穿梭计算机分析系统的建立和开心散改善抑郁症认知功能障碍研究
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摘要
抑郁症是一种严重的精神障碍疾病，以持久的心境低落、快感缺失为主要特征。认知功能障碍是抑郁症的一个主要共存症状。对于抑郁症及其导致的认知功能障碍的研究及其相关药物开发已经成为抑郁症治疗中面临的一个重要问题。为此，本课题的研究主要从两方面展开，即建立用于动物抑郁症及其认知功能障碍行为研究评价的穿梭计算机图像实时分析处理系统，同时研究传统古方KXS对于慢性应激引起的抑郁症及其所致认知功能障碍的治疗作用。
集成视频跟踪、图像分析、计算机信息处理、数据挖掘所等多种技术实现对大鼠穿梭行为活动信息的实时采集。利用Microsoft Visual C++6．0集成开发环境编程，研制开发了动物穿梭行为分析处理系统。该套系统在获取所有6项(主动回避次数、被动逃避次数、间歇期穿梭次数、主动回避反应时间、被动逃避反应时间、建立条件反射的动物只数)传统穿梭行为评价指标的同时，新建立了主动回避速度、被动逃避速度、主动回避运动路程、被动逃避运动路程、安全区时间表、错误区时间、近口区时间、逃避失败次数、首次穿梭潜伏期等9项指标。自然衰老、脑缺血等引起的不同类型认知功能障碍动物模型研究表明，新建立的9项新指标与传统指标一起构成了从不同方面系统、敏感评价各种认知功能障碍动物的联想性学习记忆、理解、反应速度、决策能力的综合评价体系。同时，该套系统集信号采集、识别、分析处理一体化，并以实时视频采集方式显示动物穿梭行为。
慢性不可预测性应激模型研究结果表明KXS水提物(0．3、0．9、2．7g／kg)、KXS方中君药人参的主要活性成份——Rg1(50、100mg／kg)可明显对抗慢性应激引起的糖水偏爱指数下降、新奇环境下首次摄食时间延长，从而显示出一定的抗抑郁效应。同时，在穿梭箱测试中，KXS(0．9、2．7g／kg)、Rg1(50mg／kg)可对慢性应激刺激可引起大鼠穿梭箱测试中主动回避次数、反应速度和运动路程的下降以及被动回避次数、反应速度和运动路程的增加，体现出对抑郁症所致认知功能障碍的改善作用。HPLC-ECD、ELISA法和免疫组织化学法等实验结果表明KXS、Rg1各剂量组可不同程度的拮抗慢性应激模可引起大鼠海马和前额叶皮层NE、DA、DOPAC和HVA含量显著下降；血清ACTH增加；海马CRF、AChE表达显著上调，BDNF表达下调；前额叶皮层CRF表达上调，BDNF和CREB表达显著下调，表明KXS、Rg1可能通过对单胺类神经递质、HPA轴、乙酰胆碱及神经营养因子通路的综合调节而发挥作用。另外，结果表明KXS与Rg1改善抑郁症及其所致认知功能障碍作用相似。
总之，本研究为抑郁症及认知功能的研究提供了一套自动化程度高、具有自主知识产权的穿梭计算机图像实时分析处理装置及客观规范、多层面、敏感评价认知功能的指标评价体系；证明了KXS和Rg1对抑郁症及其所致认知功能障碍的改善作用，为寻找防治抑郁症及其所致认知功能障碍药物提供了实验依据。
Depression is a serious and highly prevalent disorder characterized by long-termbad mood and anhedonia.Apart from mood disorder,cognitive dysfunction is a mostimportant feature in depressive patient.It is important to research the mechanism ofcognitive deficits accompanying depression and seek effective antidepressant agentswith the capability of enhancing cognitive function.Thus,this thesis includes two parts:1)establishment of a new computer-aided controlling and image analysis system forshuttle box(CISB);2)research of preventative action of Kai-Xin-San(KXS)waterextract on depressive-like symptoms and cognition deficit induced by chronic mildstress(CMS).
Firstly,by combining the advantage of video tracking,image analysis,computerinformation processing and data mining,the CISB was developed with MicrosoftVisual C++6.0 computer language,which can collect and analyze the behavioral dataof rats in real-time.9 new parameters(DPM,DAM,SAA,SPE,SAT,EAT,LFC,ECRand TND)were established to evaluate cognitive function except for 6 presentindicators(AA,PE,RTAA,RTPE,EF and ITC).Simultaneously,the system wasvalidated with young rats,mid-aged rats and cerebral ischemia rats.The resultsdemonstrate that CISB is highly reliable and accurate,and can more systematically andsensitively evaluate the cognitive behavior from multiple aspects including theassociative learning and memory,understanding,processing speed and decisionmaking compared with present parameters.Animal behavior activities can beautomatically recognized,collected and analyzed,the animal video image and itsmoving track in shuttle box also can be played on the computer screen.
Secondly,we explored the antidepressant-like and nootropic effects of a waterextract of KXS(at doses of 0.3,0.9,and 2.7g/kg/day)and ginsenoside Rgl(at doses of50,100mg/kg/day)(the effective ingredient of ginseng,which is the principal herb ofKXS)using chronic mild stress(CMS)as a well-validated model of depression.Theresults indicated that KXS and Rgl can significantly reversed the depressive symptomsin CMS model,such as decline in sucrose preference index and prolongation of latencyto feeding.Furthermore,KXS(0.9,2.7g/kg)and Rgl(50mg/kg)can also improve thecognitive impairment induced by CMS in the shuttle-box test such as increased numberof passive escapes and passive movement distance as well as decreased number of active avoidances,active movement distance and active response speed in CMS model.Biological investigation with HPLC-ECD,ELISA assay and immunohistochemicalmethods demonstrated that KXS and ginsenoside Rgl can inhibit increased AChEactivity of hippocampus;increase monoamine neurotransmitter concentration ofprefrontal cortex and hippocampus;upregulate the CREB and BDNF activities in thehippocampus and prefrontal cortex and reduce ACTH concentrations in the serum inCMS rats.Taken together,these results indicated that KXS and Rgl can exertantidepressant-like and nootropic effects in the CMS model by modulating multiplecentral nervous systems.Moreover,the effects of KXS were comparable to Rgl ondepression and cognitive dysfunction in CMS model.
In conclusion,a highly automatic and intelligent CISB apparatus as well as a setof evaluation index were established,which can objectively,scientificly,systematically evaluate the behavior activities from multiple aspects in differentdementia animal models.Furthermore,antidepressive-like and nootropic effects ofKXS and Rgl were validated,and their mechanism were explored.It might be possibleto provide a potential drug for the treatment of depressive mood disorders andcognitive dysfunction induced by depression.
集成视频跟踪、图像分析、计算机信息处理、数据挖掘所等多种技术实现对大鼠穿梭行为活动信息的实时采集。利用Microsoft Visual C++6．0集成开发环境编程，研制开发了动物穿梭行为分析处理系统。该套系统在获取所有6项(主动回避次数、被动逃避次数、间歇期穿梭次数、主动回避反应时间、被动逃避反应时间、建立条件反射的动物只数)传统穿梭行为评价指标的同时，新建立了主动回避速度、被动逃避速度、主动回避运动路程、被动逃避运动路程、安全区时间表、错误区时间、近口区时间、逃避失败次数、首次穿梭潜伏期等9项指标。自然衰老、脑缺血等引起的不同类型认知功能障碍动物模型研究表明，新建立的9项新指标与传统指标一起构成了从不同方面系统、敏感评价各种认知功能障碍动物的联想性学习记忆、理解、反应速度、决策能力的综合评价体系。同时，该套系统集信号采集、识别、分析处理一体化，并以实时视频采集方式显示动物穿梭行为。
慢性不可预测性应激模型研究结果表明KXS水提物(0．3、0．9、2．7g／kg)、KXS方中君药人参的主要活性成份——Rg1(50、100mg／kg)可明显对抗慢性应激引起的糖水偏爱指数下降、新奇环境下首次摄食时间延长，从而显示出一定的抗抑郁效应。同时，在穿梭箱测试中，KXS(0．9、2．7g／kg)、Rg1(50mg／kg)可对慢性应激刺激可引起大鼠穿梭箱测试中主动回避次数、反应速度和运动路程的下降以及被动回避次数、反应速度和运动路程的增加，体现出对抑郁症所致认知功能障碍的改善作用。HPLC-ECD、ELISA法和免疫组织化学法等实验结果表明KXS、Rg1各剂量组可不同程度的拮抗慢性应激模可引起大鼠海马和前额叶皮层NE、DA、DOPAC和HVA含量显著下降；血清ACTH增加；海马CRF、AChE表达显著上调，BDNF表达下调；前额叶皮层CRF表达上调，BDNF和CREB表达显著下调，表明KXS、Rg1可能通过对单胺类神经递质、HPA轴、乙酰胆碱及神经营养因子通路的综合调节而发挥作用。另外，结果表明KXS与Rg1改善抑郁症及其所致认知功能障碍作用相似。
总之，本研究为抑郁症及认知功能的研究提供了一套自动化程度高、具有自主知识产权的穿梭计算机图像实时分析处理装置及客观规范、多层面、敏感评价认知功能的指标评价体系；证明了KXS和Rg1对抑郁症及其所致认知功能障碍的改善作用，为寻找防治抑郁症及其所致认知功能障碍药物提供了实验依据。
Depression is a serious and highly prevalent disorder characterized by long-termbad mood and anhedonia.Apart from mood disorder,cognitive dysfunction is a mostimportant feature in depressive patient.It is important to research the mechanism ofcognitive deficits accompanying depression and seek effective antidepressant agentswith the capability of enhancing cognitive function.Thus,this thesis includes two parts:1)establishment of a new computer-aided controlling and image analysis system forshuttle box(CISB);2)research of preventative action of Kai-Xin-San(KXS)waterextract on depressive-like symptoms and cognition deficit induced by chronic mildstress(CMS).
Firstly,by combining the advantage of video tracking,image analysis,computerinformation processing and data mining,the CISB was developed with MicrosoftVisual C++6.0 computer language,which can collect and analyze the behavioral dataof rats in real-time.9 new parameters(DPM,DAM,SAA,SPE,SAT,EAT,LFC,ECRand TND)were established to evaluate cognitive function except for 6 presentindicators(AA,PE,RTAA,RTPE,EF and ITC).Simultaneously,the system wasvalidated with young rats,mid-aged rats and cerebral ischemia rats.The resultsdemonstrate that CISB is highly reliable and accurate,and can more systematically andsensitively evaluate the cognitive behavior from multiple aspects including theassociative learning and memory,understanding,processing speed and decisionmaking compared with present parameters.Animal behavior activities can beautomatically recognized,collected and analyzed,the animal video image and itsmoving track in shuttle box also can be played on the computer screen.
Secondly,we explored the antidepressant-like and nootropic effects of a waterextract of KXS(at doses of 0.3,0.9,and 2.7g/kg/day)and ginsenoside Rgl(at doses of50,100mg/kg/day)(the effective ingredient of ginseng,which is the principal herb ofKXS)using chronic mild stress(CMS)as a well-validated model of depression.Theresults indicated that KXS and Rgl can significantly reversed the depressive symptomsin CMS model,such as decline in sucrose preference index and prolongation of latencyto feeding.Furthermore,KXS(0.9,2.7g/kg)and Rgl(50mg/kg)can also improve thecognitive impairment induced by CMS in the shuttle-box test such as increased numberof passive escapes and passive movement distance as well as decreased number of active avoidances,active movement distance and active response speed in CMS model.Biological investigation with HPLC-ECD,ELISA assay and immunohistochemicalmethods demonstrated that KXS and ginsenoside Rgl can inhibit increased AChEactivity of hippocampus;increase monoamine neurotransmitter concentration ofprefrontal cortex and hippocampus;upregulate the CREB and BDNF activities in thehippocampus and prefrontal cortex and reduce ACTH concentrations in the serum inCMS rats.Taken together,these results indicated that KXS and Rgl can exertantidepressant-like and nootropic effects in the CMS model by modulating multiplecentral nervous systems.Moreover,the effects of KXS were comparable to Rgl ondepression and cognitive dysfunction in CMS model.
In conclusion,a highly automatic and intelligent CISB apparatus as well as a setof evaluation index were established,which can objectively,scientificly,systematically evaluate the behavior activities from multiple aspects in differentdementia animal models.Furthermore,antidepressive-like and nootropic effects ofKXS and Rgl were validated,and their mechanism were explored.It might be possibleto provide a potential drug for the treatment of depressive mood disorders andcognitive dysfunction induced by depression.
引文
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