In rodents, social interaction is mostly guided by chemosensory cues that are detected, processed, and interpreted by the olfactory systems, which facilitate adequate behavioral responses. The main (MOS) and the vomeronasal or accessory (AOS) olfactory systems are specialized and participate in social interaction. Although the general understanding of the olfactory processing views the AOS as responsible for social communication, growing evidence supports that both systems play relevant roles in reproduction (Brennan and Zufall, 2006; Pankevich et al., 2004) by regulating a range of behaviors, from opposite-sex discrimination to mate recognition (Baum and Kelliher, 2009). The AOS specializes in detecting non-volatile, pheromonal molecules related to reproduction, while the MOS focuses on the detection of general and volatile odors (Baum and Kelliher, 2009; Brennan and Zufall, 2006).

Due to the expression and spatial distribution of odorant receptors within the vomeronasal organ (VNO) and the olfactory epithelium (OE), the accessory and main olfactory bulb (AOB, MOB) are locally organized in zones (Mori et al., 2000). The VNO odorant receptors are segregated into the rostral and caudal AOB, receiving pheromonal information with different characteristics (Brennan et al., 1999; Inamura et al., 1999; Kumar et al., 1999; Mori et al., 2000). The MOB is also organized into zones along the dorsoventral axis, corresponding to the localization of the OE odorant receptors that influence behavioral responses (Baum and Kelliher, 2009; Lodovichi, 2021; Mori et al., 2000).

Pheromonal signals processed within the AOB promote neuroendocrine changes and regulate innate reproductive-behavior responses (Hashikawa et al., 2016; Hellier et al., 2018; Pineda et al., 2017; Yoon et al., 2005). Male sexual pheromones can affect female reproductive physiological processes, such as sexual maturation (Jouhanneau et al., 2014a; Jouhanneau et al., 2014b; Oboti et al., 2017; Vandenbergh et al., 1975), pregnancy maintenance (Bruce, 1959, Bruce, 1960), parental and sexual behavior, and olfactory bulb neurogenesis and plasticity, etc., (Corona and Levy, 2015; Corona et al., 2016; Mak et al., 2007). Prolactin (PRL) participates in some of these effects, suggesting a possible link between this hormone and odor processing for reproduction.

PRL, together with olfactory cues, is important during sexual maturation, as shown in the Vandenbergh effect, where the acceleration of puberty onset is induced by male pheromones (Vandenbergh et al., 1975). In rats, surgical removal of the VNO prevents this effect, and this, in turn, is restored with the administration of the DA-D2 receptor agonist bromocriptine, which blocks the production of PRL. Here, PRL seems to have a paradoxical effect, because the increase of PRL induced by domperidone, a DA-D2 receptor antagonist, accelerates the onset of puberty (Lomas and Keverne, 1982). Additionally, PRL administration in the medial eminence after weaning promotes an acceleration of puberty onset (Advis et al., 1982). Pituitary gland transplants from adults accelerate the puberty onset and increases PRL in pre-pubertal animals. Additionally, in kisspeptin neurons, the activation of the STAT5 pathway, the main intracellular cascade of PRL receptors (PRLRs), modifies the estrous cyclicity of females, highlighting PRL's role in sexual maturation (Gonzalez et al., 1984; Gottsch et al., 2004; Silveira et al., 2017; Smith et al., 2005). We have recently shown that chronic treatment with PRL during a juvenile, pre-pubertal stage delays the onset of puberty in female mice and alters AOBs response to sex-relevant stimuli in adulthood, by increasing the basal activity patterns of the internal cellular layer (ICL) (Corona et al., 2021).

There is scarce evidence concerning the direct effects of PRL within the olfactory bulb (OB). In 1996, Freemark and colleagues documented the presence of the PRLR in olfactory regions of rats during the perinatal period. Additionally, they reported the expression of PRLRs in the OB of lactating rats (Freemark et al., 1996). Recently, it was demonstrated that PRLRs are widely distributed in female mice's olfactory sensory neurons, and, by knocking out this receptor exclusively in the OE, females were less attracted to males as evaluated by a decreased olfactory preference, suggesting that PRL regulates the detection of social odors and influences behavioral responses (Aoki et al., 2021). However, how PRL participates in the processing of social information within OB and central areas connected to the olfactory system is still unknown. As for PRL expression, one report in ewes demonstrated its expression in the OB (Cabrera-Reyes et al., 2017). Currently, there is no evidence in mice supporting the idea that PRL promotes the synthesis of its own receptor within the OB like in other regions of the central nervous system (Cabrera-Reyes et al., 2017).

The neuroendocrine effects that are triggered by opposite-sex pheromones and are mediated by PRL in females are not well understood. This paper aims to explore PRL's influence on the OB during sexual maturation and its local functional responses when PRL and pheromones are combined.