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  • Thus the understanding of the various mechanisms of action o


    Thus, the understanding of the various mechanisms of action of estrogen and SERMs is an important medical challenge and could help to develop an “ideal” SERM, preserving the beneficial effects of estrogen in the bone and urogenital system, and reducing the unwanted side effects, mainly increased risk of venous thrombosis and breast cancer. Finally, in the future, personalized approaches based on better evaluation of the tissue-specific vulnerability could help to design more effective and safe hormonal therapies (Lobo, 2017).
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    Introduction Reproductive experience includes giving birth and raising young results in neuroplastic changes that affect the female throughout her life (Fleming et al., 2008; Bridges, 2016). This experience of maternity results in long-term modifications in neuroendocrine, neuroanatomical, and behavioral processes. Many mammals show an enhancement of maternal care following a maternal experience (parturition), and multiple maternal experiences further affect these behavioral and biological changes. In sheep, multiparous ewes show a higher level of maternal care than do primiparous ewes (Poindron et al., 1988), whereas multiparous rats display heightened levels of aggression towards male intruders when compared to the responses of primiparous rats (Nephew et al., 2009). Additionally, nulliparous (virgin) female rats induced to respond maternally by pup exposure and primiparous rats given only 2 days of pup exposure, retain maternal care behaviors up to 80 days after prior pup exposure, suggesting that maternal care/memory without parturition or with minimal pup exposure is long lasting (Scanlan et al., 2006). These findings indicate that the experience of raising young creates long-term changes in the ODM-201 structure that result in behavioral modifications maintained throughout the female\'s life. The underlying neurobiological modifications produced by reproductive experience have not yet been fully elucidated. One long-term modification that may contribute to the establishment of maternal memory is a shift in estrogen actions. Estrogens have been implicated in the onset and regulation of maternal care in rats, as female rats that were given estradiol benzoate (EB) after both a hysterectomy and ovariectomy between 10 and 19 days of pregnancy, showed shorter latencies for maternal behavior compared to rats not given EB (Rosenblatt and Siegel, 1975). In a related study it was found that ovariectomized and hysterectomized virgin rats given EB and an anti-estrogen, CI-628, had longer latencies to initiate maternal behavior than females only given EB (Siegel et al., 1978). These findings support a role for estrogens in the activation of maternal behavior. Other hormones, such as progesterone or prolactin (see Bridges, 2015) do not elicit a rapid onset of maternal behaviors by themselves. Other studies have found more Esr1 positive cells in the medial preoptic area (MPOA) of cycling primiparous females than found in age-matched, nulliparous females (Byrnes et al., 2009). This indicates that reproductive experience alters the expression of this receptor over the course of the female\'s lifespan. Additionally, higher quality of maternal care is associated with methylation of the Esr1 gene (Champagne et al., 2006), and dams who lick and groom their pups at higher rates (high LG) compared to dams with low LG have an increase in Esr1 expression in the MPOA (Champagne et al., 2003). Esr1 antagonist treatment with propyl-pyrazole-triol (PPT), moreover, reduced anxiety in parous female rats, but has little effect in age-matched, nulliparous female rats (Byrnes et al., 2012, Byrnes et al., 2013), suggesting that reproductive experience modifies the functional activation of Esr1. In female mice, null mutations of the Esr1 gene (Esr1 KO) impedes pup retrieval behavior to the nest compared to the responses of control wild type mice, and Esr1 heterozygous mice display higher incidences of infanticide (Ogawa et al., 1998). More recently, siRNA silencing of estrogen receptor-α in the medial preoptic area of female mice was found to abolish maternal care (Ribeiro et al., 2012). In a complementary study in juvenile rats, using a viral vector expressing Esr1 targeted at the medial preoptic, it was reported that overexpression of estrogen receptor-α in the medial preoptic area of juvenile female subjects reduced their latency to display maternal care to a level similar to that present in juvenile male rats (Peña and Champagne, 2014). Together these results demonstrate an important role for ER-α in maternal care and raise the possibility that estrogen receptor alpha may participate in the expression of maternal memory and the long-term enhancement of maternal care.