13.1. INTRODUCTION

Adult neurogenesis is a striking form of neural plasticity occurring in restricted regions of the mammalian brain. The past decades have witnessed tremendous research efforts in this field providing significant information regarding the anatomical, molecular, and functional mechanisms underlying neurogenesis in the adult brain. New neuron production regulates integrated brain functions, learning and memory, and adapts the brain to the changing world. Recent data in rodents indicates a link between adult neurogenesis and reproductive and social behavior. This provides the opportunity to unravel the function of this form of neural plasticity in ethologically relevant contexts and opens new perspectives to explore how the brain processes social stimuli. In this chapter we will summarize some of the major key points regarding the cues and mechanisms modulating adult neurogenesis during social interaction and possible role/s played by newborn neurons in this context. To achieve this goal we will give an overview of past and ongoing literature showing this link, with particular emphasis on our recent studies on two examples of sexual behavior: mate pheromonal imprinting in female mice, and paced mating in rats.

The early conception of the function of the brain postulated that once the brain developed it became stable and no new neurons were added in adulthood. This dogma has gradually been dropped over the past 40 years with the clear demonstration that adult neurogenesis is a striking form of structural remodeling characterizing the brain of vertebrates, though with significant differences between groups (Lindsey and Tropepe 2006; Bonfanti and Peretto 2011). In the 1970s, the issue of adult neurogenesis was regarded with skepticism although during the previous decade some proliferative activity was reported in the brain by Altman and colleagues (Altman 1963; Altman and Das 1965). Only years later, with the progress of neuroanatomical techniques and the demonstration of genesis and integration of new neurons in the adult brain of canaries (Nottebohm 1985), adult neurogenesis regained attention.

A new era in this field occurred starting from two simultaneous findings: the occurrence of a massive cell migration toward the rodents’ olfactory bulb (Luskin 1993; Lois and Alvarez-Buylla 1994) and the first isolation of adult neural stem cells (Reynolds and Weiss 1992). These studies strengthened the idea that neural plasticity in adult mammals not only occurs through synaptic remodeling but also through the addition of new neurons in the mature preexisting circuits. During the last two decades, this intriguingly persisting process in the mammalian brain was intensely investigated, and several review articles progressively made the point on its extension, features, and significance under physiological and pathological conditions (Emsley et al. 2005; Sohur et al. 2006; Gould 2007; Migaud et al. 2010; Bonfanti and Peretto 2011; Curtis et al. 2011; Fuentealba et al. 2012).

It is now clear that a constitutive/physiologic neurogenesis in adult mammals mostly occurs within two telencephalic regions, the subventricular zone–olfactory bulb system (SVZ-OB) (Lois and Alvarez-Buylla 1994) and the subgranular zone (SGZ) of dentate gyrus (DG) of the hippocampus (Kempermann et al. 2004). The neurogenic process in these regions is orchestrated by a complex interplay between intrinsic and extrinsic environmental cues. Several developmental signals, morphogens, growth factors, neurotransmitters, hormones, transcription factors, and epigenetic regulators have been described to tightly regulate specification and activity of proliferating progenitors, as well as the migration and integration of neuronal precursors within functional circuits (Hagg 2005; Faigle and Song 2013). The signaling mechanisms supporting adult neurogenesis are dynamically regulated by many environmental cues that can either positively or negatively influence the neurogenic process at the level of progenitor cells and during the integration of newborn neurons within circuits (Ma et al. 2009). This activity-dependent regulation is only beginning to be unraveled. Importantly, adult-born neurons in neurogenic regions exhibit critical periods of plasticity during a specific time window of their maturation (Nissant et al. 2009; Ming and Song 2011), and high responsiveness toward the same stimuli driving their integration/selection into circuits (Magavi et al. 2005; Kee et al. 2007). This supports a role of newborn neurons in sensory processing in DG and OB. Accordingly, several sources of data indicate that adult neurogenesis contributes to mechanisms of learning and memory (Lazarini et al. 2009; Moreno et al. 2009), and more recent hypotheses suggest that it also contributes to enhancing pattern separation (Aimone et al. 2011; Sahay et al. 2011). In this view, the continuous addition of new neurons in the olfactory bulb and hippocampus rather than being a simple mechanism of renewal of preexisting cells expands the capacity for plasticity in these regions.

In this chapter we will describe recent findings (see Feierstein et al. 2012 for review) that link reproductive and social stimuli to adult neurogenesis, particularly in the olfactory system. We will address first a brief description of the main results supporting this connection, and then, taking into account our recent work (Oboti et al. 2009, 2011; Corona et al. 2011; Portillo et al. 2012), we will focus on two striking examples of sexual behavior: (1) mate pheromonal imprinting to avoid pregnancy block in female mice and (2) paced mating in rats, namely the ability to control the sexual interaction. In both cases we demonstrate a link between adult neurogenesis and social activities underlying the reproductive function.

13.2. REPRODUCTIVE AND SOCIAL BEHAVIOR MODULATES ADULT NEUROGENESIS

A growing number of studies indicates that reproductive and social behavior modulates adult neurogenesis (Smith et al. 2001; Huang and Bittman 2002; Shingo et al. 2003; Mak et al. 2007; Larsen et al. 2008; Ruscio et al. 2008; Oboti et al. 2009; Furuta and Bridges 2009; Feierstein et al. 2010; Mak and Weiss 2010; Corona et al. 2011; Oboti et al. 2011; Sakamoto et al. 2011; Portillo et al. 2012; Brus et al. 2013). This provides the opportunity to unravel the function of this form of adult neural plasticity in ethologically relevant contexts, and in parallel, the chance to investigate how sensory stimuli underlying reproductive and social behavior are processed in the adult brain. Although several unanswered questions on the link between reproductive/social stimuli and adult neurogenesis remain to be clarified, some major/common key points can be extrapolated from the current data.

Pheromonal cues in rodents convey information about species-specificity, gender, social status, health, genetic advantage and individual recognition (see Tirindelli et al. 2009 for review). Accordingly, they have been demonstrated as major stimuli to enhance neurogenesis in both the olfactory bulb region and hippocampus (Mak et al. 2007; Larsen et al. 2008; Oboti et al. 2009, 2011; Mak and Weiss 2010). Nevertheless, other sensory stimuli/pathways are potentially involved in the modulation of adult neurogenesis occurring during reproductive and social experiences. Indeed, neurogenesis is also enhanced in pregnancy or pseudopregnancy and lactation (Shingo 2003; Larsen 2010) in male mice upon interaction with their offspring (Mak and Weiss 2010) and during pacing behavior (Corona et al. 2011; Portillo et al. 2012). These conditions and activities are driven by multiple sensory pathways and involve complex levels of brain integration and elaboration.

A direct contact (fully exploration of pheromonal cues and/or pairing) between subjects or with the stimulus (bedding or urine) is necessary to affect adult neurogenesis (Huang and Bittman 2001; Smith et al. 2001; Shingo et al. 2003; Mak et al. 2007; Larsen et al. 2008; Ruscio et al. 2008; Furuta and Bridges 2009; Oboti et al. 2009; Brus et al. 2010; Feierstein et al. 2010; Mak and Weiss 2010; Corona et al. 2011; Oboti et al. 2011; Sakamoto et al. 2011; Portillo et al. 2012). This implies activation of both the main olfactory and vomeronasal systems, which cooperate in the control of social/reproductive behavior (Keller et al. 2006). However, their relative contribution to adult neurogenesis in different social contexts still remains largely unexplored.

Interestingly, reproductive/social stimuli affect neurogenesis at two different levels of the neurogenic process, increasing proliferation of progenitor cells in the neurogenic niches and survival/integration of newborn neurons within the functional circuits. The anterior pituitary hormone prolactin (PRL) appears as a key factor promoting proliferation of SVZ progenitors during social interaction (Shingo et al. 2003; Mak et al. 2007; Larsen et al. 2008, 2010; Mak and Weiss 2010). Such enhanced proliferation per se results in increased incorporation of newborn neurons into the olfactory bulb circuits 15–20 days after the social experience (Shingo et al. 2003; Mak et al. 2007; Larsen et al. 2008). PRL in female rodents rises during mating (Erskine 1995), pregnancy and lactation (Grattan and Kokay 2008) and after prolonged exposure to male pheromones (Larsen 2008). This is crucial for adaptation and survival of the mother and fetus during pregnancy and postpartum period (Grattan and Kokay 2008). Thus, based on these functions it has been proposed that PRL-induced neurogenesis in the maternal brain early in gestation favors the parental care (Larsen et al. 2010). Similarly, PRL also increases neurogenesis in the paternal brain, possibly influencing paternal offspring recognition (Mak and Weiss 2010). Accordingly, inactivation of the PRL-enhanced neurogenesis seems to negatively affect some aspects of the parental behavior (Larsen et al. 2010; Mak and Weiss 2010), although conflicting results have been obtained after disruption of olfactory bulb neurogenesis via x-ray irradiation (Feierstein et al. 2010) or through genetically targeted ablation of newborn neurons (Sakamoto et al. 2011). Further work needs to clarify how PRL acts to stimulate proliferation in adult SVZ neurogenic niche (see for example Mak et al. 2007; Larsen et al. 2008), and to explore the involvement of other predictable factors influencing/mediating such activity during social interaction (see the following paragraphs describing the putative role of opioids released in pacing behavior).

As mentioned above, social stimuli and in particular pheromonal cues can also promote adult neurogenesis favoring the survival/integration of newborn neurons during a critical time window of their maturation. This sensory-driven activity, as detailed in the next paragraphs, appears independent from the proliferative effect exerted on progenitor cells and it is prominent in the accessory olfactory bulb (AOB) of female mice. Importantly, in this region newborn neurons are preferentially activated (show higher level of c-Fos expression) shortly after their integration by the same pheromonal cues that enhance their survival (Oboti et al. 2011). This supports a rapid functional recruitment of these cells in circuits activated by the social experience. Accordingly, depletion of these “young and excitable” neurons leads to abnormal social interaction between sexes (Feierstein et al. 2010; Sakamoto et al. 2011) and inability to recognize the mating partner (Oboti et al. 2011). Thus, during reproductive and social experiences neurogenesis increases through a double mechanism: (1) enhancing proliferation of progenitor cells, which later on provide a pool of newborn neurons potentially involved in the parental behavior, and (2) favoring survival of integrating neurons, which are rapidly involved in mechanisms of individual/partner recognition. Although further analyses are needed to clarify this mechanism, it appears committed to optimize reproductive success.

In the following paragraphs we will give two striking examples showing (1) how social stimuli/interaction can influence neurogenesis affecting SVZ progenitors proliferation and survival of newborn neurons, (2) how this process significantly increases incorporation of new cells in the AOB of rodents, and (3) how newborn neurons in the AOB of female mice are involved in processing male pheromonal cues.

13.3. ROLE OF AOB NEWBORN NEURONS IN THE PHEROMONAL MATING-INDUCED IMPRINTING

13.3.2. Male Pheromones Affect Integration of Newborn Neurons in the AOB of Adult Female Mice

Preliminary investigation of olfactory bulb neurogenesis in adult mice confirmed that a subpopulation of SVZ-derived neuroblasts acquires proper neurochemical and morphological profiles of mature inhibitory GABAergic interneurons in the AOB of both sexes (Figure 13.1) (Oboti et al. 2009). This data definitely demonstrated the AOB, just as the MOB and the hippocampus, represents a site of constitutive adult neurogenesis. Then, we showed that chronic exposure (28 days) to male soiled bedding, which contains semiochemicals present in urine and exocrine glands secretion (Brennan and Keverne 2004), significantly increases the number of new neurons in the AOB of adult females (Oboti et al. 2009). This effect was elicited only by direct contact with male bedding and not by its volatile compounds, thus supporting such experience-dependent regulation of neurogenesis requires vomeronasal organ activity.

FIGURE 13.1

Adult-generated SVZ-derived neurons in the AOB of mice: morphological analysis. 3-D reconstruction of EGFP-positive SVZ-derived precursors at 60 days after homotopic engraftment. EGFP-positive cells can be observed in the AOB layers and in the MOB GrL. (more...)

One major point was to clarify whether AOB-enhanced neurogenesis induced by long-term exposure to male pheromones depends on early proliferative effects on SVZ progenitors, as shown in other studies (Shingo et al. 2003; Mak et al. 2007; Larsen et al. 2008), or by increased survival of newborn neurons. According to the occurrence of critical periods for sensory experience-dependent survival of newly generated granule cells in MOB (Petreanu and Alvarez-Buylla 2002; Yamaguchi and Mori 2005), we found that 1-week-long familiarization/exposure to male bedding/urine enhances survival of newborn neurons during their selection/integration within circuits (affecting cells aged between 7 and 14 days) (Figure 13.2a). This effect was most prominent in the granule cell layer of the AOB and much weaker in the MOB. In addition, it was restricted to postpubertal females (absent in prepubertal females or in adult males) (Figure 13.2b) (Oboti et al. 2011). This indicated that neuronal integration in the AOB of adult female mice tightly correlates with the activity elicited in this region by exposure to male odors.

FIGURE 13.2

Sensory-driven integration and function of newborn neurons in the AOB of adult female mice. (a) Quantification of BrdU-labeled cells at 28 dpi in multiple AOB layers of p45 female mice after familiarization with male bedding performed in four different (more...)

13.4. PACED MATING AND NEUROGENESIS IN THE AOB OF ADULT RATS

13.4.2. Female Sexual Behavior and Neurogenesis

Few studies have evaluated the effects of mating on neurogenesis (see Table 13.1). One of the first studies that evaluated if the new cells generated in the adult are activated during sexual behavior was done in hamsters. For that purpose male hamsters were injected with BrdU either 10 days, 3 weeks, or 7 weeks before they were allowed to mate with a receptive female. After 90 minutes of mating subjects were sacrificed and c-Fos expression and BrdU labeling analyzed. The new neurons in the olfactory bulbs expressed Fos in those males injected with the synthetic marker 3 and 7 weeks before mating. No significant increase in the number of double-labeled neurons was observed when male hamsters were exposed to female hamster vaginal secretions, to an aggressive male, or to peppermint odor, suggesting that neurons born in adulthood are incorporated in the functional circuits that control mating behavior in the hamster (Huang and Bittman 2002).

TABLE 13.1

Studies That Have Evaluated Cell Proliferation and Neurogenesis with Different Aspects of Mating

Since the olfactory bulbs and the processing of chemosensory cues are crucial for a successful reproduction we decided to investigate if mating itself can induce the formation of new neurons in the adult olfactory bulb region. In the first study ovariectomized females, hormonally primed to induce sexual behavior, were tested under different behavioral conditions. One group of females was exposed to a sexually active male, another group of females mated in a condition where they were not able to pace the sexual interaction, and one group of females that paced the sexual interaction. All females received BrdU injections 1 hour before, immediately after, and 1 hour after the behavioral tests and sacrificed 15 days later. This would let us determine the survival of neurons produced around the time of mating. We observed a significant increase in the density of BrdU-positive cells in the granular layer of AOB when females were allowed to pace the sexual interaction in comparison to the other groups. No differences in cell density in the main olfactory bulb were found. These results indicate that pacing behavior promotes an increase in SVZ proliferation that in turn leads to a higher density of the new cells in the accessory olfactory bulb (Corona et al. 2011). This effect is specifically associated with the ability of controlling and pacing the sexual interaction since nonpaced mating did not induce changes in cell density. As well, the increase in cell density is not associated with different levels of estradiol and progesterone or behavioral differences because all groups had the same hormone (Arzate et al. 2013) and behavioral levels.

In a followup study we tested if the repetition of the stimulus could increase the number of new neurons in the olfactory bulbs after the first sexual encounter. For that purpose females were randomly assigned to one of the following groups: (1) females without sexual contact, (2) females that were given one session of paced mating, (3) females given four sessions of nonpaced mating, and (4) females given four sessions of paced mating. Some sections were analyzed for BrdU immunohistochemistry and others were double-labeled with immunofluorescence for BrdU and NeuN to label mature neurons. As in our previous experiment all groups were injected with BrdU 1 hour before, immediately after, and 1 hour after the behavioral tests. Females were sacrificed 15 days later and the density of new neurons was analyzed in the olfactory bulbs. The results of this experiment further confirmed our previous result; that is, the females that paced the sexual interaction in one session showed a higher number of mature (NeuN-positive) neurons in the granular cell layer of the AOB. The group that mated four times also had a higher number of neurons in the granular cell layer. Moreover, the group that mated four times pacing the sexual interaction also showed a significant increase in the number of neurons in the granular layer of the MOB (Arzate et al. 2013). It is clear then that paced mating induces plastic changes that eventually result in an increase in the number of new neurons in the OB 15 days after the first mating encounter. If the female mates once the increase is observed in the granular cell layer of the AOB, and if the stimulation is repeated an increase in the number of neurons is observed in the AOB and the MOB.

In our design females were sacrificed 15 days after copulation and BrdU injection, suggesting that a higher number of neurons survive the 2-week period. As already described, there is clear evidence indicating that pheromones induce cell proliferation in the adult SVZ. For example, female prairie voles exposed to a sexually mature male in tests where they could smell, see, and hear but had limited physical contact with the male for 48 hours showed an increase in the proliferation of new cells with a neuronal phenotype in the SVZ. Ovariectomized females exposed to males or intact females exposed to females showed no increase in BrdU labeling (Smith et al. 2001). It has also been shown that pheromones of the preferred dominant male stimulate cellular proliferation in the SVZ and neuronal production in the MOB (Mak et al. 2007). Since we sacrificed the females 15 days after copulation, it is possible that the time frame to observe differences in the number of cells in the SVZ had passed. Therefore, studies are now underway to evaluate cell proliferation in the SVZ and the rostral migratory stream (RMS) after exposure to sexually relevant olfactory cues and after mating. Preliminary data indicates that 2 days after females are exposed to a sexually experienced male or to amyl acetate there is a significant increase in the number of BrdU labeled cells in the SVZ (Paredes et al. 2013, manuscript in preparation). These results could indicate that in our experimental conditions, 1 hour of exposure to male pheromones or to amyl acetate is sufficient to induce cell proliferation in the SVZ. These results are in agreement with observations indicating that after the new neurons area born, their survival is activity-dependent (Alonso et al. 2006; Mandairon et al. 2006; Lazarini et al. 2009; Moreno et al. 2009). For example, it has been shown that a spaced learning paradigm as opposed to a massed paradigm increased the survival of adult-born neurons in the olfactory bulb, allowing long-term consolidation of the olfactory task (Kermen et al. 2010). As well, discrimination learning increases the number of newborn neurons in the adult OB, prolonging their survival (Alonso et al. 2006). In male mice the prolonged exposure (40 days) to an odor-enriched environment increases the number of new cells in the glomerular cell layer of the MOB, facilitating odor discrimination (Rochefort et al. 2002; Rochefort and Lledo 2005). It is also documented that the survival of newborn cells is significantly reduced in mice unilaterally deprived from sensory input by naris occlusion, suggesting that the survival of the new cells in the OB depends on sensory input (Mandairon et al. 2006). Future studies will need to determine if repeated exposures to male pheromones or to amyl acetate increases the survival of the cells observed in the SVZ. We also need to determine the functional integration of the BrdU-labeled neurons 45 days after paced mating once the new neurons integrate into functional circuits.

13.5. CONCLUDING REMARKS

Here we have shown that social stimuli underlying reproductive behavior in rodents enhance incorporation of newborn neurons in adult neurogenic regions, particularly in the olfactory bulb region. This occurs through a double action that influences proliferation of progenitors/precursors and incorporation of newborn neurons within functional circuits. Pheromonal cues contained in urine and hormones such as PRL are important mediators of this mechanism. Nevertheless, additional studies are needed to better characterize the nature and source of the sensory cues driving increased incorporation of newborn neurons as well as the molecular players and brain circuits/systems mediating this mechanism during social interaction. For example, our experiments of urine fractionation suggest the survival of new neurons in the AOB is regulated by molecules included in the LMW urine fraction, but whether MHC peptide ligands (already known to convey individuality in the Bruce effect) or MUPs testosterone-dependent volatile ligands are involved in such activity remains to be determined. Similarly, the possible role of opioids and the involvement of the reward state in controlling proliferation of SVZ progenitors deserve further investigation.

Concerning the role played by OB newborn neurons, the data reviewed in this chapter supports that they are involved in recognizing the mating partner, which is critical to avoiding pregnancy block in mice, and learning the odor of the offspring, to favor selective care and preventing inbreeding. Thus, waiting for further feasible confirmations, the occurrence of adult neurogenesis in key regions controlling social stimuli appears of extraordinary functional importance in the context of the reproductive behavior.

ACKNOWLEDGMENTS

This chapter was supported by PRIN 2010-2011 to Paolo Peretto and by CONACyT 167101 and DGAPA IN200512 to Raúl G. Paredes.

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