Prolactin promotes the recruitment of main olfactory bulb cells and enhances the behavioral exploration toward a socio-sexual stimulus in female mice.

Olfactory communication is triggered by pheromones that profoundly influence neuroendocrine responses to drive social interactions. Two principal olfactory systems process pheromones: the main and the vomeronasal or accessory system. Prolactin receptors are expressed in both systems suggesting a participation in the processing of olfactory information. We previously reported that prolactin participates in the sexual and olfactory bulb maturation of females. Therefore, we explored the expression of prolactin receptors within the olfactory bulb during sexual maturation and the direct responses of prolactin upon pheromonal exposure. Additionally, we assessed the behavioral response of adult females exposed to male sawdust after prolactin administration and the consequent activation of main and accessory olfactory bulb and their first central relays, the piriform cortex and the medial amygdala. Last, we investigated the intracellular pathway activated by prolactin within the olfactory bulb. Here, prolactin receptor expression remained constant during all maturation stages within the main olfactory bulb but decreased in adulthood in the accessory olfactory bulb. Behaviorally, females that received prolactin actively explored the male stimulus. An increased cFos activation in the amygdala and in the glomerular cells of the whole olfactory bulb was observed, but an augmented response in the mitral cells was only found within the main olfactory bulb after prolactin administration and the exposure to male stimulus. Interestingly, the ERK pathway was upregulated in the main olfactory bulb after exposure to a male stimulus. Overall, our results suggest that, in female mice, prolactin participates in the processing of chemosignals and behavioral responses by activating the main olfactory system and diminishing the classical vomeronasal response to pheromones.

Lactation attenuates pro-oxidant reactions in the maternal brain.

Reactive oxygen species (ROS) are intimately linked to bioenergetics and redox biology, contributing to cellular functioning and physiological signaling, but also acting as toxic agents during oxidative stress. Hence, the balance between pro-oxidant reactions and the activity of antioxidant defenses sustains a basal oxidative status, controls the increase of redox signaling, and mediates potential pathological events during oxidative stress. Maternal experience, especially during nursing, requires high energetic demands and expenditure to ensure the well-being of the offspring. The mother must adapt from satisfying her own needs to additionally fulfilling those of her descendants. Oxidative stress has been proposed as one of the reproductive trade-off hallmarks. However, the oxidative shielding hypothesis has also been proposed in the context of reproduction. The reproductive experience induces a wide range of well-documented changes in the female brain, which potentially lead to protection against the enhanced oxidative activity. To date, the metabolic and cellular mechanisms that underlie lactation-induced neuroprotection against oxidants are unknown. The neuroendocrine changes in the brain of the lactating dam promote diminished propensity to excitotoxic brain injury and stress, as well as enhanced neuroprotection and plasticity. In addition to review studies on the oxidant balance due to motherhood, we included new data from our laboratory, addressing the importance of measuring pro-oxidant reactions in separated brain regions. The hippocampus of lactating rats exhibits lower levels of pro-oxidant reactions than that of virgin rats, supporting the oxidative shielding hypothesis in lactation.

Prolactin neuroprotective action against excitotoxic insult in the hippocampus of male mice.

Prolactin (PRL) is known to exert neuroprotective effects against excitotoxic damage in the hippocampus of female rats, both in vitro and in vivo. It is still unknown whether this effect can be seen in the male hippocampus and intracellular signaling mediating such action. To assess this, adult male CD-1 mice were subjected to excitotoxic damage with kainic acid (KA; i.c.v.), after a) no manipulation (control group), b) treatment with saline, and c) treatment with PRL (8 µg of PRL/100 µl of saline s.c.). Treatments consisted of one daily injection of the mentioned dosage for seven consecutive days until the day of the excitotoxic lesion. Neurodegeneration (Fluoro-Jade C), neuronal survival (NeuN) and astrogliosis (GFAP) markers were identified with immunohistochemistry in the CA1, CA3 and CA4 areas of the dorsal hippocampus, as well as PRL-related protein levels by Western blot in the whole hippocampus 48 h after excitotoxicity. Anatomical measurements revealed a preferential protective effect of PRL against excitotoxic damage in the CA3 hippocampal subfield, with lower levels of cell death and neurodegeneration, compared to controls. In CA4, the results were not conclusive, and no damage was observed in CA1 after KA administration. PRL treatment provoked an upregulation of active Akt, a well-known cell survival pathway, after KA administration. PRL also caused downregulation of active MAPK, independently of the excitotoxic damage. The present results indicate a neuroprotective role for PRL preferentially located in the CA3 area of the hippocampus of male mice, possibly mediated by Akt-related survival mechanisms.

Reproductive status impact on tau phosphorylation induced by chronic stress.

Sex and exposure to chronic stress have been identified as risk factors for developing Alzheimer's disease (AD). Although AD has been demonstrated to be more prevalent in females, sex is often overlooked in research studies, likely due to the complexity of the hormonal status. In female rats, the reproductive status can modulate the well-known increase in tau phosphorylation (pTau) caused by the exposure to acute physical and psychological stressors. To test the hypothesis that reproductive status can impact hippocampal pTau induced by chronic stress, cohorts of virgin, lactating (4-5 days pp), and post-maternal (1-month post-weaned) rats were subjected to a daily 30-min episode of restraint stress for 14 days and were sacrificed either 20 min or 24 h after their last stress/handling episode. Western blot analysis of two well-characterized AD-relevant pTau epitopes (AT8 and PHF-1) and upstream pTau mechanisms (e.g. GSK3ß) analysis, showed that stressed post-maternal rats have increased pTau in comparison to stressed lactating rats 20 min after their last stress episode. Furthermore, an increase in pTau was also seen 24 h after the last stress episode in stressed post-maternal rats in comparison to their non-stressed controls in the detergent-soluble fraction. GSK3 analysis showed an increase in total levels of GSK3ß in virgin rats and an increase of inactive levels of GSK3ß in post-maternal rats, which suggests a different stress response in pTau after the rat has gone through the maternal experience. Interestingly, post-maternal rats also presented the more variability in their estrous cycles in response to stress. Besides no differences in pTau, non-stressed lactating rats showed an increase in inactive GSK3ß 24 h after the last handling episode. Immunohistochemical detection of the PHF-1 epitope revealed increased pTau in the CA4/hilar subfield of the hippocampus of virgin and post-maternal rats exposed to chronic stress shortly after their last stress episode. Overall, lactating rats remained unresponsive to chronic restraint stress. These results suggest increased sensitivity of the virgin and post-maternal rats to hippocampal stress-induced pTau with chronic restraint stress compared to lactating rats. Because no differences were detected in response to stress by lactating rats and an exaggerated response was observed in post-maternal rats, current results support the hypothesis that lactation affects tau processing in the brain of the female.

Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin.

Sex differences are important to consider when studying different psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD). These disorders can be affected by dimorphic changes in the central nervous system and be influenced by sex-specific hormones and neuroactive steroids. In fact, AD is more prevalent in women than in men. One of the main characteristics of AD is the formation of neurofibrillary tangles, composed of the phosphoprotein Tau, and neuronal loss in specific brain regions. The scope of this work is to review the existing evidence on how a set of hormones (estrogen, progesterone, and prolactin) affect tau phosphorylation in the brain of females under both physiological and pathological conditions.