Reproductive experience (i.e. pregnancy, parturition and lactation) results in long lasting alterations in the female mammal's neural and endocrine systems. In the previous grant period, using a rat animal model, we demonstrated that reproductive experience alters circulating prolactin and estradiol levels, estradiol-stimulated prolactin secretion, neural prolactin receptor expression, and prolactin receptor transduction mechanisms. Significant effects of reproductive experience on anxiety-like behavior were also found in reproductively experienced animals during their subsequent reproductive cycles that were dependent upon the stage of the estrous cycle and the age of the female. Based on these findings, we propose to test the following hypothesis: """"""""Reproductive Experience Induces a Fundamental Shift in the Neural Regulation of Hormone Secretion and Action in Female Mammals."""""""" We propose that this shift in hormone sensitivity is brought about in part by an up-regulation of prolactin receptor function in both neural and peripheral tissues that renders endocrine target tissues less dependent on circulating hormones. In addition, we propose that differential shifts in the sensitivities of estrogen receptor subtypes develop as a function of reproductive experience that alter the female's responses to estrogen. Specific studies will investigate the effects of reproductive experience on prolactin and estradiol receptor expression, prolactin transduction mechanisms, and shifts in estradiol and prolactin receptor sensitivity. Another experiment examines whether postpartum hyperprolactinemia and the age of reproductive experience contribute to the effects of reproductive experience on subsequent endocrine activity. Next, a series of studies investigate the impact of reproductive experience on anxiety, examining the hormonal regulation of anxiety within the context of the female's reproductive experience and how aging may interact with reproductive experience to affect anxiety. Finally, the possible effects of reproductive experience on non-neural endocrine target tissues, i.e. mammary tissue and liver, are examined to determine whether hormone receptor systems are altered in non-neural tissues as they are in the brain. Techniques used include real time RT-PCR, Western blot analysis, in situ hybridization, radioimmunoassay, and behavioral testing. The results of these studies should provide insight regarding the role of the hypothalamus in neuroendocrine plasticity and significant information regarding the transformative nature of reproductive experience. Most female mammals, including women, become pregnant and give birth one or more times over the course of their lifetimes. To date, little attention has been given to the long-term impact of this reproductive experience on the female's physiology and health later in adulthood. The present proposal uses a rodent model to examine this issue. Hormone levels, the responsiveness of the brain to hormones, and anxiety will be characterized following reproductive experience. The effects of reproductive experience on mammary gland and liver hormone receptors will also be compared with those in brain to determine the breath of established reproductive experience-induced changes. Overall, reproductive experience-induced shifts in endocrine activities may affect endocrine-related diseases and behaviors later in adulthood, i.e. breast cancer, autoimmune diseases, and postpartum mood disorders.
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