外侧缰核在大鼠甲状腺功能低下导致抑郁行为中的作用和机制

It was widely known that many organ disorders could be induced by hypothyroidism. What should be not neglected is the fact that nearly 50% of hypothyroidism are associated with depressive like symptoms. It has been reported that there is a close relationship between hypothyroidism-induced depression and changes of serotoninergic neurons in dorsal raphe nuclus. Lateral habenula(LHb), as a link between thyroid and dorsal raphe nucleus, has drawn an increasing attention due to its important role in the onset of depression. Our study intends to target on LHb, to investigate the effect LHb on hypothyroidism-induced depression and the underlying mechanism via experimental approach using appropriate techniques of behavior test, molecular biology, immunofluorescence and in vivo and in vitro electrophysiology recording. .We will first determine the changes of LHb function in hypothyroidism-induced depression rats. Then we will investigate the role of excited LHb in thyroid function and behavior of normal rats. Next will test whether LHb lesion could reverse the depressive-like behavior by mediating the 5-HT level in dorsal raphe nucleus. Finally we will study whether the depressive-like behavior could be improved by thyroxin injection into LHb in hypothyroidism rats, and also whether this effect is associated with affecting LHb neurons and then changing the activity of dorsal raphe nucleus. Further experiments for validating whether the mechanism of thyroxin’s effect on LHb neuronal activity involves a presynaptic effect or a postsynaptic effect will be conducted. Successful completion of the proposed study will provide a new insight into the pathogenesis of hypothyroidism-induced depression, which will significantly advance the research in the field of habenula function.

甲状腺功能低下（甲低）导致的多器官障碍已为人们所认识，而不能忽视的是有50%甲低患者伴有抑郁症状。已有报道，甲低所致抑郁障碍与中缝背核5-羟色胺(5-HT)神经元改变有关，外侧缰核（LHb)密切联系甲状腺和中缝背核，并且在抑郁症发病中有重要作用而引起人们关注。因此我们以LHb作为靶点，应用行为学、分子生物学、免疫荧光、整体和离体电生理记录等多种技术，从不同水平探讨LHb在甲低抑郁发病中的作用和机制。首先观察甲低抑郁鼠LHb的功能是否有改变；探讨兴奋LHb对正常鼠甲状腺功能和行为的影响，以及损毁LHb是否通过影响中缝背核5-HT含量改变甲低大鼠的抑郁行为；最后探讨甲状腺素注射到LHb是否改善甲低大鼠的抑郁行为，其机制与影响LHb神经元活动、进而改变中缝背核的功能有关，对LHb神经元影响是突触前/突触后机制将被涉及。这一研究将为甲低致抑郁的发病机制提出新的解释，也是对LHb功能研究的进一步拓展

甲状腺功能低下（甲低）所导致的多器官障碍已为人们所认识，而不能忽视的是有50%的甲低患者伴有抑郁症状。单胺类神经递质在抑郁症发病中的作用一直是人们所关注的焦点，已有报道，甲低所导致的抑郁障碍与中缝核5-羟色胺系统的改变有关，外侧缰核（lateral habenula,LHb)密切联系甲状腺和中缝核5-羟色胺系统，并且在抑郁症发病中具有重要作用而引起人们的关注。因此本课题主要研究了单胺类递质的调控中心—LHb在甲低伴抑郁症中的作用及机制。所获结果如下：.1.建立了甲状腺功能低大鼠模型，并观察到甲低大鼠表现有明显的抑郁样行为。.2.证明了甲状腺功能低下大鼠LHb和DRN的改变。表现为甲状腺功能低下大鼠LHb活动度明显增高，甲状腺素β受体表达上调，β钙调蛋白激酶Ⅱ的表达显著增高。甲状腺功能低下大鼠DRN活动度明显降低，甲状腺功能低下大鼠DNR内5-HT含量降低。.3.证明了LHb损毁可明显改善甲状腺功能低下大鼠的抑郁样行为，LHb损毁可增加甲状腺功能低下大鼠DRN内5-HT水平。.4.证明了补充甲状腺素可以改善甲状腺功能低下大鼠的抑郁行为，其机制是降低甲状腺功能低下大鼠LHb神经元的活动度，恢复甲状腺功能低下大鼠DRN的神经元细胞活性。.5.建立了PTU甲低模型，并观察到PTU组大鼠外侧缰核cFos表达升高，GFAP表达降低，Iba1表达降低（小胶质细胞标志物）， NR1表达下降。.6.证明了PTU大鼠LHb微量注射T3后抑郁行为得到了改善。.7.我们还观察了与甲低相关的另一调通路LHb-VTA通路在厌恶和奖赏行为。研究发现小鼠LHb中单个神经元同时接受奖赏和厌恶刺激信息，LHb中的奖赏和厌恶汇聚神经元主要是谷氨酸神经元；兴奋LHb谷氨酸神经元诱发小鼠厌恶行为，抑制LHb谷氨酸神经元并未产生奖赏行为；兴奋和抑制LHb到VTA的谷氨酸轴突末梢分别产生厌恶和奖赏行为；VTA单个神经元汇聚奖赏和厌恶两种刺激信号,并接受LHb谷氨酸神经元的调控。. 以上研究证明了LHb在甲低所致抑郁行为中具有重要作用，其机制与影响中缝核5-HT神经元活动有关，也可能通过影响VTA多巴胺系统的活动来实现。