. Brain Res 1993;609:98–102. [32] Dluzen DE, Muraoka S, Engelmann M, Ebner K, Landgraf R. Oxytocine induces preservation of social recognition in male rats by activating a-adrenoceptors of the olfactory bulb. Eur J Neurosci 2000;12:760–6. [33] Dluzen DE, Park JH, Kim K. Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter mRNA by estrogen. Mol Brain Res 2002;108:121–8. [34] Dorries KM, Adkins-Regan E, Halpern BP. Sensitivity and behavioral responses to the pheromone androstenone are not mediated by the vomeronasal organ in domestic pins. Brain Behav Evol 1997;49:53–62.

G. Sanchez-Andrade, K.M. Kendrick / Behavioural Brain Research 200 (2009) 323–335 [35] Dorries KM, Adkins-Rregan E, Halpern BP. Olfactory sensitivity to the pheromone, androstenone, is sexually dimorphic in the pig. Physiol Behav 1995;57:255–9. [36] Dulac C, Torello AT. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nat Rev Neurosci 2003;4:551–62. [37] Dulac C, Wagner S. Genetic analysis of brain circuits underlying pheromone signaling. Ann Rev Genet 2006;40:449–67. [38] Dunbar R. Evolution of the social brain. Science 2003;302:1160–1. [39] Dunbar RIM. The social brain hypothesis. Evol Anthropol 1998;6:178–90. [40] Dunbar RIM, Shultz S. Evolution in the social brain. Science 2007;317:1344–7. [41] Engelmann M, Wotjak CT, Landgraf R. Social discrimination procedure: an alternative method to investigate juvenile recognition abilities in rats. Physiol Behav 1995;58:315–21. [42] Ennis M, Zhou FM, Ciombor KJ, Aroniadou-Anderjaska V, Hayar A, Borrelli E, et al. Dopamine D2 receptor-mediated presynaptic inhibition of olfactory nerve terminals. J Neurophysiol 2001;86:2986–97. [43] Fendt M, Endres T, Apfelbach R. Temporary inactivation of the bed nucleus of the stria terminalis but not of the amygdala blocks freezing induced by trimethylthiazoline, a component of fox feces. J Neurosci 2003;23:23–8. [44] Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 2001;21: 8278–85. [45] Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet 2000;25:284–8. [46] Ferguson JN, Young LJ, Insel TR. The neuroendocrine basis of social recognition. Front Neuroendocrinol 2002;23:200–24. [47] Frankland PW, Josselyn A, Anagnostaras SG, Kogan JH, Takahashi E, Silva AJ. Consolidation of CS and US representations in associative fear conditioning. Hippocampus 2004;14:557–69. [48] Galef BG, Wigmore SW. Transfer of information concerning distant foods: a laboratory investigation of the ‘information-centre’ hypothesis. Anim Behav 1983;31:748–58. [49] Galef BGJ, Mason JR, Preti G, Bean NJ. Carbon disulfide: a semiochemical mediating socially-induced diet choice in rats. Physiol Behav 1988;42:119–24. [50] Gall CM, Hendry SHC, Seroogy KB, Jones EG, Haycock JW. Evidence for coexistence of gaba and dopamine in neurons of the rat olfactory-bulb. J Comp Neurol 1987;266:307–18. [51] Gass P, Wolfer DP, Balschun D, Rudolph D, Frey U, Lipp HP, et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn Mem 1998;5:274–88. [52] Guan XB, Dluzen D. Castration reduces potassium-stimulated norepinephrine release from superfused olfactory bulbs of male-rats. Brain Res 1991;568:147–51. [53] Guerra-Araiza C, Miranda-Martinez A, Neri-Gómez T, Camacho-Arroyo I. Sex steroids effects on the content of GAD, TH, GABA(A), and glutamate receptors in the olfactory bulb of the male rat. Neurochem Res 2008;33: 1568–73. [54] Guevara-Guzman R, Barrera-Mera B, de la Riva C, Kendrick KM. Release of classical transmitters and nitric oxide in the rat olfactory bulb, evoked by vaginocervical stimulation and potassium, varies with the oestrous cycle. Eur J Neurosci 2000;12:80–8. [55] Guevara-Guzman R, Barrera-Mera B, Weiss ML. Effects of the estrous cycle on olfactory bulb response to vaginocervical stimulation in the rat: results from electrophysiology ans Fos immunocytochemistry experiments. Brain Res Bull 1997;44:141–9. [56] Hammock EAD, Young LJ. Oxytocin, vasopressin and pair bonding: implications for autism. Philos Trans R Soc Lon B Biol Sci 2006;361:2187–98. [57] Haskins JT, Moss RL. Action of estrogen and mechanical vaginocervical stimulation on the membrane excitability of hypothalamic and midbrain neurons. Brain Res Bull 1983;10:489–96. [58] Hebb ALO, Zacharko RM, Dominguez H, Laforest S, Gauthier M, Levac C, et al. Changes in brain cholecystokinin and anxiety-like behavior following exposure of mice to predator odor. Neuroscience 2003;116:539–51. [59] Hebb ALO, Zacharko RM, Gauthier M, Trudel F, Laforest S, Drolet G. Brief exposure to predator odor and resultant anxiety enhances mesocorticolimbic activity and enkephalin expression in CD-1 mice. Eur J Neurosci 2004;20:2415–29. [60] Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003;54:1389–98. [61] Heyes CM. Social learning in animals: categories and mechanisms. Biol Rev Cam Philos Soc 1994;69:207–31. [62] Hlinak Z. Social recognition in ovariectomized and estradiol-treated female rats. Horm Behav 1993:27. [63] Hrabovszky E, Kallo I, Hajszan T, Shughrue PJ, Merchenthaler I, Liposits Z. Expression of estrogen receptor-beta messenger ribonucleic acid in oxytocin and vasopressin neurons of the rat supraoptic and paraventricular nuclei. Endocrinology 1998;13:2600–4. [64] Huck UW, Lisk RD, Kim S, Evans AB. Olfactory discrimination of estrous condition by the male golden hamster. Behav Neural Biol 1989;51:1–10. [65] Hurst JL, Payne CE, Nevison CM, Marie AD, Humphries RE, Robertson DH, et al. Individual recognition in mice mediated by major urinary proteins. Nature 2001;414:631–4. [66] Izquierdo I, Bevilaqua LRM, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control memory consolidation. Trends Neurosci 2006;29:496–505.

333

[67] James B. The importance of NMDA/nitric oxide signalling in mouse olfactory memory. Cambridge: University of Cambridge; 2003. p. 230. [68] Johnson BA, Woo CC, Duong HC, Nguyen V, Leon M. A learned odor evokes an enhanced Fos-like glomerular response in the olfactory-bulb of young-rats. Brain Res 1995;699:192–200. [69] Johnston RE, Derzie A, Chiang G, Jernigan P, Lee HC. Individual scent signatures in golden-hamsters—evidence for specialization of function. Anim Behav 1993;45:1061–70. [70] Kanwisher N, Yovel G. The fusiform face area: a cortical region specialized for the perception of faces. Philos Trans R Soc Lon B Biol Sci 2006;361: 2109–28. [71] Kaut KP, Bunsey MD. The effects of lesions to the rat hippocampus or rhinal cortex on olfactory and spatial memory: retrograde and anterograde findings. Cogn Affect Behav Neurosci 2001;1:270–86. [72] Keller M, Meurisse M, Levy F. Mapping of brain networks involved in consolidation of lamb recognition memory. Neuroscience 2005;133:359–69. [73] Keller M, Meurisse M, Levy F. Mapping the neural substrates involved in maternal responsiveness and lamb olfactory memory in parturient ewes using Fos imaging. Behav Neurosci 2004;118:1274–84. [74] Keller M, Meurisse M, Poindron P, Nowak R, Ferreira G, Shayit M, et al. Maternal experience influences the establishment of visual/auditory, but not olfactory recognition of the newborn lamb by ewes at parturition. Dev Psychobiol 2003;43:167–76. [75] Keller M, Perrin G, Meurisse M, Ferreira G, Levy F. Cortical and medial amygdala are both involved in the formation of olfactory offspring memory in sheep. Eur J Neurosci 2004;20:3433–41. [76] Kelliher KR, Chang YM, Wersinger SR, Baum MJ. Sex difference and testosterone modulation of pheromone-induced neuronal Fos in the ferret’s main olfactory bulb and hypothalamus. Biol Reprod 1998;59:1454–63. [77] Kendrick KM. Neurobiological correlates of visual and olfactory recognition in sheep. Behav Process 1994;33:89–111. [78] Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000;85:111S–24S. [79] Kendrick KM, Da Costa AP, Broad KD, Ohkura S, Guevara R, Levy F, et al. Neural control of maternal behaviour and olfactory recognition of offspring. Brain Res Bull 1997;44:383–95. [80] Kendrick KM, GuevaraGuzman R, Zorrilla J, Hinton MR, Broad KD, Mimmack M, et al. Formation of olfactory memories mediated by nitric oxide. Nature 1997;388:670–4. [81] Kendrick KM, Keverne EB. Importance of progesterone and estrogen priming for the induction of maternal-behavior by vaginocervical stimulation in sheep—effects of maternal experience. Physiol Behav 1991;49: 745–50. [82] Kendrick KM, Levy F, Keverne EB. Changes in the sensory processing of olfactory signals induced by birth in sheep. Science 1992;256:833–6. [83] Kendrick KM, Levy F, Keverne EB. Importance of vaginocervical stimulation for the formation of maternal bonding in primiparous and multiparous parturient ewes. Physiol Behav 1991;50:595–600. [84] Kendrick KM, Mimmack ML, Hinton MR, Broad KD. Up-regulation of class 1 metabotrophic glutamate variation receptors and consolidation of olfactory memory. Eur J Neurosci 2000;12:85–185. [85] Keverne EB, Levy F, Guevara-Guzman R, Kendrick KM. Influence of birth and maternal experience on olfactory bulb neurotransmitter release. Neuroscience 1993;56:557–65. [86] Kobayakawa K, Kobayakawa R, Matsumoto H, Oka Y, Imai T, Ikawa M, et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 2007;450:U503–5. [87] Kogan JH, Frankland PW, Silva AJ. Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 2000;10:45–56. [88] Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005;435:673–6. [89] Larrazolo-Lopez A, Kendrick KM, Aburto-Arciniega M, Arriaga-Avila V, Morimoto S, Frias M, et al. Vaginocervical stimulation enhances social recognition memory in rats via oxytocin release in the olfactory bulb. Neuroscience 2008;152:585–93. [90] Lee JW, Erskine MS. Vaginocervical stimulation suppresses the expression of c-fos induced by mating in thoracic, lumbar and sacral segments of the female rat. Neuroscience 1996;74:237–49. [91] Leinders-Zufall T, Brennan P, Widmayer P, Chandramani P, Maul-Pavicic A, Jager M, et al. MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 2004;306:1033–7. [92] Levy F. Neurobiological mechanisms involved in recognition of olfactory signature of the young in sheep. J Soc Biol 2002;196:77–83. [93] Levy F, Gervais R, Kindermann U, Orgeur P, Piketty V. Importance of betanoradrenergic receptors in the olfactory-bulb of sheep for recognition of lambs. Behav Neurosci 1990;104:464–9. [94] Levy F, Guevara-Guzman R, Hinton MR, Kendrick KM, Keverne EB. Effects of parturition and maternal experience on noradrenaline and acetylcholinerelease in the olfactory-bulb of sheep. Behav Neurosci 1993;107:662–8. [95] Levy F, Locatelli A, Piketty V, Tillet Y, Poindron P. Involvement of the main but not the accessory olfactory system in maternal-behavior of primiparous and multiparous ewes. Physiol Behav 1995;57:97–104. [96] Levy F, Richard P, Meurisse M, Ravel N. Scopolamine impairs the ability of parturient ewes to learn to recognise their lambs. Psychopharmacology 1997;129:85–90.

334

G. Sanchez-Andrade, K.M. Kendrick / Behavioural Brain Research 200 (2009) 323–335

[97] Lin DY, Zhang SZ, Block E, Katz LC. Encoding social signals in the mouse main olfactory bulb. Nature 2005;434:470–7. [98] Luo M, Fee MS, Katz LC. Encoding pheromonal signals in the accessory olfactory bulb of behaving mice. Science 2003;299:1196–201. [99] Malnic B, Hirono J, Sato T, Buck LB. Combinatorial receptor codes for odors. Cell 1999;96:713–23. [100] Matochick JA. Role of the main olfactory system in recognition of between individual spiny mice. Physiol Behav 1998;42:217–22. [101] Medina JH, Bekinschtein P, Carnmarota M, Izquierdo I. Do memories consolidate to persist or do they persist to consolidate? Behav Brain Res 2008;192:61–9. [102] Meredith M. Vomeronasal, olfactory, hormonal convergence in the brain—cooperation or coincidence? Olfaction and taste Xii, vol. 855; 1998. p. 349–61. [103] Meredith M, Westberry JM. Distinctive responses in the medial amygdala to same-species and different-species pheromones. J Neurosci 2004;24: 5719–25. [104] Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, SH, et al. Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 2003;144:2055–67. [105] Morgan MA, Schulkin J, Pfaff DW. Estrogens and non-reproductive behaviors related to activity and fear. Neurosci Biobehav Rev 2004;28:55–63. [106] Mori K, Takahashi YK, Igarashi KM, Yamaguchi M. Maps of odorant molecular features in the mammalian olfactory bulb. Physiol Rev 2006;86:409–33. [107] Moriceau S, Sullivan RM. Unique neural circuitry for neonatal olfactory learning. J Neurosci 2004;24:1182–9. [108] Mykytowy R, Goodrich BS. Skin glands as organs of communication in mammals. J Invest Dermatol 1974;62:124–31. [109] Natynczuk SE, Macdonald DW. Scent, sex, and the self-calibrating rat. J Chem Ecol 1994;20:1843–57. [110] Nomura M, Durbak L, Chan J, Smithies O, Gustafsson JA, Korach KS, et al. Genotype/age interactions on aggressive behavior in gonadally intact estrogen receptor beta knockout (beta ERKO) male mice. Horm Behav 2002;41:288–96. [111] Nyby J, Kay E, Bean NJ, Dahinden Z, Kerchner M. Male-mouse (Mus musculus) attraction to airborne urinary odors of conspecifics and to food odors—effects of food-deprivation. J Comp Psychol 1985;99:479–90. [112] Olmos G, Naftolin F, Pérez J, Tranque PA, Garcia-Segura LM. Synaptic remodeling in the rat arcuate nucleus during the estrous cycle. Neuroscience 1989;32:663–7. [113] Penn D, Potts W. MHC-disassortative mating preferences reversed by crossfostering. Philos Trans R Soc Lon B Biol Sci 1998;265:1299–306. [114] Petrulis A, Alvarez P, Eichenbaum H. Neural correlates of social odor recognition and the representation of individual distinctive social odors within entorhinal cortex and ventral subiculum. Neuroscience 2005;130:259–74. [115] Pfaff DW, Pfaffman C. Olfactory and hormonal influences on basal fore-brain of male rat. Brain Res 1969;15:137. [116] Poindron P, Lévy F. Physiological, sensory and experiential determinants of maternal behavior in sheep. In: Krasnegor NA, Bridges RS, editors. Mammalian parenting. Oxford, UK: Oxford University Press; 1990. p. 133–56. [117] Polan HJ, Hofer MA. Maternally directed orienting behaviors of newborn rats. Dev Psychobiol 1999;34:269–79. [118] Popik P, Vetulani J, Bisaga A, van Ree JM. Recognition cue in the rat’s social memory paradigm. J Basic Clin Physiol Pharmacol 1991;2:315–27. [119] Rangel S, Leon M. Early odor preference training increases olfactory-bulb norepinephrine. Dev Brain Res 1995;85:187–91. [120] Richter K, Wolf G, Engelmann M. Social recognition memory requires two stages fo protein synthesis in mice. Learn Mem 2005;12:407–13. [121] Rolls ET. The orbitofrontal cortex. In: Roberts AC, Robbins TW, Weiskrantz L, editors. The prefrontal cortex. Oxford: Oxford University Press; 1998. p. 67–86. [122] Roullet F, Datiche F, Lienard F, Cattarelli M. Learning-stage dependent Fos expression in the rat brain during acquisition of an olfactory discrimination task. Behav Brain Res 2005;157:127–37. [123] Rowell TE. Till death us do part—long-lasting bonds between ewes and their daughters. Anim Behav 1991;42:681–2. [124] Rudick CN, Gibbs RB, Woolley CS. A role for the basal forebrain cholinergic system in estrogen-induced disinhibition of hippocampal pyramidal cells. J Neurosci 2003;23:4479–90. [125] Ryan BC, Young NB, Moy SS, Crawley JN. Olfactory cues are sufficient to elicit social approach behaviors but not social transmission of food preference in C57BL/6J mice. Behav Brain Res 2008;193:235–42. [126] Sànchez-Andrade G. Ovarian cycle influences on neural plasticity and olfactory learning in the mouse. Cambridge: University of Cambridge; 2005. p. 271. [127] Sànchez-Andrade G, James BM, Kendrick KM. Neural encoding of olfactory recognition memory. J Reprod Dev 2005;51:547–58. [128] Sanchez-Andrade G, Kendrick KM. Role of estrogen ␣ and ␤ receptors on social olfactory recogntion in mice. Soc Neurosci Abstr 2005:776–8. [129] Sànchez-Andrade G, Kendrick KM. Estrous—cycle dependent effects on mouse olfactory memory and NMDA—evoked plasticity. Soc Neurosci Abstr 2005:517–9. [130] Schaal B, Coureaud G, Langlois D, Ginies C, Semon E, Perrier G. Chemical and behavioural characterization of the rabbit mammary pheromone. Nature 2003;424:68–72. [131] Schwende FJ, Wiesler D, Jorgenson JW, Carmack M, Novotny M. Urinary volatile constituents of the house mouse, Mus musculus, and their endocrine dependency. J Chem Ecol 1986;12:277–96.

[132] Serguera C, Triaca V, Kelly-Barrett J, Al Banchaabouchi M, Minichiello L. Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy. Nat Neurosci 2008;11:949–56. [133] Shang Y, Dluzen DE. Nisoxetine infusion into the olfactory bulb enhances the capacity for male rats to identify conspecifics. Neuroscience 2001;104:957–64. [134] Shang YL, Dluzen DE. Castration reduces olfactory bulb norepinephrin transporter function as indicated by response to noradrenergic uptake blockers. Brain Res 1998;779:119–24. [135] Shughrue PJ, Askew GR, Dellovade TL, Merchenthaler I. Estrogen-binding sites and their functional capacity in estrogen receptor double knockout mouse brain. Endocrinology 2002;143:1643–50. [136] Shughrue PJ, Dellovade TL, Merchenthaler I. Estrogen modulates oxytocin gene expression in regions of the rat supraoptic and paraventricular nuclei that contain estrogen receptor-beta. Prog Brain Res 2002;139:15–29. [137] Shughrue PJ, Lane MV, Merchenthaler I. Biologically active estrogen receptorbeta: evidence from in vivo autoradiographic studies with estrogen receptor alpha—knockout mice. Endocrinology 1999;140:2613–20. [138] Singer AG, Agosta WC, Clancy AN, Macrides F. The chemistry of vomeronasally detected pheromones—characterization of an aphrodisiac protein. Ann NY Acad Sci 1987;519:287–98. [139] Singh PB, Brown RE, Roser B. MHC antigens in urine as olfactory recognition cues. Nature 1987;327:161–4. [140] Spehr M, Kelliher KR, Li XH, Boehm T, Leinders-Zufall T, Zufall F. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J Neurosci 2006;26:1961–70. [141] Spehr M, Spehr J, Ukhanov K, Kelliher KR, Leinders-Zufall T, Zufall F. Parallel processing of social signals by the mammalian main and accessory olfactory systems. Cell Mol Life Sci 2006;63:1476–84. [142] Staubli U, Ivy G, Lynch G. Hippocampal denervation causes rapid forgetting of olfactory information in rats. Proc Natl Acad Sci USA 1984;81:5885–7. [143] Stopka P, Janotova K, Heyrovsky D. The advertisement role of major urinary proteins in mice. Physiol Behav 2007;91:667–70. [144] Sullivan RM, Landers M, Yeaman B, Wilson DA. Neurophysiology—good memories of bad events in infancy. Nature 2000;407:38–9. [145] Sullivan RM, Wilson DA. Molecular biology of early olfactory memory. Learn Mem 2003;10:1–4. [146] Sullivan RM, Wilson DA. The role of norepinephrine in the expression of learned olfactory neurobehavioral responses in infant rats. Psychobiology 1991;19:308–12. [147] Sullivan RM, Wilson DA, Leon M. Norepinephrine and learning-induced plasticity in infant rat olfactory system. J Neurosci 1989;9:3998–4006. [148] Sundberg H, Doving K, Novikov S, Ursin H. A method for studying responses and habituation to odors in rats. Behav Neural Biol 1982;34:113–9. [149] Swann J, Rahaman F, Bijak T, Fiber J. The main olfactory system mediates pheromone-induced fos expression in the extended amygdala and preoptic area of the male Syrian hamster. Neuroscience 2001;105:695–706. [150] Tang AC, Nakazawa M, Romeo RD, Reeb BC, Sisti H, McEwen BS. Effects of long-term estrogen replacement on social investigation and social memory in ovariectomized C57BL/6 mice. Horm Behav 2005;47:350–7. [151] Tashiro Y, Kaneko T, Nagatsu I, Kikuchi H, Mizuno N. Increase of tyrosine hydroxylase-like immunoreactive neurons in the nucleus-accumbens and the olfactory-bulb in the rat with the lesion in the ventral tegmental area of the midbrain. Brain Res 1990;531:159–66. [152] Tate AJ, Fischer H, Leigh AE, Kendrick KM. Behavioural and neurophysiological evidence for face identity and face emotion processing in animals. Philos Trans R Soc Lon B Biol Sci 2006;361:2155–72. [153] Thor DH, Holloway WR. Social memory of the male laboratory rat. J Comp Physiol Psychol 1982;96:1000–6. [154] Trombley PQ. Noradrenergic modulation of synaptic transmission between olfactory-bulb neurons in culture—implications to olfactory learning. Brain Res Bull 1994;35:473–84. [155] Trombley PQ, Shepherd GM. Synaptic transmission and modulation in the olfactory bulb. Curr Opin Neurobiol 1993;3:540–7. [156] Valsecchi P, Choleris E, Moles A, Guo C, Mainardi M. Kinship and familiarity as factors affecting social transfer of food preferences in adult Mongolian gerbils (Meriones unguiculatus). J Comp Psychol 1996;110:243–51. [157] Valsecchi P, Galef BG. Social influence on the food preference of house mice (Mus musculus). Int J Comp Psychol 1989;2:245–56. [158] Vernetmaury E, Polak EH, Demael A. Structure–activity relationship of stressinducing odorants in the rat. J Chem Ecol 1984;10:1007–18. [159] Wanisch K, Wotjak CT, Engelmann M. Long-lasting second stage of recognition memory consolidation in mice. Behav Brain Res 2008;186:191–6. [160] Wei CJ, Linster C, Cleland TA. Dopamine D-2 receptor activation modulates perceived odor intensity. Behav Neurosci 2006;120:393–400. [161] Wilson DA, Leon M. Noradrenergic modulation of olfactory-bulb excitability in the postnatal rat. Developmental. Brain Res 1988;42:69–75. [162] Wilson DA, Sullivan RM. Neurobiology of associative learning in the neonate—early olfactory learning. Behav Neural Biol 1994;61:1–18. [163] Winslow JT, Camacho F. Cholinergic modulation of a decrement in social-investigation following repeated contracts between mice. Psychopharmacology 1995;121:164–72. [164] Woo CC, Leon M. Increase in a focal population of juxtaglomerular cells in the olfactory bulb associated with early learning. J Comp Neurol 1991;305:48–56. [165] Woo CC, Leon M. Sensitive period for neural and behavioral-response development to learned odors. Dev Brain Res 1987;36:309–13.

G. Sanchez-Andrade, K.M. Kendrick / Behavioural Brain Research 200 (2009) 323–335 [166] Wrenn CC, Harris AP, Saavedra MC, Crawley JN. Social transmission of food preference in mice: methodology and application to galanin-overexpressing transgenic mice. Behav Neurosci 2003;117:21–31. [167] Wyatt T. Key roles for chemical communication in animal biology—insights from a comparative approach. Comp Biochem Physiol A Mol Integr Physiol 2007;148:S1–2. [168] Wyatt TD. Pheromones and animal behaviour: communication by smell and taste. In: Pheromones and animal behaviour: communication by smell and taste. Cambridge University Press; 2003. p. 1–391. [169] Xu FQ, Schaefer M, Kida I, Schafer J, Liu N, Rothman DL, et al. Simultaneous activation of mouse main and accessory olfactory bulbs by odors or pheromones. J Comp Neurol 2005;489:491–500.

335

[170] Yamazaki K, Beauchamp GK, Curran M, Bard J, Boyse EA. Parent-progeny recognition as a function of MHC odortype identity. Proc Natl Acad Sci USA 2000;97:10500–2. [171] Yamazaki Y, Beauchamp GK, Kupniewski D, Bard J, Thomas L, Boyse EA. Familial imprinting determines H-2 selective mating preferences. Science 1988;240:1331–2. [172] Yokoi M, Mori K, Nakanishi S. Refinement of odor molecule tuning by dendrodendritic synaptic inhibition in the olfactory bulb. Proc Natl Acad Sci USA 1995;92:3371–5. [173] Young LJ, Wang ZX, Donaldson R, Rissman EF. Estrogen receptor alpha is essential for induction of oxytocin receptor by estrogen. Neuroreport 1998;9: 933–6.