神经颗粒素在睡眠剥夺损害认知功能中的作用及机制研究
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摘要
持续性工作状态所导致的睡眠剥夺(Sleep Deprivation, SD)对人的认知功能及工作能力的影响,一直是现代预防医学及许多行业(如航空、航海、救援、运输、医疗等)所关注的问题。国内外大量研究表明,SD损害认知功能,导致学习、记忆能力下降,反应迟钝,注意力分散,定向障碍,出现幻觉等,但其具体的神经生物学机制尚未完全阐明。神经颗粒素(Neurogranin, Ng)是近年来发现的脑特异性蛋白质,在脑内主要分布于海马、前额皮层、纹状体和杏仁核等与认知功能高度相关的重要脑区。作为突触后蛋白激酶C (protein kinase C, PKC)的作用底物和Ca2+敏感性钙调蛋白(calmodulan, CaM)结合蛋白,Ng主要通过调控Ca2+和CaM依赖性酶包括Ca~(2+) -CaM依赖性蛋白激酶Ⅱ(Ca~(2+)-calmodulin dependent protein kinaseⅡ, CaMKⅡ)等,参与学习记忆过程。大量研究报道,Ng是参与调控学习记忆过程的一个重要蛋白,参与了学习记忆过程中起核心作用的信号转导以及突触可塑性的主要调控环节。为此,本课题从Ng及其信号转导途径入手,探讨Ng在SD损害认知功能过程中的变化及其在信号转导途径中是否发挥着重要的调控作用。
本课题以大鼠为研究对象,对其进行24h、48h和72h SD。利用旷场实验观察大鼠在SD前、后的神经行为改变,以脑立体定位电生理法测量大鼠海马齿状回长时程增强效应(long-term potentiation, LTP)。通过实时荧光定量PCR、Western blot、免疫组化等技术对Ng与SD损害认知功能的关系进行深入研究。由于Ng的基因表达受维生素A(Vitamin A, V A)的活性代谢物-视黄酸(retinol acid, RA)和甲状腺激素(Triiodothyronine, T3)的调控,因此本研究观察了外源性补充RA和T3在预防和减轻SD损害认知功能中的作用,进一步印证Ng在SD损害认知功能中的作用。因此本研究的主要内容包括三部分:一、SD对大鼠神经行为和认知功能的影响;二、Ng在SD损害认知功能中的作用;三、上调Ng的表达在减轻SD损害认知功能中的作用。在第一部分和第二部分实验中以雄性Wistar大鼠为实验动物,大鼠适应环境1周后,随机分为3组:即24h,48h和72h实验组,每组再分为睡眠剥夺组(SD组)和对照组(C组)。利用睡眠剥夺箱对大鼠进行SD。在第三部分实验中,实验动物随机分为4组:即72h对照组(72h C组)、72h睡眠剥夺+生理盐水组(72h SD组)、72h睡眠剥夺+RA组(72h SD+RA组)、72h睡眠剥夺+T3组(72h SD+T3组)。干预组的大鼠于SD前一天开始腹腔注射RA或T3 (150μg/kg),1次/天,持续4天。
研究结果将有助于进一步阐明SD损害认知功能的机制,为深入开展防治措施的研究提供理论借鉴,开拓新思路。主要研究结果如下:
一、SD对大鼠神经行为和认知功能的影响
旷场行为实验中,24h和48h SD后大鼠站立次数显著增加(P<0.05)、穿行格数有增加趋势,表明大鼠自发行为和探究活动增加,中枢神经系统的兴奋性增强,呈现早期焦虑症状。随SD时间延长至72h后,大鼠穿行格数显著降低(P<0.05),表明神经系统的兴奋性由增强转为抑制。
高频刺激前,SD组和C组的群峰电位(Population spike, PS)幅值无显著性差异(P>0.05)。高频刺激后,两组PS峰幅值均明显升高,出现LTP。24h、48h和72h SD组的PS峰增加幅度较相对应的C组均明显降低(P<0.05),提示SD对海马神经突触可塑性和神经元兴奋性产生了明显的损伤作用,学习记忆能力下降。
二、Ng及其信号转导途径在SD损害认知功能的作用
N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)是广泛分布于中枢神经系统的谷氨酸敏感性离子通道受体。NR1为功能亚单位,是NMDA受体的必需组分;NR2是调节亚单位,调节受体功能和活化水平。大鼠海马NR1 mRNA水平在24h和48h SD后有降低趋势,72h SD后较C组显著降低(P<0.05);NR2A mRNA水平在48h SD后有降低趋势,72h SD后显著降低(P<0.05);在24h、48h和72h SD后,海马NR2B mRNA水平与C组比无统计学差异。大鼠前额皮层NR1和NR2A mRNA水平在24h SD后均未见改变,在48h和72h SD后都表现出降低的趋势,其中NR2A mRNA在72h SD后较C组显著降低(P<0.05);在24h、48h和72h SD后,前额皮层NR2B mRNA水平都未发生改变。表明SD可以使大鼠海马和前额皮层NR1和NR2A mRNA表达水平降低,且随着SD时间的延长,降低更为明显。
大鼠海马Ng mRNA以及蛋白表达水平在SD24h、48h和72h后,较C组均显著降低(P<0.05);在SD24h和48h后,大鼠前额皮层Ng mRNA以及蛋白水平较C组有降低趋势,在SD72h后显著降低(P<0.05)。同时,海马PKC和CaMKⅡmRNA水平在SD 48h和72h后显著降低(P<0.05);前额皮层PKC和CaMKⅡmRNA水平在72h SD后显著降低(P<0.05)。结果提示:SD可能通过影响中枢重要脑区中以Ng为上游调控子的信号转导通路,损害机体的学习记忆功能。
三、上调Ng的表达在减轻SD损害认知功能中的作用
外源性补充RA和T3的大鼠海马和前额皮层中Ng蛋白水平均显著升高(P<0.05),且与C组无显著性差异。旷场行为实验中,腹腔注射RA和T3的SD组站立次数有增多趋势、穿行格数为显著增加(P<0.05),接近C组的水平;其PS峰升幅较SD组显著增高(P<0.05; P<0.01),并且与C组无显著性差异。提示RA和T3通过上调Ng表达,明显消除或减轻了SD对海马神经突触可塑性和神经元兴奋性的损伤作用。同时进一步证实了Ng在SD损害认知功能中的重要作用。
总之, SD可能通过影响中枢重要脑区中以Ng为上游调控子的信号转导通路,损害机体的学习记忆功能。因此,Ng可作为改善SD损害认知功能的药物作用靶点,对提高工作效率,保护职业人群健康,具有重要的意义。
Sleep deprivation (SD) caused by the state of continuing work can interfere with people's cognitive function and work capacity. And it has been considered as an important problem by modern preventive medicine and a lot of industries (such as aviation, marine, rescue, transportation, medical care, etc.). Multiple studies have been demonstrated that SD damaged cognitive function, resulting in learning and memory disability, unresponsive, distraction, disorientation, hallucinations, etc. However, the mechanisms by which SD impairs cognitive function are not clear. As a brain specific protein, Ng is involved in learning and memory process, and plays as central role in signal transduction and synaptic plasticity of the main aspects of regulation. In this study, we have observed the changes of Ng in the process of impairing cognitive function by SD and determined weather Ng exerts important functions in the signal transduction pathway.
This study conducted in rats after 24h, 48h and 72h SD. Open field test (OFT) was used to observe the changes of nervous behavior of the rats before and after SD. Electrophysiological brain stereotactic method was used to test long-term potentiation (LTP) in dentate gyrus (DG) of the rats. An in-depth study in the relationship between Ng signal transduction pathway and SD damages cognitive function was done through real-time fluorescence quantitative PCR, Western blot, immunohistochemical techniques. It has been reported that Ng is one of the target genes regulated by retinoic acid (RA)-the active metabolite of VA and thyroid hormone (Triiodothyronine, T3). RA and T3 regulate the expression of gene through their corresponding nuclear receptor. Therefore we observated the roles of RA and T3 in protecting the damagment of cognitive function by SD in this study, and confirmed the important role of Ng in the peocess of SD damaged cognitive function. The results of this study may help to clarify the mechanisms in impairmentof cognitive function by SD furtherly and might provide theorical reference in preventing measures. The main findings are as follows:
1. Observation the effects of SD to neurobehavior and cognitive function.
Male Wistar rats were used in this study. After adapted to environment for one week, the animals were randomly divided into three groups: 24h, 48h and 72h experimental group. Each group was divided into sleep deprivation group (SD group) and control group (C group) (n=8 for each group). SD model was established by sleep deprivation box.
The number of rearing was increased significantly after 24h and 48h SD (P <0.05) in OFT, and the number of crossing was in upward trend, indicating that spontaneous behavior and exploration activity was increased of rats, the excitement of central nervous system was enhanced, and showing early anxiety symptoms. With the sleep deprivation period was extended to 72h, the number of crossing was reduced obviously (P <0.05), showing that the excitement of the nervous system was switched from enhancement to inhibition.
The amplitude of population spike (PS) was no significant difference between SD group and C group (P> 0.05) before high-frequency stimulation (HFS). The PS in the three SD groups were significantly lower than those of the C groups respectively (P <0.05), which indicated that the function of hippocampus was damaged by SD, likely through restraining the synaptic plasticity and excitability of neurons.
2. Involvement of Ng and signal transduction pathways in the effects of SD on the cognitive function.
The expression of NR1 mRNA in hippocampus of SD group was lower than that of C group after 24h and 48h SD,and significantly lower after 72h SD (P<0.05); The expression of NR2A mRNA of SD group was lower than that of C group after 48h SD,and significantly lower after 72h SD (P<0.05); The expressions of NR2B mRNA in hippocampus after 24h, 48h and 72h SD weren’t changed. The expressions of NR1 and NR2A mRNA in prefrontal cortex weren’t changed after 24h SD, and were lower than those of C groups after 48h and 72h SD,in which the expression of NR2A was significantly lower after 72h SD(P<0.05); The expressions of NR2B mRNA in prefrontal cortex after 24h, 48h and 72h SD weren’t changed either. These indicaded the expressions of NR1 and NR2A mRNA were down regulated by SD.
The levels of Ng mRNA in the hippocampus of 24h, 48h and 72h SD groups were lower obviously (P <0.05), also the expression of PKC and CaMKⅡmRNA were lower distinctly after 48h and 72h SD (P <0.05). Besides, The levels of Ng, PKC,CaMKⅡmRNA in prefrontal cortex of SD group were lower after 24h and 48h SD,and significantly lower only after 72h SD (P <0.05). The results were shown that the expressions of Ng, PKC and CaMKⅡin the hippocampus and prefrontal cortex were lower obviously. And the extent of reduction was more obvious with the time of SD extended. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity.
The levels of Ng expression in the hippocampus were lower significantly after 24h, 48h and 72h SD (P <0.05). The Ng protein expression level of prefrontal cortex in 72h SD group was striking decreased compared with C group coordinately (P<0.05).
3. Effects of increase the expression of Ng on alleviating the impairment of cognitive function by SD.
Experimental animals were randomly divided into four groups: 72h C group, 72h SD+NaCl group, 72h SD + RA group and 72h SD + T3 group. RA or T3 was injected intraperitonealy one day before SD in the intervention groups (150 g / kg). 1 times / day, continuing four days.
The expressions of Ng protein in hippocampus and prefrontal cortex of 72hSD + RA and 72hSD + T3 groups were significantly higher than that of 72h SD group (P <0.05). There was no significant difference between them and C group. The number of rearing was in upward trend and the number of crossing was increased obviously (P <0.05) in OFT after administration of RA and T3. The amplitude of PS was significantly higher (P <0.05; P <0.01), and there was no significant difference between them and C group.
In short, SD might affect signal transduction pathway in which Ng as the upstream regulation of important brain regions. This may damage learning and memory function. Thus, Ng might be a potential target for curative therapeutic attempts to improve cognitive function and working efficiency, and protect the health of the professional population.
本课题以大鼠为研究对象,对其进行24h、48h和72h SD。利用旷场实验观察大鼠在SD前、后的神经行为改变,以脑立体定位电生理法测量大鼠海马齿状回长时程增强效应(long-term potentiation, LTP)。通过实时荧光定量PCR、Western blot、免疫组化等技术对Ng与SD损害认知功能的关系进行深入研究。由于Ng的基因表达受维生素A(Vitamin A, V A)的活性代谢物-视黄酸(retinol acid, RA)和甲状腺激素(Triiodothyronine, T3)的调控,因此本研究观察了外源性补充RA和T3在预防和减轻SD损害认知功能中的作用,进一步印证Ng在SD损害认知功能中的作用。因此本研究的主要内容包括三部分:一、SD对大鼠神经行为和认知功能的影响;二、Ng在SD损害认知功能中的作用;三、上调Ng的表达在减轻SD损害认知功能中的作用。在第一部分和第二部分实验中以雄性Wistar大鼠为实验动物,大鼠适应环境1周后,随机分为3组:即24h,48h和72h实验组,每组再分为睡眠剥夺组(SD组)和对照组(C组)。利用睡眠剥夺箱对大鼠进行SD。在第三部分实验中,实验动物随机分为4组:即72h对照组(72h C组)、72h睡眠剥夺+生理盐水组(72h SD组)、72h睡眠剥夺+RA组(72h SD+RA组)、72h睡眠剥夺+T3组(72h SD+T3组)。干预组的大鼠于SD前一天开始腹腔注射RA或T3 (150μg/kg),1次/天,持续4天。
研究结果将有助于进一步阐明SD损害认知功能的机制,为深入开展防治措施的研究提供理论借鉴,开拓新思路。主要研究结果如下:
一、SD对大鼠神经行为和认知功能的影响
旷场行为实验中,24h和48h SD后大鼠站立次数显著增加(P<0.05)、穿行格数有增加趋势,表明大鼠自发行为和探究活动增加,中枢神经系统的兴奋性增强,呈现早期焦虑症状。随SD时间延长至72h后,大鼠穿行格数显著降低(P<0.05),表明神经系统的兴奋性由增强转为抑制。
高频刺激前,SD组和C组的群峰电位(Population spike, PS)幅值无显著性差异(P>0.05)。高频刺激后,两组PS峰幅值均明显升高,出现LTP。24h、48h和72h SD组的PS峰增加幅度较相对应的C组均明显降低(P<0.05),提示SD对海马神经突触可塑性和神经元兴奋性产生了明显的损伤作用,学习记忆能力下降。
二、Ng及其信号转导途径在SD损害认知功能的作用
N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)是广泛分布于中枢神经系统的谷氨酸敏感性离子通道受体。NR1为功能亚单位,是NMDA受体的必需组分;NR2是调节亚单位,调节受体功能和活化水平。大鼠海马NR1 mRNA水平在24h和48h SD后有降低趋势,72h SD后较C组显著降低(P<0.05);NR2A mRNA水平在48h SD后有降低趋势,72h SD后显著降低(P<0.05);在24h、48h和72h SD后,海马NR2B mRNA水平与C组比无统计学差异。大鼠前额皮层NR1和NR2A mRNA水平在24h SD后均未见改变,在48h和72h SD后都表现出降低的趋势,其中NR2A mRNA在72h SD后较C组显著降低(P<0.05);在24h、48h和72h SD后,前额皮层NR2B mRNA水平都未发生改变。表明SD可以使大鼠海马和前额皮层NR1和NR2A mRNA表达水平降低,且随着SD时间的延长,降低更为明显。
大鼠海马Ng mRNA以及蛋白表达水平在SD24h、48h和72h后,较C组均显著降低(P<0.05);在SD24h和48h后,大鼠前额皮层Ng mRNA以及蛋白水平较C组有降低趋势,在SD72h后显著降低(P<0.05)。同时,海马PKC和CaMKⅡmRNA水平在SD 48h和72h后显著降低(P<0.05);前额皮层PKC和CaMKⅡmRNA水平在72h SD后显著降低(P<0.05)。结果提示:SD可能通过影响中枢重要脑区中以Ng为上游调控子的信号转导通路,损害机体的学习记忆功能。
三、上调Ng的表达在减轻SD损害认知功能中的作用
外源性补充RA和T3的大鼠海马和前额皮层中Ng蛋白水平均显著升高(P<0.05),且与C组无显著性差异。旷场行为实验中,腹腔注射RA和T3的SD组站立次数有增多趋势、穿行格数为显著增加(P<0.05),接近C组的水平;其PS峰升幅较SD组显著增高(P<0.05; P<0.01),并且与C组无显著性差异。提示RA和T3通过上调Ng表达,明显消除或减轻了SD对海马神经突触可塑性和神经元兴奋性的损伤作用。同时进一步证实了Ng在SD损害认知功能中的重要作用。
总之, SD可能通过影响中枢重要脑区中以Ng为上游调控子的信号转导通路,损害机体的学习记忆功能。因此,Ng可作为改善SD损害认知功能的药物作用靶点,对提高工作效率,保护职业人群健康,具有重要的意义。
Sleep deprivation (SD) caused by the state of continuing work can interfere with people's cognitive function and work capacity. And it has been considered as an important problem by modern preventive medicine and a lot of industries (such as aviation, marine, rescue, transportation, medical care, etc.). Multiple studies have been demonstrated that SD damaged cognitive function, resulting in learning and memory disability, unresponsive, distraction, disorientation, hallucinations, etc. However, the mechanisms by which SD impairs cognitive function are not clear. As a brain specific protein, Ng is involved in learning and memory process, and plays as central role in signal transduction and synaptic plasticity of the main aspects of regulation. In this study, we have observed the changes of Ng in the process of impairing cognitive function by SD and determined weather Ng exerts important functions in the signal transduction pathway.
This study conducted in rats after 24h, 48h and 72h SD. Open field test (OFT) was used to observe the changes of nervous behavior of the rats before and after SD. Electrophysiological brain stereotactic method was used to test long-term potentiation (LTP) in dentate gyrus (DG) of the rats. An in-depth study in the relationship between Ng signal transduction pathway and SD damages cognitive function was done through real-time fluorescence quantitative PCR, Western blot, immunohistochemical techniques. It has been reported that Ng is one of the target genes regulated by retinoic acid (RA)-the active metabolite of VA and thyroid hormone (Triiodothyronine, T3). RA and T3 regulate the expression of gene through their corresponding nuclear receptor. Therefore we observated the roles of RA and T3 in protecting the damagment of cognitive function by SD in this study, and confirmed the important role of Ng in the peocess of SD damaged cognitive function. The results of this study may help to clarify the mechanisms in impairmentof cognitive function by SD furtherly and might provide theorical reference in preventing measures. The main findings are as follows:
1. Observation the effects of SD to neurobehavior and cognitive function.
Male Wistar rats were used in this study. After adapted to environment for one week, the animals were randomly divided into three groups: 24h, 48h and 72h experimental group. Each group was divided into sleep deprivation group (SD group) and control group (C group) (n=8 for each group). SD model was established by sleep deprivation box.
The number of rearing was increased significantly after 24h and 48h SD (P <0.05) in OFT, and the number of crossing was in upward trend, indicating that spontaneous behavior and exploration activity was increased of rats, the excitement of central nervous system was enhanced, and showing early anxiety symptoms. With the sleep deprivation period was extended to 72h, the number of crossing was reduced obviously (P <0.05), showing that the excitement of the nervous system was switched from enhancement to inhibition.
The amplitude of population spike (PS) was no significant difference between SD group and C group (P> 0.05) before high-frequency stimulation (HFS). The PS in the three SD groups were significantly lower than those of the C groups respectively (P <0.05), which indicated that the function of hippocampus was damaged by SD, likely through restraining the synaptic plasticity and excitability of neurons.
2. Involvement of Ng and signal transduction pathways in the effects of SD on the cognitive function.
The expression of NR1 mRNA in hippocampus of SD group was lower than that of C group after 24h and 48h SD,and significantly lower after 72h SD (P<0.05); The expression of NR2A mRNA of SD group was lower than that of C group after 48h SD,and significantly lower after 72h SD (P<0.05); The expressions of NR2B mRNA in hippocampus after 24h, 48h and 72h SD weren’t changed. The expressions of NR1 and NR2A mRNA in prefrontal cortex weren’t changed after 24h SD, and were lower than those of C groups after 48h and 72h SD,in which the expression of NR2A was significantly lower after 72h SD(P<0.05); The expressions of NR2B mRNA in prefrontal cortex after 24h, 48h and 72h SD weren’t changed either. These indicaded the expressions of NR1 and NR2A mRNA were down regulated by SD.
The levels of Ng mRNA in the hippocampus of 24h, 48h and 72h SD groups were lower obviously (P <0.05), also the expression of PKC and CaMKⅡmRNA were lower distinctly after 48h and 72h SD (P <0.05). Besides, The levels of Ng, PKC,CaMKⅡmRNA in prefrontal cortex of SD group were lower after 24h and 48h SD,and significantly lower only after 72h SD (P <0.05). The results were shown that the expressions of Ng, PKC and CaMKⅡin the hippocampus and prefrontal cortex were lower obviously. And the extent of reduction was more obvious with the time of SD extended. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity.
The levels of Ng expression in the hippocampus were lower significantly after 24h, 48h and 72h SD (P <0.05). The Ng protein expression level of prefrontal cortex in 72h SD group was striking decreased compared with C group coordinately (P<0.05).
3. Effects of increase the expression of Ng on alleviating the impairment of cognitive function by SD.
Experimental animals were randomly divided into four groups: 72h C group, 72h SD+NaCl group, 72h SD + RA group and 72h SD + T3 group. RA or T3 was injected intraperitonealy one day before SD in the intervention groups (150 g / kg). 1 times / day, continuing four days.
The expressions of Ng protein in hippocampus and prefrontal cortex of 72hSD + RA and 72hSD + T3 groups were significantly higher than that of 72h SD group (P <0.05). There was no significant difference between them and C group. The number of rearing was in upward trend and the number of crossing was increased obviously (P <0.05) in OFT after administration of RA and T3. The amplitude of PS was significantly higher (P <0.05; P <0.01), and there was no significant difference between them and C group.
In short, SD might affect signal transduction pathway in which Ng as the upstream regulation of important brain regions. This may damage learning and memory function. Thus, Ng might be a potential target for curative therapeutic attempts to improve cognitive function and working efficiency, and protect the health of the professional population.
引文
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