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中枢催产素(OT)在生殖状态下对全身催产素释放的自我调节功能。催产素在分娩期间被释放，以帮助子宫收缩，哺乳期间催产素的分泌对乳汁的传递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，参与行为、解剖和生理适应，有助于成功哺乳。我们发现，在妊娠期间，催产素受体(OTR)的结合增加，只有在妊娠期阻断OTR，才会减少对哺乳后代的乳汁输送，从而减少体重增加。然而，妊娠期间阻断卵泡刺激素受体降低哺乳效率的机制(S)尚不清楚。我们将检验这一假设，即妊娠期间的OTR刺激是遗传和电生理适应所必需的，这是1)增加OT合成和2)OT神经元敏感性所必需的，以保证充分的哺乳反应。为了验证这一建议，具体目的是确定在妊娠期间阻断OTR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)催产素神经元膜的发育和哺乳期的突触适应；以及4)催产素神经元对哺乳和给予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的放射免疫分析、微透析、分离的OT细胞和下丘脑片的电生理评估以及OT神经元中c-fos的激活来实现。这些措施将在处女动物和怀孕动物身上执行，在怀孕中后期中央给予OT拮抗剂或载体。提高哺乳效率以确保婴儿充分发育，将使母乳喂养的婴儿数量增加到建议的水平，这将降低各种疾病和病理的发生率和严重性。

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.