催产素分泌系统决定母乳授乳成败机制的研究

Breastfeeding is essential for maternal and child health；however, in our country it is less than 30% of all mothers who can keep pure breastfeeding up to six months. Lactation failure is mainly due to "milk shortage" because of premature birth, cesarean section, and various forms of maternal separation from the babies. Successful breastfeeding depends on the normal activity of oxytocin-secreting system; disorders of the activity of this system can cause low milk availability. Our preliminary studies showed that disorders of the activity of oxytocin-secreting system evoked by the separation of mothers from the babies occur at multiple cellular and molecular levels. However, there is neither report so far at home and abroad to indicate the extent of disorders of oxytocin-secreting system activity under the stimuli of various adverse factors nor their underlying mechanisms at cellular and molecular levels. To resolve these questions, this study will use lactating rats to observe effects of the separation of dams from their pups, cesarean section and unfamiliar male rat invasion on the milk-ejection reflex and the activity of oxytocin-secreting system. The methods to be used in this study include behavioral assessments, in vivo and in vitro electrophysiological recordings, immunohistochemistry, co-immunoprecipitation, enzyme-linked immunoassay, etc. Finally, the study will observe effects of oxytocin application through nasal approaches on the consequence of early dam-pup separation. This study will determine the major neurophysiological reasons of postpartum milk shortage, and explore possibilities of prevention and treatment of lactation failure by nasal application of oxytocin.

母乳喂养对母婴健康至关重要，但是在我国保持纯母乳喂养达6个月以上的母亲，不足全部产妇的30%。授乳失败主要是由于早产、剖腹产以及各种形式的母子分离所致的"乳汁不足"。成功的授乳依赖催产素分泌系统的正常活动；该系统活动的紊乱可以导致乳汁不足。本课题组的初步研究表明，母子分离所致催产素分泌系统活动的紊乱发生在多个细胞与分子层次。 但是，不同因素所致催产素分泌系统活动紊乱的程度及其细胞与分子机制, 迄今为止在国内外尚无研究报道。为此，本研究利用授乳大鼠，采用行为学评估、体内外电生理记录、免疫组织化学、蛋白质交联与酶联免疫等技术，来观察母子分离、剖腹产和陌生雄性大鼠侵入等刺激对射乳反射和催产素分泌系统活动的影响。最后，本研究还将观察经鼻腔应用催产素改善催产素分泌系统的活动对早期母子分离效应的影响。这项研究将确定产后乳汁不足的主要神经生理机制，并探讨应用催产素来预防与治疗授乳失败的可能性。

利用正常和慢性应激的授乳大鼠模型，确定产后授乳与乳汁不足的神经机制神经，并探讨应用催产素（OXT）来预防与治疗授乳失败的可能性，其主要成果包括，授乳中关键性的OXT神经元的激活有赖于OXT神经元和星形胶质细胞协调作用，涉及下丘脑-垂体-肾上腺皮质（HPA）轴的活动。授乳早中期母子分离与剖宫产等所致授乳失败与谷氨酸和OXT分泌增多导致下丘脑神经元异常兴奋性反应有关。在OXT神经元，OXT受体与其下游信号分子脱偶联，OXT受体激活相关的信号分子与HCN3和NaV1.2等离子通道相互作用改变，OXT神经元呈现爆发式放电能力下降，从而导致向远隔脑区和血中脉冲式释放OXT减少；母鼠出现产后抑郁和乳汁不足，继发性的乳腺组织退化和长期母乳授乳失败。陌生雄性大鼠侵入应激实验中发现，陌生雄鼠侵入导致的母鼠授乳效率降低可以随着刺激时间的延长得到自发改善，但是母鼠抑郁和焦虑样行为仍然存在。这种部分适应性改变与视上核的活动增强、OXT受体信号系统与离子通道的相互发生改变有关。本项研究也发现，经鼻应用OXT（IAO）后母子大鼠的母性行为和授乳效率的降低有所改善。在IAO后母子分离大鼠视上核细胞活动呈双向改变，急性过度激活的非OXT神经元活动减低而OXT神经元慢性激活明显增加，视上核OXT神经元活动改善。但是，IAO也使母子分离大鼠HPA轴活动明显增加，而乳腺的退行性改变也仅部分恢复。以上发现表明，IAO可以通过调节星形胶质细胞可塑性及OXT神经元活动来改善母乳授乳，但是同时激活的HPA轴活动以及缺乏对乳腺退行性变的直接改善作用，降低了内源性OXT系统及其所调控的射乳反射对外源性OXT的反应。有必要考虑通过直接作用于OXT神经元活动调节的关键靶点，或动员内源性OXT分泌活动来减轻外源性OXT的副作用，保证乳腺具有对血中OXT的反应性，达到长期改善母乳授乳的效果。

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