中枢5-HT缺陷小鼠下丘脑催产素-结肠催产素受体功能轴的变化和机制

The monoamine neurotransmitter serotonin (5-HT) exerts a wide spectrum of actions in the central nervous system including mood, rhythm, food intake, and a variety of behaviors.It was reported that, in centrol 5-HT deficient mice, anxiety-like behaviors reduce,contextual fear memory enhances,and the sensitive to stressful stimuli decreases. Oxytocin (OT) has been reported to be very important in regulating social cognition and stress in human. Our previous studies showed that OT regulates colonic activity via OT receptor,OT also reverses the anoxemia-induced inhibition of colonic motility. Recently, our preliminary experiment showed that, in centrol 5-HT deficient mice, the response of colon on OT decreases. OT expression decreases in hypothalamus of centrol 5-HT dificient mice. In this project,we plan to investigate the centrol 5-HT - hypothalamic and pituitary OT - colonic OT receptor axis in centrol 5-HT dificent mice both in vivo and in vitro. The methods include functional methods on intestine; fluorescence molecular tomography; laser scanning confocal microscopy; et al. The research of this new brain-gut axis is useful for widening our knowlodge of cross-talk between brain and gut. It is also useful for providing the new ideas and experimental proofs for further study the centrol nervous system diseases or mental sickness accompanied with intestinal dysfunction, or intestinal diseases accompanied with centrol nervous or mental dysfunction.

中枢5-HT作为重要的单胺类神经递质与精神情绪、生物节律、摄食、各种行为等相关。有研究发现，中枢5-HT缺陷小鼠的焦虑样行为减少、恐惧相关记忆增加、小鼠对刺激的反应能力下降。催产素（Oxytocin,OT）被认为在调节人类认知行为和应激中有重要作用。我们研究发现，OT通过结肠OT受体调节结肠收缩活动，且可以反转缺氧引起的结肠收缩活动抑制。我们新近预实验发现，中枢5-HT缺陷小鼠结肠对OT的反应减弱，下丘脑OT的表达降低。在此基础上，我们选择中枢5-HT缺陷小鼠，采用肠功能学研究方法、诱发荧光断层成像分析技术、激光扫描共聚显微技术等，从整体、组织、细胞和分子水平研究中枢5-HT对下丘脑和垂体OT-结肠OT受体功能轴的影响和机制，该新脑-肠轴的研究，拓宽了对脑肠信息交流的认识，并为进一步阐明中枢神经、精神疾患并发的消化道功能异常或消化道疾患与中枢神经、精神异常的相关性等开辟新的思路和实验依据。

中枢 5-HT 作为重要的单胺类神经递质与精神情绪、生物节律、摄食、各种行为等相关。有研究发现，中枢5-HT 缺陷小鼠的焦虑样行为减少、恐惧相关记忆增加、小鼠对刺激的反应能力下降。催产素（Oxytocin,OT）被认为在调节人类认知行为和应激中有重要作用。我们研究发现，OT通过结肠OT受体调节结肠收缩活动，且可以反转缺氧引起的结肠收缩活动抑制。本课题选择中枢5-HT 缺陷小鼠，采用肠功能学研究方法、诱发荧光断层成像分析技术、激光扫描共聚显微技术等，从整体、组织、细胞和分子水平研究中枢5-HT对下丘脑和垂体OT-结肠OT受体功能轴的影响和机制。主要研究结果包括：1.野生型小鼠随着年龄的增长，肠推进时间缩短；中枢5-HT缺陷小鼠随着年龄的增长，肠推进时间没有明显差异。2.OT对中枢5-HT缺陷小鼠和野生型小鼠结肠收缩均有促进作用，但OT对中枢5-HT缺陷小鼠结肠平滑肌收缩活动的促进作用明显较野生型小鼠弱（n = 8, P < 0.05）。3.OT受体阻断剂阿托西班（atosiban）阻断OT诱发的中枢5-HT缺陷小鼠的结肠收缩活动。4.河豚毒素（tetrodotoxin）阻断OT诱发的中枢5-HT缺陷小鼠的结肠收缩活动。六甲溴铵（hexamethonium）和阿托品（atropine）对OT的作用无影响。5.OT受体在结肠肌间神经丛表达。6.中枢5-HT缺陷小鼠血清OT浓度降低，下丘脑OT浓度降低，垂体OT浓度没有明显变化。上述结果表明，中枢5-HT通过影响下丘脑OT的合成，进而影响结肠肌间神经丛OT受体对OT的反应参与调节结肠收缩活动。 该新脑-肠轴的研究，拓宽了对脑肠信息交流的认识，并为进一步阐明中枢神经、精神疾患并发的消化道功能异常或消化道疾患与中枢神经、精神异常的相关性等开辟新的思路和实验依据。