CENTRAL CONTROL OF OXYTOCIN RELEASE DURING GESTATION

描述（由申请人提供）：本研究项目的总体目标是描述生殖状态期间中枢催产素（OT）对全身OT释放的自动调节功能。催产素在分娩过程中释放，以帮助子宫收缩，在哺乳期间分泌的催产素是必不可少的乳汁输送和后代的正常生长。最近的研究发现，中枢OT系统在妊娠期间被激活，并参与行为，解剖和生理适应，这有助于成功的泌乳。我们已经发现，OT受体（OTR）结合增加，在妊娠期间，和OTR的封锁，只有在妊娠期间，减少牛奶交付给哺乳后代，导致体重增加减少。然而，妊娠期间阻断OTR降低泌乳效率的机制尚不清楚。我们将检验以下假设：妊娠期间OTR刺激是遗传和电生理适应所必需的，1）增加OT合成和2）OT神经元敏感性是对哺乳做出反应时足够的乳汁输送所必需的。为了验证这一建议，具体目标是确定妊娠期间OTR阻断对以下方面的影响：1）大细胞核中的OT结合，2）妊娠和哺乳中期大细胞核中的OT mRNA和神经叶中的OT含量，3）OT神经元膜的发育和哺乳特征的突触适应，OT神经元对吸吮和兴奋性神经递质的反应敏感性。这些目标将通过受体放射自显影，OT mRNA的生化指标，神经叶，透析液和血浆中OT的放射免疫测定，微透析，分离的OT细胞和下丘脑切片的电生理评价，以及OT神经元中c-fos的激活来解决。将对未交配动物和妊娠中晚期OT拮抗剂或溶媒集中给药后的妊娠动物进行这些测量。提高哺乳效率以确保婴儿充分发育，将使母乳喂养婴儿的数量增加到建议的水平，这将降低各种疾病和病理的发病率和严重程度。

DESCRIPTION (provided by applicant): The overall objective of this research project is to characterize the autoregulatory functions of central oxytocin (OT) on systemic OT release during reproductive states. OT is released during parturition to aid in uterine contraction, and OT secretion during nursing is essential for milk delivery and normal growth of the offspring. Recent studies find that the central OT system is activated during gestation, and participates in behavioral, anatomical, and physiological adaptations, which contribute to successful lactation. We have found that OT receptor (OTR) binding increases during gestation, and that blockade of OTR, only during gestation, decreases milk delivery to suckling offspring, resulting in reduced weight gain. However, the mechanism(s) by which OTR blockade during gestation diminishes lactational efficiency is unknown. We will test the HYPOTHESIS that OTR stimulation during gestation is required for genetic and electrophysiological adaptations necessary for 1) increased OT synthesis and 2) OT neuron sensitivity required for adequate milk delivery in response to suckling. To test this proposal, the SPECIFIC AIMS are to determine the effects of OTR blockade DURING GESTATION on; 1) OT binding in magnocellular nuclei, 2) OT mRNA in magnocellular nuclei and OT content in the neural lobe during gestation and mid-lactation, 3) development of OT neuron membrane and synaptic adaptations characteristic of lactation, and 4) response sensitivity of OT neurons to suckling and administration of excitatory neurotransmitters. These Aims will be addressed using receptor autoradiography, biochemical measures of OT mRNA, radioimmunoassay of OT in neural lobe, dialysate, and plasma, microdialysis, electrophysiological evaluation of isolated OT cells and in hypothalamic slices, and activation of c-fos in OT neurons. These measures will be performed on virgin animals, and pregnant animals following central administration of an OT antagonist or vehicle during mid-late gestation. Increasing efficiency of lactation to ensure adequate infant growth will increase the number of breast fed infants to recommended levels, which will decrease the incidence and severity of a wide range of illnesses and pathologies.