CENTRAL CONTROL OF OXYTOCIN RELEASE DURING GESTATION

妊娠期间催产素释放的集中控制

• 批准号: 6865301
• 负责人: STEVEN BEALER BEALER
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865301
• 关键词: antisense nucleic acid; autoradiography; clinical research; developmental nutrition; excitatory aminoacid; fos protein; gene expression; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; hypothalamus; laboratory rat; lactation; neurons; neuroregulation; newborn animals; oligonucleotides; oxytocin; peptide hormone biosynthesis; pregnancy; radioimmunoassay; single cell analysis; synaptogenesis; tissue /cell culture

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.

描述（由申请人提供）：该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 释放的自动调节功能。分娩过程中释放 OT 以帮助子宫收缩，哺乳期间 OT 的分泌对于产奶和后代的正常生长至关重要。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，这有助于成功哺乳。我们发现，OT 受体 (OTR) 结合在妊娠期间增加，并且仅在妊娠期间阻断 OTR 会减少对哺乳后代的乳汁输送，从而导致体重增加减少。然而，妊娠期间 OTR 阻断降低泌乳效率的机制尚不清楚。我们将测试以下假设：妊娠期间的 OTR 刺激是遗传和电生理适应所必需的，这些适应是 1) 增加 OT 合成和 2) OT 神经元敏感性所需的，以响应哺乳而充分输送乳汁。为了测试该提案，具体目标是确定妊娠期间 OTR 封锁的影响； 1) 大细胞核中的 OT 结合，2) 妊娠和哺乳中期期间大细胞核中的 OT mRNA 和神经叶中的 OT 含量，3) OT 神经元膜的发育和哺乳期突触适应特征，以及 4) OT 的反应敏感性神经元哺乳和兴奋性神经递质的管理。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学评估以及 OT 神经元中的 c-fos 激活来实现。这些措施将在未交配动物和妊娠中后期中央施用 OT 拮抗剂或媒介物后的怀孕动物上进行。提高哺乳效率以确保婴儿充分生长，将使母乳喂养婴儿的数量增加到推荐水平，从而降低多种疾病和病理的发生率和严重程度。