小脑顶核通过下丘脑核团介导参与细胞因子致卒中后抑郁发病机制的研究

Inflamatory cytokines play an important role in the pathogenesis of post-stroke depression (PSD). However, the reason why the inflamatory cytokines keep high level persistently remains unclear. Supported by the Nation Natural Science Foundation of China (Director Foundation),we preliminarily confirmed that the damaged cerebellar fastigial nucleus(FN) acts as the initiating agent of keeping inflamatory cytokines in high level.But the way which FN influences on cytokines is unknown.Our preliminary work found that the discharge frequency of hypothalamus(HT) neuron increased after stimulating on FN. Therefore,we will study the following contents: ①To study the alterations of molecular metabolism contributed to inflamatory cytokines,of the HT in PSD such as blood flow and blood oxygen in PSD rats by molecular imaging technology.②To confirm that there exist neuroanatomical and functional circuits exerting effect on inflamatory cytokines between FN and HT nucleus. ③To find changes of neurotransmitters, which are related to inflamatory cytokines in PSD, between the FN and the HT.④To further confirm the alterations of FN such as blood flow and blood oxygen in PSD rats by molecular imaging technology. Meanwhile, to quantitatively analyze the changes of ultrastructure of FN and detect the expressions of ERKI/2 and p38 of apoptosis pathway of the nerve cells in FN. And the study also target to detect the increased expressions of the inflamatory cytokines(IL-1β,IL-6 and TNF-α) in blood and in areas of hippocampus and frontal lobe, and the augmented microglia activity in areas of hippocampus and frontal lobe by approaches of molecular biology. At last, our final aim is to prove the hypotheses that after stroke, the damaged FN, by way of influencing on HT, affects the expressions of inflamatory cytokines. We are convinced that the study may help to further clarify the pathogenesis of PSD and undoubtedly open up a new therapeutic trend for PSD.

炎性细胞因子在卒中后抑郁（PSD）中起重要作用，但其持续升高的机制不详。前期在国家自然科学主任基金资助下，我们初步证实PSD时损伤的小脑顶核（FN）是炎性细胞因子持续升高的始动因素，但通过何途径不明。前期我们发现电刺激FN可使下丘脑（HT）外侧区放电增加，故我们推测PSD时FN可能通过HT核团介导而使炎性因子增加。故本课题①用分子影像学技术研究PSD时HT内影响炎性因子的分子代谢等改变；②证实FN与HT核团间存在影响炎性因子的解剖与功能通路；③研究FN与HT间与炎性因子有关联的神经递质改变；④用分子影像学证实PSD时FN的血流、血氧等功能改变并定量分析FN的超微结构变化及凋亡通路ERKI/2和p38的表达；同时检测炎性因子IL-1β、IL-6和TNF-α的表达及小胶质细胞的活性。从而证实我们的假说即FN通过HT核团介导影响炎性因子表达。此研究将为阐明PSD发病机制，进而为其防治开辟新方向。

炎性细胞因子在卒中后抑郁（PSD）中起重要作用，但其持续升高的机制不详。前期在国家自然科学主任基金资助下，我们初步证实PSD时损伤的小脑顶核（FN）是炎性细胞因子持续升高的始动因素，但通过何途径不明。由于下丘脑（HT）是神经内分泌的调节中枢，故我们推测PSD时FN可能通过HT核团介导而使炎性因子增加。. 本研究按期完成。在前期工作基础上，本课题发现:1. PSD大鼠小脑顶核的形态结构发生了明显损害; 2. 电刺激小脑顶核，大多数下丘脑外侧区神经元的自发放电活动受抑制，证实小脑顶核和下丘脑外侧区间存在电传导通路；3. 利用高效液相仪，我们发现PSD组、小脑顶核损毁组和小脑上脚交叉损毁组的下丘脑内GABA减少，Glu增加，电刺激小脑顶核则增加GABA含量。4. 免疫组化分析发现，PSD组、小脑顶核损毁组和小脑上脚交叉损毁组的海马CA1区炎性细胞因子含量增加，提示小脑顶核损伤可能增加了炎性细胞因子表达。. 这些研究结果初步支持我们的猜想，为进一步阐明PSD的发病机制提供新思路，同时为本课题的进一步深入地研究奠定了坚实的基础。