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表征生殖状态下中枢催产素（OT）对全身OT释放的自我调节功能。OT在分娩时释放，以帮助子宫收缩，哺乳期间分泌OT对产乳和后代的正常生长是必不可少的。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，有助于成功哺乳。我们发现妊娠期卵巢受体（OTR）结合增加，仅在妊娠期阻断OTR，会减少哺乳期子代的产奶量，导致体重增加减少。然而，妊娠期OTR阻断降低泌乳效率的机制尚不清楚。我们将验证以下假设：妊娠期间的OTR刺激是遗传和电生理适应所必需的：1)增加OT合成；2)在哺乳过程中，OT神经元敏感性需要足够的产奶量。为了验证这一建议，具体目的是确定妊娠期间OTR阻断对；1)大细胞核中的OT结合，2)妊娠期和哺乳期中期大细胞核中的OT mRNA和神经叶中的OT含量，3)哺乳期OT神经元膜发育和突触适应特征，4)OT神经元对哺乳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的生化测量、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估以及OT神经元中c-fos的激活来解决。这些措施将在初生动物和怀孕动物身上进行，在妊娠中后期给予OT拮抗剂或载体。提高哺乳效率以确保婴儿的适当生长，将使母乳喂养婴儿的数量增加到建议水平，这将减少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.