不同时程慢性应激对大鼠抑郁行为与海马神经可塑性相关蛋白BDNF/CREB/Bcl-2的影响
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摘要
目的
抑郁症是以心境低落、情绪低落、思维迟缓、意志活动减退为主要特征的综合征,是情感性精神障碍中的一种,具有高发病、高复发、高致残的特点。最近研究表明全球抑郁症发病率约为3.1%,我国的发病率约为3-5%。约有25-30%的抑郁症患者有过自杀行为,11-19%自杀身亡。WHO的全球疾病负担合作研究指出：预计2020年抑郁症将成为继冠心病后的世界第二大疾病负担源。抑郁症所引起的自杀、社会功能损害和精神残疾给个体、家庭和社会带来沉重的负担,但抑郁症的发病机制及相关问题迄今未明,因此需要迫切深入研究抑郁症的发病机制、治疗机制,寻找合适的生物学标记(biological marker)关联抑郁症状的变化,从而有利于其预防、早期干预、治疗、预防复发等。
抑郁症的发生与多基因遗传、心理因素和环境因素都有关。其中最重要的环境因素和心理因素是应激事件。目前,应激致抑郁症的病理机制尚不明确。
研究发现,海马区的神经元在成年后仍能再生,海马区的神经细胞对应激的破坏作用最敏感。在应激过程中,海马参与整合感知的信息、解释环境信息的意义以及调控生物体的行为和神经内分泌反应。多项研究提示应激可导致大脑特定部位、尤其是海马区的神经元萎缩。生物精神病学和心理学的研究均提示：大脑是一个开放、活动的靶器官,它对内源性、外源性的不同应激有着一个可塑(可变换)的调解作用。神经可塑性(Neuroplasticity)指神经系统为不断适应外界环境的变化而改变自身结构的能力,包括神经组织的正常发展和成熟、新技能的获得、在神经系统受损以及感觉剥夺后的代偿,它既有可能是结构(structural)上的可塑性变化、也可能是功能(functional)上的可塑性变化。成年中枢神经系统的神经可塑性的表现为树突功能的改变,长时程增强(LTP),突触重塑,突触发生,轴突出芽,轴突延长,神经元再生和抗凋亡等。多种临床和实验室研究均提出海马区神经可塑性与抑郁症的发生可能有重要关系。
然而目前为止,仍然不清楚神经结构可塑性和功能可塑性调节的内在发生机制,尤其是在抑郁症的发病过程中。
抑郁症的神经可塑性假说提出：应激能够调节与神经元再生、抗凋亡、轴突和树突改变相关的因子的表达,如BDNF.CREB.Bcl-2、MAPs等,这些因子能够依次影响海马的神经可塑性,导致神经元损伤和神经元再生之间的平衡被破坏了,使得颗粒细胞减少,锥形神经元萎缩和数目减少,继而海马的体积下降,功能受损,最终出现抑郁症的临床表现,最后导致抑郁症的发生。
cAMP应答元件结合蛋白(cAMP response element binding protein, CREB)作为一种转录因子参与短时记忆向长时记忆的转化,其磷酸化受到了cAMP通路、Ca2+-CaMK通路等多种信号通路的调控,其中cAMP/PKA是经典的调控通路。在cAMP/PKA—CREB—BDNF信号通路中,G蛋白耦联受体(GPCR)可以与多种神经递质或神经肽结合,其活化可以导致cAMP环化酶(AC)活性升高,随后通过升高cAMP的水平而激活PKA,活化的PKA催化亚基最终使得CREB Serl33磷酸化,调节转录因子得活性,从而介导了细胞对外界刺激的反应。上述这些因子的活动构成环腺苷酸/蛋白激酶A一环腺苷酸反应元件结合蛋白(cAMP/PKA—CREB)信号通路,脑源性神经营养因子(BDNF)和抗凋亡因子Bcl-2的启动子区内含CRE序列,均受到CREB的调控。基于以上的认识,可以选择BDNF—CREB—Bcl—2信号途径进行研究。
许多研究都已经研究了不同的应激方式对大鼠抑郁行为和不同神经可塑性相关蛋白的研究,但是,目前尚缺乏慢性应激的时程、治疗时程与抑郁行为之间的关联性研究及机制研究。这可能是一个了解抑郁症患者在遭受应激后发病缓慢,临床抗抑郁治疗治疗起效缓慢、起效时间有差别的重要线索之一
本研究拟探讨慢性应激时间的长短对大鼠抑郁行为和海马神经可塑性相关蛋白BDNF—CREB—Bcl—2信号途径的影响,拟探讨海马神经可塑性相关蛋白BDNF—CREB—Bcl—2信号途径在抑郁症发病中的可能中介机制。
方法
1、利用随机数字表将大鼠分为四组：(ⅰ)正常成年组；(ⅱ)1周CMS组；(ⅲ)2周CMS组;(iv)3周CMS组。
2、慢性不可预见应激抑郁模型(CMS)制备：接受各种不同的不可预知的随机应激,包括冰水游泳(4℃,5min):热应激(45℃,5min):夹尾(1min)：禁水(24h)：禁食(48h)：明暗颠倒(24小时)；束缚(2小时,2次)。以一周为一个时程,每天采取的应激方式随意抽取。
3、行为学测试：在应激前后、用药前后和停药后进行。(1)旷场实验(open filed):反映抑郁行为。行为学实验采用WMZ动物运动轨迹记录分析系统(Ethovision系统,荷兰Noldus公司)。(ⅱ)蔗糖消耗测试(Sucrose preference tests):：每次禁水后,给予1%蔗糖溶液,测定24h内饮用量、体重变化。反映快感缺乏。
4、海马神经再生的观察：大鼠行为学检测完毕后继续喂养1周,成年大鼠腹腔注射BrdU (50mg/kg)二小时一次,共三次,最后一次后24小时,心脏灌流制备免疫组化切片和HE染色,以光学焦显微镜观测BrdU阳性细胞,记数比较；
5、实验结束后,麻醉大鼠断头去脑,取海马组织,采用逆转录聚合酶链反应(RT-PCR)检测海马区BDNF/CREB/Bcl-2mRNA的表达,Western-blot方法测定海马区BDNF/CREB/Bcl-2的蛋白的表达。
6、数据处理：SPSS13.0统计学软件。
结果
1、行为学结果：大鼠旷场内10分钟的总行程、内围场地的行程、直立次数,1W应激组大鼠小于C对照组(P<0.05),2W应激组大鼠小于C对照组(P<0.05),3W应激组大鼠也明显小于C对照组(P<0.05),1W应激组大鼠、2W应激组大鼠,3W应激组大鼠之间相比无明显差异(P>0.05)；大鼠总液体消耗量、糖水消耗量、糖水偏好率,1W应激组大鼠小于C对照组(P<0.05),2W应激组大鼠小于C对照组(P<0.05),3W应激组大鼠也明显小于C对照组(P<0.05),1W应激组大鼠、2W应激组大鼠,3W应激组大鼠之间相比无明显差异(P>0.05)。在1周、2周、3周的不同慢性应激模型中,大鼠均出现明显的抑郁行为。
2、冰冻切片HE染色显示：1W应激组大鼠的海马齿状回BrdU阳性细胞数22.19±6.08低于C对照组的海马齿状回BrdU阳性细胞数31.75±8.48(P<0.05),3W应激组大鼠的海马齿状回BrdU阳性细胞数19.57±5.28也明显低于C对照组的海马齿状回BrdU阳性细胞数31.75±8.48(P<0.01),1W应激组大鼠、3W应激组大鼠的海马齿状回BrdU阳性细胞数之间相比无明显差异(P>0.05)。2W应激组大鼠的海马齿状回BrdU阳性细胞数29.78±6.78与C对照组的海马齿状回BrdU阳性细胞数31.75±8.48无显著差异(P>0.05)。
3、RT-PCR检测显示：与正常对照组C组对比,1W应激组大鼠BDNFmRNA/CREB mRNA/Bcl-2mRNA的水平低于C对照组(P<0.05),3W应激组大鼠BDNFmRNA水平低于C对照组(P<0.05),1W应激组大鼠和3W应激组大鼠之间BDNFmRNA/CREB mRNA/Bcl-2mRNA水平无明显差异(P>0.05)；与正常对照组对比,2W应激组大鼠BDNFmRNA/CREB mRNA/Bcl-2mRNA水平无明显差异(P>0.05)。
4, WESTERN BLOT检测显示：与正常对照组C组对比,lW应激组大鼠的BDNF/CREB/Bcl-2的蛋白水平低于C对照组(P<0.05),3W应激组大鼠的BDNF/CREB/Bcl-2蛋白水平低于C对照组(P<0.05),1W应激组大鼠和3W应激组大鼠之间的BDNF/CREB/Bcl-2蛋白水平无明显差异；与正常对照组对比,2W应激组大鼠的BDNF/CREB/Bcl-2蛋白水平无明显差异(P>0.05)。
结论
本研究的结果提示海马区的神经可塑性相关蛋白BDNF/CREB/Bcl-2的水平变化可能与抑郁行为的变化存在一定的关联性。神经可塑性相关蛋自BDNF/CREB/Bcl-2可能与抑郁症的发病有关联,提示了患者遭受应激后发病缓慢、症状波动的可能机制,需进一步探讨
Background:The pathogenesis of depression is complicated and involves multiple genetic, psychological, and environmental factors. The most important environmental factor is stress. The connection between stress and depression is still far from clear.
The hippocampus is only one of two brain regions where robust neurogenesis continues into adulthood, and nerve cells in the hippocampus are among the most sensitive to the deleterious effects of stress. There are reports that stress can cause damage and atrophy of neurons in certain brain structures, most notably the hippocampus o A decrease of hippocampal volume is detected by MRI in both depressive patients and in postmortem studies. Increasing evidences indicate that hippocampus plays an important role in the pathogenesis of depression.
Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis. The neuroplasticity hypothesis emerged. It hypothesized that stress can modulate the expression of various factors involved in cell survival and growth/anti-apoptotic factors, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B cell leucemia protein2(Bcl-2), and mitogen-activated protein (MAP) kinases, which may, in turn, affect neuroplasticity in the hippocampus, ultimately resulting in depression.
A number of animal models were developed to study the molecular effects of stress and the underlying neurobiological mechanisms of depression. Chronic mild stress (CMS) model (long-term exposure (i.e, greater than1weeks) to multiple, mild and inescapable stressors) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients.
Many researches have studied different stress (acute stress or chronic stress) effect on different neuroplasticity-related proteins. But less is known about how chronic mild stress influences neuroplasticity-related proteins expression in the hippocampus by the time of the stress. This may be an important clue to the pathogenesis of depression. We made some changes in the classic CMS model.7different classic mild stressors were used randomly in a7-days period, and then repeated in the next7-days period. We subjected rats treated with chronic mild stress of three different periods (1week of exposure to CMS group,2weeks of exposure to CMS group and3weeks of exposure to CMS group),
Our experiments therefore address the following questions:(1) What are the effects of different CMS on the levels of neuroplasticity-related proteins BDNF/CREB/Bcl-2expression?(2) Is there a relationship between the changes of neuroplasticity-related proteins BDNF/CREB/Bcl-2and depressive-like behaviors in the CMS rats?
Objective:To address these questions, we subjected rats treated with CMS of three different periods, investigated their depression-like behavioral changes and hippocampal neuroplasticity-related proteins'changes, and wanted to explore the possible mechanism.
Method:(1)Animals were sepatated into one of four groups rcontrol group, rats without stress:M1group, rats subjected to CMS for1week:M2group, rats subjected to CMS for2weeks:and M3group, rats subjected to CMS for3weeks.(2) The CMS procedure, which involves the sequential exposure to various unpredictable mild stressors, is designed to maximize the unpredictable nature of the stressors..(3) Rats' depression-like behaviors were observed in opening field test and1%sucrose preference test were tested before and after the experimentation of each group.(4) After bahvior test, rats were sacrificed and hippocampus were isolated. Neurogenesis in hippocampal dentate gyrus was detected by using immunohistochemistry method.(5)Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed BDNF/CREB/Bcl-2mRNA and protein expression in the rat hippocampus.(6) Statistics:All values were expressed as mean±SD. A one-way ANOVA was used for comparisons among groups and the Least-significant Difference was used for post-hoc multiple comparisons. Statistical significance was defined as p<0.05.
Results:(1) Compared with Controlled group, total diatance(cm) in10minutes/center distance(cm) in10minutes/rearing counts were decreased in MI group (P <0.05), M2group (P<0.05), and M3group (P<0.05) There was no significant difference in the total diatance in10minutes/center distance(cm) in10minutes/rearing counts among the M1, M2and M3groups (p>0.05). Compared with Controlled group, levels of total fluid consumption/sucrose consumption/sucrose preference consumption were decreased in MI group (P<0.05), M2group (P<0.05), and M3group (P<0.05). There was no significant difference in levels of total fluid consumption among the M1, M2and M3groups (p>0.05).(2) Compared with Controlled group (31.75±8.48),BrdU-labeled cells in the dentate gyrus were decreased in M1group (22.19±6.08):(P<0.05),and M3group(19.57±5.28)(P<0.05), there was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between Ml group and M3group(P>0.05).There was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between M2group(29.78±6.78) and control group(P>0.05).(3) RT-PCR analysis:Compared with controlled group, levels of BDNFmRNA/CREBmRNA/Bcl-2mRNA were decreased in MI group (P<0.05),and M3group (P<0.05), there was no significant difference in the levels of BDNFmRNA between M1group and M3group(P>0.05).There was no significant difference in the levels of BDNFmRNA between M2group and control group(P>0.05).(4) Immunoblotting analysis:Compared to that in the controlled group,the amount of BDNF protein/CREB protein/Bcl-2protein in MI group and M3group both decreased significantly (p<0.05), there was no significant difference in the amount of BDNF protein between M1group and M3group(P>0.05).however,2week's chronic mild stress did not affect the amount of BDNF protein (p>0.05).
Conclusion:Our findings illustrated that different chronic mild stress might have different effects on proteins implicated in neuroplasticity, providing insight into the role of neuroplasticity-related proteins in the depression.
抑郁症是以心境低落、情绪低落、思维迟缓、意志活动减退为主要特征的综合征,是情感性精神障碍中的一种,具有高发病、高复发、高致残的特点。最近研究表明全球抑郁症发病率约为3.1%,我国的发病率约为3-5%。约有25-30%的抑郁症患者有过自杀行为,11-19%自杀身亡。WHO的全球疾病负担合作研究指出：预计2020年抑郁症将成为继冠心病后的世界第二大疾病负担源。抑郁症所引起的自杀、社会功能损害和精神残疾给个体、家庭和社会带来沉重的负担,但抑郁症的发病机制及相关问题迄今未明,因此需要迫切深入研究抑郁症的发病机制、治疗机制,寻找合适的生物学标记(biological marker)关联抑郁症状的变化,从而有利于其预防、早期干预、治疗、预防复发等。
抑郁症的发生与多基因遗传、心理因素和环境因素都有关。其中最重要的环境因素和心理因素是应激事件。目前,应激致抑郁症的病理机制尚不明确。
研究发现,海马区的神经元在成年后仍能再生,海马区的神经细胞对应激的破坏作用最敏感。在应激过程中,海马参与整合感知的信息、解释环境信息的意义以及调控生物体的行为和神经内分泌反应。多项研究提示应激可导致大脑特定部位、尤其是海马区的神经元萎缩。生物精神病学和心理学的研究均提示：大脑是一个开放、活动的靶器官,它对内源性、外源性的不同应激有着一个可塑(可变换)的调解作用。神经可塑性(Neuroplasticity)指神经系统为不断适应外界环境的变化而改变自身结构的能力,包括神经组织的正常发展和成熟、新技能的获得、在神经系统受损以及感觉剥夺后的代偿,它既有可能是结构(structural)上的可塑性变化、也可能是功能(functional)上的可塑性变化。成年中枢神经系统的神经可塑性的表现为树突功能的改变,长时程增强(LTP),突触重塑,突触发生,轴突出芽,轴突延长,神经元再生和抗凋亡等。多种临床和实验室研究均提出海马区神经可塑性与抑郁症的发生可能有重要关系。
然而目前为止,仍然不清楚神经结构可塑性和功能可塑性调节的内在发生机制,尤其是在抑郁症的发病过程中。
抑郁症的神经可塑性假说提出：应激能够调节与神经元再生、抗凋亡、轴突和树突改变相关的因子的表达,如BDNF.CREB.Bcl-2、MAPs等,这些因子能够依次影响海马的神经可塑性,导致神经元损伤和神经元再生之间的平衡被破坏了,使得颗粒细胞减少,锥形神经元萎缩和数目减少,继而海马的体积下降,功能受损,最终出现抑郁症的临床表现,最后导致抑郁症的发生。
cAMP应答元件结合蛋白(cAMP response element binding protein, CREB)作为一种转录因子参与短时记忆向长时记忆的转化,其磷酸化受到了cAMP通路、Ca2+-CaMK通路等多种信号通路的调控,其中cAMP/PKA是经典的调控通路。在cAMP/PKA—CREB—BDNF信号通路中,G蛋白耦联受体(GPCR)可以与多种神经递质或神经肽结合,其活化可以导致cAMP环化酶(AC)活性升高,随后通过升高cAMP的水平而激活PKA,活化的PKA催化亚基最终使得CREB Serl33磷酸化,调节转录因子得活性,从而介导了细胞对外界刺激的反应。上述这些因子的活动构成环腺苷酸/蛋白激酶A一环腺苷酸反应元件结合蛋白(cAMP/PKA—CREB)信号通路,脑源性神经营养因子(BDNF)和抗凋亡因子Bcl-2的启动子区内含CRE序列,均受到CREB的调控。基于以上的认识,可以选择BDNF—CREB—Bcl—2信号途径进行研究。
许多研究都已经研究了不同的应激方式对大鼠抑郁行为和不同神经可塑性相关蛋白的研究,但是,目前尚缺乏慢性应激的时程、治疗时程与抑郁行为之间的关联性研究及机制研究。这可能是一个了解抑郁症患者在遭受应激后发病缓慢,临床抗抑郁治疗治疗起效缓慢、起效时间有差别的重要线索之一
本研究拟探讨慢性应激时间的长短对大鼠抑郁行为和海马神经可塑性相关蛋白BDNF—CREB—Bcl—2信号途径的影响,拟探讨海马神经可塑性相关蛋白BDNF—CREB—Bcl—2信号途径在抑郁症发病中的可能中介机制。
方法
1、利用随机数字表将大鼠分为四组：(ⅰ)正常成年组；(ⅱ)1周CMS组；(ⅲ)2周CMS组;(iv)3周CMS组。
2、慢性不可预见应激抑郁模型(CMS)制备：接受各种不同的不可预知的随机应激,包括冰水游泳(4℃,5min):热应激(45℃,5min):夹尾(1min)：禁水(24h)：禁食(48h)：明暗颠倒(24小时)；束缚(2小时,2次)。以一周为一个时程,每天采取的应激方式随意抽取。
3、行为学测试：在应激前后、用药前后和停药后进行。(1)旷场实验(open filed):反映抑郁行为。行为学实验采用WMZ动物运动轨迹记录分析系统(Ethovision系统,荷兰Noldus公司)。(ⅱ)蔗糖消耗测试(Sucrose preference tests):：每次禁水后,给予1%蔗糖溶液,测定24h内饮用量、体重变化。反映快感缺乏。
4、海马神经再生的观察：大鼠行为学检测完毕后继续喂养1周,成年大鼠腹腔注射BrdU (50mg/kg)二小时一次,共三次,最后一次后24小时,心脏灌流制备免疫组化切片和HE染色,以光学焦显微镜观测BrdU阳性细胞,记数比较；
5、实验结束后,麻醉大鼠断头去脑,取海马组织,采用逆转录聚合酶链反应(RT-PCR)检测海马区BDNF/CREB/Bcl-2mRNA的表达,Western-blot方法测定海马区BDNF/CREB/Bcl-2的蛋白的表达。
6、数据处理：SPSS13.0统计学软件。
结果
1、行为学结果：大鼠旷场内10分钟的总行程、内围场地的行程、直立次数,1W应激组大鼠小于C对照组(P<0.05),2W应激组大鼠小于C对照组(P<0.05),3W应激组大鼠也明显小于C对照组(P<0.05),1W应激组大鼠、2W应激组大鼠,3W应激组大鼠之间相比无明显差异(P>0.05)；大鼠总液体消耗量、糖水消耗量、糖水偏好率,1W应激组大鼠小于C对照组(P<0.05),2W应激组大鼠小于C对照组(P<0.05),3W应激组大鼠也明显小于C对照组(P<0.05),1W应激组大鼠、2W应激组大鼠,3W应激组大鼠之间相比无明显差异(P>0.05)。在1周、2周、3周的不同慢性应激模型中,大鼠均出现明显的抑郁行为。
2、冰冻切片HE染色显示：1W应激组大鼠的海马齿状回BrdU阳性细胞数22.19±6.08低于C对照组的海马齿状回BrdU阳性细胞数31.75±8.48(P<0.05),3W应激组大鼠的海马齿状回BrdU阳性细胞数19.57±5.28也明显低于C对照组的海马齿状回BrdU阳性细胞数31.75±8.48(P<0.01),1W应激组大鼠、3W应激组大鼠的海马齿状回BrdU阳性细胞数之间相比无明显差异(P>0.05)。2W应激组大鼠的海马齿状回BrdU阳性细胞数29.78±6.78与C对照组的海马齿状回BrdU阳性细胞数31.75±8.48无显著差异(P>0.05)。
3、RT-PCR检测显示：与正常对照组C组对比,1W应激组大鼠BDNFmRNA/CREB mRNA/Bcl-2mRNA的水平低于C对照组(P<0.05),3W应激组大鼠BDNFmRNA水平低于C对照组(P<0.05),1W应激组大鼠和3W应激组大鼠之间BDNFmRNA/CREB mRNA/Bcl-2mRNA水平无明显差异(P>0.05)；与正常对照组对比,2W应激组大鼠BDNFmRNA/CREB mRNA/Bcl-2mRNA水平无明显差异(P>0.05)。
4, WESTERN BLOT检测显示：与正常对照组C组对比,lW应激组大鼠的BDNF/CREB/Bcl-2的蛋白水平低于C对照组(P<0.05),3W应激组大鼠的BDNF/CREB/Bcl-2蛋白水平低于C对照组(P<0.05),1W应激组大鼠和3W应激组大鼠之间的BDNF/CREB/Bcl-2蛋白水平无明显差异；与正常对照组对比,2W应激组大鼠的BDNF/CREB/Bcl-2蛋白水平无明显差异(P>0.05)。
结论
本研究的结果提示海马区的神经可塑性相关蛋白BDNF/CREB/Bcl-2的水平变化可能与抑郁行为的变化存在一定的关联性。神经可塑性相关蛋自BDNF/CREB/Bcl-2可能与抑郁症的发病有关联,提示了患者遭受应激后发病缓慢、症状波动的可能机制,需进一步探讨
Background:The pathogenesis of depression is complicated and involves multiple genetic, psychological, and environmental factors. The most important environmental factor is stress. The connection between stress and depression is still far from clear.
The hippocampus is only one of two brain regions where robust neurogenesis continues into adulthood, and nerve cells in the hippocampus are among the most sensitive to the deleterious effects of stress. There are reports that stress can cause damage and atrophy of neurons in certain brain structures, most notably the hippocampus o A decrease of hippocampal volume is detected by MRI in both depressive patients and in postmortem studies. Increasing evidences indicate that hippocampus plays an important role in the pathogenesis of depression.
Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis. The neuroplasticity hypothesis emerged. It hypothesized that stress can modulate the expression of various factors involved in cell survival and growth/anti-apoptotic factors, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B cell leucemia protein2(Bcl-2), and mitogen-activated protein (MAP) kinases, which may, in turn, affect neuroplasticity in the hippocampus, ultimately resulting in depression.
A number of animal models were developed to study the molecular effects of stress and the underlying neurobiological mechanisms of depression. Chronic mild stress (CMS) model (long-term exposure (i.e, greater than1weeks) to multiple, mild and inescapable stressors) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients.
Many researches have studied different stress (acute stress or chronic stress) effect on different neuroplasticity-related proteins. But less is known about how chronic mild stress influences neuroplasticity-related proteins expression in the hippocampus by the time of the stress. This may be an important clue to the pathogenesis of depression. We made some changes in the classic CMS model.7different classic mild stressors were used randomly in a7-days period, and then repeated in the next7-days period. We subjected rats treated with chronic mild stress of three different periods (1week of exposure to CMS group,2weeks of exposure to CMS group and3weeks of exposure to CMS group),
Our experiments therefore address the following questions:(1) What are the effects of different CMS on the levels of neuroplasticity-related proteins BDNF/CREB/Bcl-2expression?(2) Is there a relationship between the changes of neuroplasticity-related proteins BDNF/CREB/Bcl-2and depressive-like behaviors in the CMS rats?
Objective:To address these questions, we subjected rats treated with CMS of three different periods, investigated their depression-like behavioral changes and hippocampal neuroplasticity-related proteins'changes, and wanted to explore the possible mechanism.
Method:(1)Animals were sepatated into one of four groups rcontrol group, rats without stress:M1group, rats subjected to CMS for1week:M2group, rats subjected to CMS for2weeks:and M3group, rats subjected to CMS for3weeks.(2) The CMS procedure, which involves the sequential exposure to various unpredictable mild stressors, is designed to maximize the unpredictable nature of the stressors..(3) Rats' depression-like behaviors were observed in opening field test and1%sucrose preference test were tested before and after the experimentation of each group.(4) After bahvior test, rats were sacrificed and hippocampus were isolated. Neurogenesis in hippocampal dentate gyrus was detected by using immunohistochemistry method.(5)Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed BDNF/CREB/Bcl-2mRNA and protein expression in the rat hippocampus.(6) Statistics:All values were expressed as mean±SD. A one-way ANOVA was used for comparisons among groups and the Least-significant Difference was used for post-hoc multiple comparisons. Statistical significance was defined as p<0.05.
Results:(1) Compared with Controlled group, total diatance(cm) in10minutes/center distance(cm) in10minutes/rearing counts were decreased in MI group (P <0.05), M2group (P<0.05), and M3group (P<0.05) There was no significant difference in the total diatance in10minutes/center distance(cm) in10minutes/rearing counts among the M1, M2and M3groups (p>0.05). Compared with Controlled group, levels of total fluid consumption/sucrose consumption/sucrose preference consumption were decreased in MI group (P<0.05), M2group (P<0.05), and M3group (P<0.05). There was no significant difference in levels of total fluid consumption among the M1, M2and M3groups (p>0.05).(2) Compared with Controlled group (31.75±8.48),BrdU-labeled cells in the dentate gyrus were decreased in M1group (22.19±6.08):(P<0.05),and M3group(19.57±5.28)(P<0.05), there was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between Ml group and M3group(P>0.05).There was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between M2group(29.78±6.78) and control group(P>0.05).(3) RT-PCR analysis:Compared with controlled group, levels of BDNFmRNA/CREBmRNA/Bcl-2mRNA were decreased in MI group (P<0.05),and M3group (P<0.05), there was no significant difference in the levels of BDNFmRNA between M1group and M3group(P>0.05).There was no significant difference in the levels of BDNFmRNA between M2group and control group(P>0.05).(4) Immunoblotting analysis:Compared to that in the controlled group,the amount of BDNF protein/CREB protein/Bcl-2protein in MI group and M3group both decreased significantly (p<0.05), there was no significant difference in the amount of BDNF protein between M1group and M3group(P>0.05).however,2week's chronic mild stress did not affect the amount of BDNF protein (p>0.05).
Conclusion:Our findings illustrated that different chronic mild stress might have different effects on proteins implicated in neuroplasticity, providing insight into the role of neuroplasticity-related proteins in the depression.
引文
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