NEURAL AND ENDOCRINE CONSEQUENCES OF PARITY

大多数成年雌性哺乳动物繁殖活跃，会生一次或多次。然而，令人惊讶的是，很少有人注意到先前的生殖经验对成年女性内分泌和神经功能可能产生的长期影响。目前的建议是基于这样的发现，即生育会导致女性血液中催乳素(PRL)和雄激素的长期变化，在有生殖经验的大鼠中，PRL分泌类似地减少，而在女性和大鼠中，多巴胺能张力增加。这项建议的总体目标是描述由先前的产次引起的内分泌和神经变化的程度和基础。第一个系列的研究将描述产次对分娩和未分娩雌性大鼠脑下垂体RL和雌二醇分泌的影响。然后将研究产次对雌激素受体的影响，以及产次是否会减少雌激素对催乳素的反馈调节。接下来，将测量哺乳期间升高的催乳素对成年后自身分泌的贡献。第二系列实验将确定产次如何增加多巴胺能功能，这种增加可能是产期动物PRL分泌减少的基础。将测量产次对多巴胺受体的影响，第二信使介导多巴胺的作用，以及雌激素对下丘脑和下丘脑外区域多巴胺释放的调节(使用体内微透析系统结合高效液相色谱法)。然后将评估由于先前的胎次而导致的多巴胺神经元对PRL调节的敏感性的可能降低。第三组研究将检验产次对催乳素分泌的影响是否与年龄有关。初产年龄对成年后期循环雌激素水平的影响以及雌激素对催乳素分泌的调节将被确定。总体而言，这些研究将确定导致成年女性上一次生育所产生的内分泌和神经功能变化的潜在机制，这些变化可能会影响女性一生中广泛的生物过程，包括行为、生殖能力、免疫功能和激素分泌。

Most adult female mammals are reproductively active and give birth once or multiple times. Surprisingly, little attention, however, has been given to the possible long-term effects of prior reproductive experience on endocrine and neural functions in adult females. The present proposal draws upon the finding that parity produces long-term alterations in circulating prolactin (PRL) and androgens in women, similar reductions in PRL secretion in reproductively experienced rats, and an increase in dopaminergic tone in both women and rats. The overall aim of this proposal is to characterize the extent and basis of the endocrine and neural changes induced by prior parity. The first series of studies will characterize the effects of parity on pituitary RL and estradiol secretion in parous and nulliparous female rats. The effects of parity on estrogen receptors and whether parity produces a reduction in estrogen feedback regulation on PRL will then be investigated. Next, the contribution of elevated PRL during lactation on its own secretion later in adulthood will be measured. The second series of experiments will determine how parity may increase dopaminergic function, an increase which may underlie the reductions in PRL secretion in parous animals. The effects of parity on dopamine receptors, second messengers that mediate dopamine action, and estrogenic regulation of dopamine release both in hypothalamic and extrahypothalamic areas (using an in vivo microdialysis system combined with HPLC) will be measured. The possible decrease in sensitivity of dopamine neurons to PRL regulation as a result of prior parity will then be evaluated. The third set of studies will examine whether the effects of parity on PRL secretion are age-dependent. The effects of the age of first parity on circulating estrogen levels late in adulthood and estrogen regulation of PRL secretion will be determined. Overall, these studies will identify underlying mechanisms which contribute to the alterations in endocrine and neural functions produced by a previous parity in the adult female, alterations which may affect a wide spectrum of biological processes, including behavior, reproductive fertility, immune function, and hormone secretion, over the life span of the female.