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    • 参芪解郁方对母婴分离子代大鼠成年后Papez环路相关脑区磁共振波谱的影响

    • Effect of Shenqi Jieyu Formula on magnetic resonance spectroscopy of Papez circuit-related brain regions in adult offspring of maternal separation rats

    • 李伯梁

      12 ,  

      姜圣楠

      3 ,  

      唐启盛

      2 ,  

      孙迪

      12 ,  

      曲淼

      2 ,  
    • 北京中医药大学学报   2024年47卷第10期 页码:1416-1426
    • DOI:10.3969/j.issn.1006-2157.2024.10.012    

      中图分类号: R285.5
    • 纸质出版日期:2024-10-30

      收稿日期:2024-03-31

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  • 李伯梁, 姜圣楠, 唐启盛, 等. 参芪解郁方对母婴分离子代大鼠成年后Papez环路相关脑区磁共振波谱的影响[J]. 北京中医药大学学报, 2024,47(10):1416-1426. DOI: 10.3969/j.issn.1006-2157.2024.10.012.

    LI Boliang, JIANG Shengnan, TANG Qisheng, et al. Effect of Shenqi Jieyu Formula on magnetic resonance spectroscopy of Papez circuit-related brain regions in adult offspring of maternal separation rats[J]. Journal of Beijing University of Traditional Chinese Medicine, 2024,47(10):1416-1426. DOI: 10.3969/j.issn.1006-2157.2024.10.012.

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    摘要

    目的

    通过磁共振波谱(MRS)观察母婴分离子代大鼠成年后Papez环路海马和前额叶皮质内代谢物水平,探讨参芪解郁方对其抑郁、焦虑样行为的作用及机制。

    方法

    将24只孕16 d SD大鼠按照随机数字表法分为正常组、模型组、参芪解郁方组、盐酸氟西汀组,每组6只。仔鼠出生后第1~21天每天进行4 h母婴分离。从第15天开始,给母鼠灌胃相应药物,每天1次,连续7 d(参芪解郁方组:12.5 g/kg,盐酸氟西汀组:2.33 mg/kg),灌胃期间正常哺乳。第22天,仔鼠断乳,按母鼠的实验分组,将每只母鼠分娩的子代仔鼠按照随机数字表法,选取雌雄各1只,每组6只,组成正常雌鼠组、模型雌鼠组、参芪解郁方雌鼠组、盐酸氟西汀雌鼠组、正常雄鼠组、模型雄鼠组、参芪解郁方雄鼠组、盐酸氟西汀雄鼠组。饲养8周后,各组子代大鼠分别进行强迫游泳实验、蔗糖水消耗实验、旷场实验和高架十字迷宫实验,采用MRS检测海马和前额叶皮质N-乙酰天[门]冬氨酸(NAA)、胆碱化合物(Cho)、谷氨酸(Glu)、肌醇(mI)和肌酸(Cr)的相对值。

    结果

    与正常雌鼠和雄鼠组比较,模型雌鼠和雄鼠组体质量降低,蔗糖水消耗量、旷场实验水平得分和垂直得分减少,强迫游泳不动时间增加,双侧海马和前额叶皮质NAA/Cr、Glu/Cr值下降(均P<0.01);模型雌鼠组高架十字迷宫进入开放臂次数比例和开放臂停留时间比例减少,右侧海马的Cho/Cr值升高(P<0.05)。与模型雌鼠和雄鼠组比较,参芪解郁方、盐酸氟西汀雌鼠和雄鼠组体质量增加,强迫游泳不动时间减少,蔗糖水消耗量、旷场实验水平得分和垂直得分增加(P<0.01);参芪解郁方和盐酸氟西汀雌鼠组高架十字迷宫进入开放臂次数比例和开放臂停留时间比例较模型雌鼠组增加(P<0.01)。与模型雌鼠组比较,参芪解郁方和盐酸氟西汀雌鼠组双侧海马和前额叶皮质的NAA/Cr、Glu/Cr值升高(P<0.05);参芪解郁方和盐酸氟西汀雄鼠组右侧海马、双侧前额叶皮质的NAA/Cr值和双侧海马、右侧前额叶皮质的Glu/Cr值较模型雄鼠组升高(P<0.05);参芪解郁方、盐酸氟西汀雌鼠和雄鼠组右侧海马的Cho/Cr值降低(P<0.05)。

    结论

    生命早期,母婴分离可致子代成年后出现抑郁、焦虑样行为,参芪解郁方可能通过调节Papez环路相关脑区代谢物水平发挥抗抑郁、焦虑作用。

    Abstract

    Objective

    To explore the effect and mechanism of Shenqi Jieyu Formula (SQJYF) on depression and anxiety-like behavior in adult offspring rats after maternal separation (MS). This was done by observing the levels of metabolites in the hippocampus and prefrontal cortex of the Papez circuit through magnetic resonance spectroscopy (MRS).

    Methods

    Twenty-four Sprague-Dawley rats at 16 days of pregnancy were divided into the normal, model, SQJYF, and fluoxetine groups using the random number table method, with six rats per group. MS was performed 4 h a day from the first to the 21st day after birth. Starting from the 15th day, the corresponding medications(SQJYF group: 12.5 g/kg, fluxetine group: 2.33 mg/kg) were administered to mother rats once a day for 7 consecutive days. Normal breastfeeding was performed during the gavage. The offspring rats were weaned on the 22nd day. According to the experimental grouping of mother rats, one male and one female offspring rat of each mother rat were randomly selected using the random number table method, with six rats per group. They were divided into normal, model, SQJYF, and fluoxetine female and male rat groups, respectively. After 8 weeks of feeding, the offspring rats in each group were subjected to forced swimming test(FST), the sucrose water consumption test, and open field tests (OFT), and the elevated plus maze (EPM) test was conducted. The relative values of N-acetyl-aspartate (NAA), choline (Cho), glutamic acid (Glu), myo-inositol (mI), and creatine (Cr) in the hippocampus and prefrontal cortex were detected using MRS.

    Results

    Compared with that of the normal female and male rat groups, the weight of the rats in the model group was decreased as well as sucrose water consumption and the horizontal and vertical scores of OFT, whereas the immobility time of FST increased. Compared with the normal female and male rat group, the NAA/Cr and Glu/Cr values in the bilateral hippocampus and prefrontal cortex of the female and male rats in the model group decreased (all P<0.01). The proportion of rats entering the open arm and open arm residence time of the model female rat group in the EPM test decreased, whereas the Cho/Cr value of the right hippocampus of the female rats in the model group increased (P<0.05). Compared with the model female and male rat group, the weight of the rats in the SQJYF and fluoxetine groups increased, the immobility time of FST decreased, but the sucrose water consumption and the horizontal and vertical OFT scores increased (P<0.01). The proportion of rats entering the open arm and open arm residence time in the EPM increased in the SQJYF and fluoxetine female rat groups compared to those of the model female rat group (P<0.01). Compared with the model female rat group, the NAA/Cr and Glu/Cr values in the bilateral hippocampus and prefrontal cortex of female rats in the SQJYF and fluoxetine groups increased. The NAA/Cr and Glu/Cr values in the right hippocampus and prefrontal cortex of male rats in the SQJYF and fluoxetine groups were higher than those in the model group (P<0.05), whereas the Cho/Cr value in the right hippocampus of female and male rats in the SQJYF and fluoxetine groups decreased (P<0.05).

    Conclusion

    MS in early life can lead to depression and anxiety-like behavior in adult offspring. However, SQJYF may exert antidepressant and anti-anxiety effects by regulating the metabolite levels in related brain regions of the Papez circuit.

    关键词

    母婴分离; 磁共振波谱; Papez环路; 子代; 参芪解郁方; 大鼠

    Keywords

    maternal separation; magnetic resonance spectroscopy; Papez circuit; offspring; Shenqi Jieyu Formula; rats

    抑郁症是以心境低落为表现的一类精神疾病,具有显著而持久的特点,其发病率呈现逐渐升高的趋势[

    1],研究发现成年期的抑郁发生多与童年的不良经历有关[2]。个体在生命早期遭遇的负性事件是成年后发生精神疾病的高危因素[3],母婴分离是生命早期的一种社会剥夺方式,会造成子代持久的大脑结构改变,影响中枢神经系统的发育,导致子代成年后情感、行为和认知的异常[4],增加成年后患精神疾病的风险[5]。动物研究表明,生命早期的母婴分离不仅会导致母鼠的抑郁样表现,还会引起子代大鼠的抑郁、焦虑样行为,且子代雌鼠和雄鼠存在着不同的抑郁样表现[6-8]。目前已有许多研究应用母婴分离模拟早期应激来研究子代成年后的精神疾病。

    磁共振波谱(MRS)是一种无创性的检测活体内细胞水平组织代谢物含量的成像技术,可对脑内多种代谢物的水平进行测定。课题组前期采用MRS对母婴分离后产后抑郁症大鼠进行研究,发现产后抑郁症大鼠存在脑内代谢物含量的异常,参芪解郁方可调节脑内代谢物水平[

    9]。当前采用MRS技术对子代成年后抑郁的研究尚少,子代成年抑郁发病与脑内代谢物含量改变的关系有待进一步探究。本研究分别选取子代雌性和雄性大鼠,观察母婴分离对其各自行为学的影响,探究生命早期母婴分离大鼠子代成年后海马和前额叶皮质的MRS改变,探索早期应激事件对于子代成年后精神疾病的作用及其机制,为参芪解郁方治疗抑郁症的临床应用提供实验参考。

    1 材料

    1.1 动物

    24只SPF级SD孕鼠(北京维通利华实验动物技术有限公司),生产许可证号:SCXK(京)2012-0001,3月龄,孕16 d,体质量(220±10) g,喂养于北京中医药大学动物实验中心,自由饮水和摄食,室内光照周期为每天7:00~19:00明亮,共计12 h,室内安静,相对湿度60%~70%,室温20~22 ℃。

    1.2 伦理审查

    本实验经北京中医药大学实验动物伦理委员会审查批准,批件编号:BUCM-4-201612501-4022。

    1.3 药物

    参芪解郁方由党参12 g(批号:17002031)、黄芪20 g(批号:17003621)、炒酸枣仁30 g(批号:17007501)、当归15 g(批号:17008431)、郁金15 g(批号:17002581)、陈皮10 g(批号:17003621)、山萸肉30 g(批号:17000871)、佛手9 g(批号:17005782)组成,中药配方颗粒购于北京中医药大学第三附属医院,以蒸馏水溶解,每毫升生药含量1.25 g,于4 ℃冰箱贮存备用,临用前加热。盐酸氟西汀胶囊购于礼来苏州制药有限公司(规格:20 mg/粒,批号:2090A,国药准字HJ20160501),临用时溶于蒸馏水中,混合均匀,质量浓度为0.233 g/L。

    1.4 主要仪器及设备

    大鼠旷场箱:自制,木质,内壁为黑色的内空立方体,80 cm×80 cm×40 cm,内底面用黄线划分为面积相等的25块方格;强迫游泳钢化玻璃水缸:自制,圆柱形玻璃缸,直径25 cm、高60 cm;高架十字迷宫:北京中医药大学中药学院;PharmaScan 7.0/16US型动物核磁共振活体成像仪(德国Bruker公司);气体麻醉仪(德国Phoenix公司)。

    2 方法

    2.1 分组与造模

    孕16 d SD大鼠购入后单笼适应性喂养3 d,3 d后进行旷场实验,筛选出评分相近的24只孕鼠,按照随机数字表法,将其随机分为4组,分别为正常组、模型组、参芪解郁方组、盐酸氟西汀组。待孕鼠分娩后进行母婴分离,按母鼠的实验分组,将每只母鼠产下的仔鼠按照随机数字表法选取雌雄各1只,共选取雌性和雄性各6只,组成正常雌鼠组、模型雌鼠组、参芪解郁方雌鼠组、盐酸氟西汀雌鼠组、正常雄鼠组、模型雄鼠组、参芪解郁方雄鼠组、盐酸氟西汀雄鼠组,8组,共48只。其余仔鼠与选取仔鼠在母婴分离期间一同进行分离操作,分离结束后,选取仔鼠进行下一步研究,其余仔鼠正常饲养。

    仔鼠出生当天记为P0,于P1—P21进行每天4 h(9:00~13:00)的母婴分离,期间避免任何干扰,存放仔鼠的饲养笼均使用各自母鼠用过的垫料,保持幼鼠温度(30±1)℃。正常组不做任何干预,继续与母鼠饲养于同一笼。母婴分离结束后将幼鼠送回对应母鼠笼中,在P22仔鼠断乳,按照性别及各自分组分笼饲养至第8周结束,在此期间仔鼠自由饮水摄食。

    2.2 给药

    自母鼠产后第15天开始灌胃给药,每日1次,连续1周,参芪解郁方组给予自拟参芪解郁方配方颗粒灌胃,盐酸氟西汀组予盐酸氟西汀胶囊灌胃,根据体表面积折算的等效剂量比例换算,按60 kg成人用量7倍计算每100 g大鼠用量,灌胃剂量分别为12.5 g/kg和2.33 mg/kg;正常组和模型组不进行药物干预,在相同时间灌胃予等体积双蒸水。母鼠灌胃期间正常哺乳,在P22仔鼠断乳,仔鼠饲养至第8周后进行行为学实验和MRS检测。

    2.3 行为学评价

    2.3.1 大鼠生长及活动状态

    雌性大鼠和雄性大鼠分笼饲养期间,观察大鼠的生长状况及活动状态。于P22、P29、P36、P43、P50测量大鼠体质量。

    2.3.2 蔗糖水消耗实验

    实验参照文献[

    10]进行,实验之前,大鼠禁水24 h,实验时,将1%蔗糖水溶液放置于鼠笼中由大鼠自由饮用,1 h后计算每只大鼠的蔗糖水消耗量。蔗糖水消耗量(g)=测定前瓶体质量(g)-测定后瓶体质量(g)。

    2.3.3 旷场实验(OFT)

    将大鼠轻放置在内底面中央,观察记录安静、遮光环境下5 min内大鼠的活动情况。以穿格次数(四肢均需进入方格内)作为水平得分,以直立次数(两前肢均离地)作为垂直得分。每只大鼠检测后,用70%乙醇溶液对旷场进行清洗,避免前一只大鼠余留的排泄物及其气味等信息对下一只大鼠的测试结果产生干扰。

    2.3.4 强迫游泳实验(FST)

    FST分为2 d进行,第1天时进行强迫游泳训练,将大鼠在安静状态下置于水深35 cm的圆柱形强迫游泳缸内,水温24~25 ℃,进行预游泳15 min,结束后用毛巾擦干大鼠放回笼内。第2天同一时间进行强迫游泳正式实验,记录同样条件下5 min内大鼠呈现不动状态(即大鼠在水中停止挣扎呈直立漂浮状态,或仅有偶尔的肢体运动以保持头部浮于水面)、挣扎状态(即大鼠俯冲、前肢拍打水面及攀爬缸壁的状态)及游泳状态(即大鼠围缸主动游泳的状态)的时间。

    2.3.5 高架十字迷宫(EPM)

    测试开始之前,按顺序将每只大鼠放入一个塑料盒(60 cm×60 cm×35 cm)中自由探究5 min,然后迅速将大鼠置于EPM的中央区域,使其面向其中一个开放臂,保持室内安静,记录5 min内大鼠的活动状态。①进入开放臂次数(OE):大鼠4个爪子全部进入为准,1个爪子完全退出则本次活动完成。②进入闭合臂次数(CE):大鼠4个爪子全部进入为准。③进入开放臂时间(OT):以s为计算单位。④进入闭合臂时间(CT):以s为单位计算。再分别计算:进入开放臂次数比例(%)=OE/(OE+CE)×100%;开放臂停留时间比例(%)=OT/(OT+CT)×100%。

    2.4 MRS检测

    大鼠麻醉后俯卧位固定于扫描床上,头部固定,在大鼠躯干上覆盖棉布以维持正常体温,扫描期间保持室温20~22 ℃,连接呼吸监控接收装置,监测大鼠的呼吸,使其维持70~80次/min的频率。

    在大鼠双侧海马及前额叶皮质区域,分别选取一处立方体感兴趣区(3 mm×3 mm×3 mm),经匀场和抑水后,采用PRESS序列采集1H谱,谱宽为1 500 Hz,采样点数为2 048,TR=2 500 ms,TE=20 ms,累加次数为500次,所得1H谱经傅里叶变换,基线校正后,指定水峰的化学位移为1 400.56 Hz,进而确定1H谱上的各代谢物谱峰信号,其中N-乙酰天[门]冬氨酸(NAA)为601.94 Hz、胆碱化合物(Cho)为959.53 Hz、谷氨酸(Glu)为700.28 Hz、肌醇(mI)为1 060.84 Hz、肌酸(Cr)为893.97 Hz。测定上述谱峰的高度,分别计算出NAA/Cr、Cho/Cr、Glu/Cr、mI/Cr的数值。

    2.5 统计方法

    本研究采用SPSS 26.0软件进行统计分析,符合正态分布的计量资料以均值±标准差(x¯±s)描述。多组间比较采用单因素方差分析,方差齐时进一步组间两两比较采用LSD检验,方差不齐时采用Dunnett′s T3检验。不符合正态分布的数据以中位数(四分位数间距)[M(P25P75)]描述,组间比较采用Kruskal Wallis检验。各组雌鼠和雄鼠不同阶段体质量采用重复测量方差分析。以P<0.05表示差异有统计学意义。

    3 结果

    3.1 各组雌鼠和雄鼠生长及活动状态比较

    相比于正常雌鼠和雄鼠组,模型两组活动范围较小,喜蜷卧,睡眠时间增加,毛发干枯无光泽,饮食减少,梳理毛发次数减少。模型雌鼠组以上外观及活动状态表现较模型雄鼠组更加明显。参芪解郁方和盐酸氟西汀各组状态略好于模型组,但未达到正常水平。

    多组间、不同时间点和交互作用差异均有统计学意义。与正常雌鼠和雄鼠组比较,模型两组体质量均下降(P<0.01)。与模型雌鼠和雄鼠组比较,参芪解郁方、盐酸氟西汀各组体质量升高(P<0.01)。与模型雌鼠组比较,模型雄鼠组体质量在各个时点均较高(P<0.01)。结果见表1

    表1  各组雌鼠和雄鼠不同阶段体质量比较(g;x¯±sn=6)
    Table 1  Comparison of body weight of female and male rats in each group at different stages (g; x¯±s; n=6)
    组别Group剂量DoseP22P29
    正常雌鼠组Normal female rat group   45.81±1.99 73.89±1.28
    模型雌鼠组Model female rat group   32.84±4.44○○ 64.99±3.11○○
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 54.65±1.91○○●● 92.01±2.02○○●●
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 51.47±0.96○○●● 86.46±1.26○○●●△
    正常雄鼠组Normal male rat group   51.17±4.08 89.81±8.62
    模型雄鼠组Model male rat group   38.33±3.30●●** 77.46±5.05●●**
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 56.83±1.82**## 98.28±2.87**##
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 53.62±2.01## 90.86±1.19##
    组别GroupP36P43P50
    正常雌鼠组Normal female rat group 122.48±3.97 171.18±5.76 214.82±6.94
    模型雌鼠组Model female rat group 113.82±5.06○○ 154.07±5.98○○ 197.96±4.60○○
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 140.00±5.64○○●● 183.41±8.63○○●● 233.59±8.09○○●●
    盐酸氟西汀雌鼠组Fluoxetine female rat group 137.89±1.76○○●● 180.21±4.68○●● 220.00±6.19●●△△
    正常雄鼠组Normal male rat group 139.45±6.51 212.67±8.47 320.64±8.27
    模型雄鼠组Model male rat group 123.36±4.17●●** 196.64±7.85●●** 303.20±10.58●●**
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 160.59±7.21**## 234.50±9.59**## 352.63±14.37**##
    盐酸氟西汀雄鼠组Fluoxetine male rat group 153.73±5.26**##▲ 227.81±9.12**## 339.55±8.53**##▲

    注:F组别=398.121,P<0.001;F时间=6 929.999,P<0.001;F交互=103.637,P<0.001。与正常雌鼠组比较,○P<0.05,○○P<0.01;与模型雌鼠组比较,●●P<0.01;与参芪解郁方雌鼠组比较,△P<0.05,△△P<0.01;与正常雄鼠组比较,**P<0.01;与模型雄鼠组比较,##P<0.01;与参芪解郁方雄鼠组比较,▲P<0.05。

    Note:Fgroup=398.121, P<0.001; Ftime=6 929.999, P<0.001; Finteraction=103.637, P<0.001. ○P<0.05, ○○P<0.01 compared with the normal female rat group; ●●P<0.01 compared with the model female rat group; △P<0.05, △△P<0.01 compared with the Shenqi Jieyu Formula female rat group;**P<0.01 compared with the normal male rat group; ##P<0.01 compared with the model male rat group; ▲P<0.05 compared with the Shenqi Jieyu Formula male rat group.

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    3.2 各组雌鼠和雄鼠OFT得分比较

    与正常雌鼠和雄鼠组比较,模型两组的水平得分和垂直得分均降低(P<0.01)。与模型雌鼠和雄鼠组比较,参芪解郁方、盐酸氟西汀各组的水平得分和垂直得分升高(P<0.01)。模型雄鼠组的水平得分较模型雌鼠组升高(P<0.01)。结果见表2

    表2  各组雌鼠和雄鼠OFT水平得分、垂直得分,以及蔗糖水消耗量比较[M(P25P75);x¯±sn=6]
    Table 2  Comparison of the horizontal and vertical scores in open field tests and the consumption of sucrose water of female and male rats in each group [M(P25P75);x¯±sn=6]
    组别Group剂量Dose水平得分Horizontal scores垂直得分Vertical scores蔗糖水消耗量Consumption of sucrose water/g
    正常雌鼠组Normal female rat group   95(90,100) 18(15,21) 12.35±0.71
    模型雌鼠组Model female rat group   57(53,61)○○ 9(7,9)○○ 9.13±0.51○○
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 87(84,91)○○●● 13(12,14)○○●● 11.23±0.86○●●
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 85(81,91)○○●● 15(13,16)○●● 11.63±0.76●●
    正常雄鼠组Normal male rat group   96(91,100) 18(15,22) 13.82±1.08
    模型雄鼠组Model male rat group   79(72,83)●●** 10(8,12)** 10.58±0.62●●**
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 93(88,95)## 17(14,19)## 12.02±1.04**##
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 91(87,94)## 17(14,18)## 12.62±0.60*##
    H/F   34.271 32.679 18.823
    P   <0.001 <0.001 <0.001

    注:与正常雌鼠组比较,○P<0.05,○○P<0.01;与模型雌鼠组比较,●●P<0.01;与正常雄鼠组比较,*P<0.05,**P<0.01;与模型雄鼠组比较,##P<0.01。

    Note:○P<0.05, ○○P<0.01 compared with the normal female rat group; ●●P<0.01 compared with the model female rat group; *P<0.05,**P<0.01 compared with the normal male rat group; ##P<0.01 compared with the model male rat group.

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    3.3 各组雌鼠和雄鼠蔗糖水消耗量比较

    与正常雌鼠和雄鼠组比较,模型两组的蔗糖水消耗量均减少(P<0.01)。与模型雌鼠和雄鼠组比较,参芪解郁方、盐酸氟西汀各组的蔗糖水消耗量均增加(P<0.01)。与模型雌鼠组比较,模型雄鼠组的蔗糖水消耗量较多(P<0.01)。结果见表2

    3.4 各组雌鼠和雄鼠FST结果比较

    与正常雌鼠和雄鼠组比较,模型两组的不动时间均增加,挣扎时间均减少(P<0.01)。与模型两组比较,参芪解郁方、盐酸氟西汀各组的不动时间均减少(P<0.01);参芪解郁方、盐酸氟西汀雌鼠组的挣扎时间较模型雌鼠组增加(P<0.05)。模型雄鼠组的不动时间较模型雌鼠组短(P<0.01)。结果见表3

    表3  各组雌鼠和雄鼠FST不动时间、挣扎时间和游泳时间比较(s;x¯±sn=6)
    Table 3  Comparison of the immobility time, struggling time, and swimming time in forced swimming test of female and male rats in each group (s; x¯±s; n=6)
    组别Group剂量Dose不动时间Immobility time挣扎时间Struggling time游泳时间Swimming time
    正常雌鼠组Normal female rat group   55.30±13.23 141.62±31.46 103.08±34.21
    模型雌鼠组Model female rat group   117.73±5.86○○ 89.23±6.08○○ 93.03±9.28
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 74.10±7.91○○●● 112.72±6.20○○● 113.18±11.93
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 71.03±4.67○○●● 114.33±6.44○● 114.63±7.77
    正常雄鼠组Normal male rat group   53.92±12.81 142.70±35.56 103.38±39.23
    模型雄鼠组Model male rat group   99.47±2.73●●** 98.33±4.81** 102.20±3.58
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 61.62±6.02## 118.62±6.73* 119.77±10.94
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 63.78±6.55*## 113.28±7.58** 122.93±9.99
    F   45.063 6.657 1.543
    P   <0.001 <0.001 0.181

    注:与正常雌鼠组比较,○P<0.05,○○P<0.01;与模型雌鼠组比较,●P<0.05,●●P<0.01;与正常雄鼠组比较,*P<0.05,**P<0.01;与模型雄鼠组比较,##P<0.01。

    Note:○P<0.05, ○○P<0.01 compared with the normal female rat group; ●P<0.05, ●●P<0.01 compared with the model female rat group; *P<0.05,**P<0.01 compared with the normal male rat group; ##P<0.01 compared with the model male rat group.

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    3.5 各组雌鼠和雄鼠EPM结果比较

    模型雌鼠组进入开放臂次数比例和开放臂停留时间比例均较正常雌鼠组减少(P<0.01)。参芪解郁方和盐酸氟西汀雌鼠组、模型雄鼠组进入开放臂次数比例和开放臂停留时间比例均较模型雌鼠组升高(P<0.01)。结果见表4

    表4  各组雌鼠和雄鼠EPM进入开放臂次数比例和开放臂停留时间比例(%;x¯±sn=6)
    Table 4  The proportion of entering the open arm and time spent in the open arm in elevated plus maze of female and male rats in each group (%; x¯±s; n=6)
    组别Group剂量Dose进入开放臂次数比例Proportion of entering the open arm开放臂停留时间比例Proportion of time spent in the open arm
    正常雌鼠组Normal female rat group   40.89±1.79 44.43±3.64
    模型雌鼠组Model female rat group   32.19±1.29○○ 23.79±2.74○○
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 41.58±3.18●● 45.40±2.88●●
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 42.90±2.07●● 45.22±4.19●●
    正常雄鼠组Normal male rat group   43.60±3.98 47.77±3.15
    模型雄鼠组Model male rat group   42.28±3.42●● 46.80±2.16●●
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 44.42±2.61 46.77±2.63
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 45.44±2.14 47.38±2.32
    F   13.880 42.072
    P   <0.001 <0.001

    注:与正常雌鼠组比较,○○P<0.01;与模型雌鼠组比较,●●P<0.01。

    Note:○○P<0.01 compared with the normal female rat group; ●●P<0.01 compared with the model female rat group.

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    3.6 MRS结果

    3.6.1 各组雌鼠和雄鼠双侧海马脑代谢物的相对值比较

    模型雌鼠和雄鼠组双侧海马的NAA/Cr、Glu/Cr值均较正常组降低(P<0.01);模型雌鼠组右侧海马的Cho/Cr值较正常雌鼠组升高(P<0.05)。参芪解郁方和盐酸氟西汀雌鼠组双侧海马的NAA/Cr、Glu/Cr值较模型雌鼠组升高(P<0.01),右侧海马的Cho/Cr值较模型雌鼠组降低(P<0.05)。参芪解郁方和盐酸氟西汀雄鼠组右侧海马的NAA/Cr值和双侧海马的Glu/Cr值较模型雄鼠组升高(P<0.01),右侧海马的Cho/Cr值较模型雄鼠组降低(P<0.05)。结果见表5表6

    表5  各组雌鼠和雄鼠左侧海马脑代谢物相对值(x¯±sn=6)
    Table 5  The relative value of brain metabolites in the left hippocampus of female and male rats in each group (x¯±s; n=6)
    组别Group剂量DoseNAA/CrCho/CrGlu/CrmI/Cr
    正常雌鼠组Normal female rat group   1.86±0.19 0.87±0.16 0.81±0.06 0.53±0.07
    模型雌鼠组Model female rat group   1.26±0.15○○ 0.99±0.06 0.38±0.15○○ 0.54±0.17
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 1.77±0.18●● 0.89±0.06 0.73±0.08●● 0.57±0.09
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 1.76±0.26●● 0.86±0.08 0.74±0.08●● 0.57±0.10
    正常雄鼠组Normal male rat group   1.94±0.25 0.87±0.17 0.80±0.10 0.54±0.09
    模型雄鼠组Model male rat group   1.48±0.07** 1.01±0.27 0.47±0.15** 0.54±0.10
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 1.66±0.18 0.90±0.04 0.75±0.10## 0.56±0.16
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 1.67±0.21 0.85±0.10 0.73±0.10## 0.57±0.11
    F   7.693 1.147 13.403 0.110
    P   <0.001 0.354 <0.001 0.997

    注:与正常雌鼠组比较,○○P<0.01;与模型雌鼠组比较,●●P<0.01;与正常雄鼠组比较,**P<0.01;与模型雄鼠组比较,##P<0.01。

    Note:○○P<0.01 compared with the normal female rat group; ●●P<0.01 compared with the model female rat group;**P<0.01 compared with the normal male rat group; ##P<0.01 compared with the model male rat group.

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    表6  各组雌鼠和雄鼠右侧海马脑代谢物相对值(x¯±sn=6)
    Table 6  The relative value of brain metabolites in the right hippocampus of female and male rats in each group (x¯±s; n=6)
    组别Group剂量DoseNAA/CrCho/CrGlu/CrmI/Cr
    正常雌鼠组Normal female rat group   1.89±0.11 0.87±0.13 0.79±0.07 0.53±0.10
    模型雌鼠组Model female rat group   1.25±0.21○○ 1.03±0.14 0.44±0.17○○ 0.54±0.05
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 1.71±0.18●● 0.84±0.13 0.74±0.11●● 0.52±0.10
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 1.80±0.14●● 0.84±0.08 0.73±0.12●● 0.52±0.16
    正常雄鼠组Normal male rat group   1.92±0.24 0.87±0.13 0.80±0.12 0.54±0.14
    模型雄鼠组Model male rat group   1.26±0.12** 1.01±0.14 0.47±0.20** 0.53±0.09
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 1.82±0.22## 0.84±0.14# 0.72±0.14## 0.54±0.07
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 1.83±0.21## 0.84±0.05# 0.74±0.13## 0.55±0.13
    F   13.210 2.510 6.135 0.050
    P   <0.001 0.031 <0.001 >0.999

    注:与正常雌鼠组比较,○P<0.05,○○P<0.01;与模型雌鼠组比较,●P<0.05, ●●P<0.01;与正常雄鼠组比较,**P<0.01;与模型雄鼠组比较,#P<0.05,##P<0.01。

    Note:○P<0.05, ○○P<0.01 compared with the normal female rat group; ●P<0.05, ●●P<0.01 compared with the model female rat group;**P<0.01 compared with the normal male rat group; #P<0.05, ##P<0.01 compared with the model male rat group.

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    3.6.2 各组雌鼠和雄鼠双侧前额叶皮质脑代谢物的相对浓度比较

    模型雌鼠和雄鼠组双侧前额叶皮质的NAA/Cr、Glu/Cr值均较正常组下降(P<0.01)。参芪解郁方和盐酸氟西汀雌鼠组双侧前额叶皮质的NAA/Cr、Glu/Cr值较模型雌鼠组升高(P<0.05,P<0.01)。参芪解郁方和盐酸氟西汀雄鼠组双侧前额叶皮质的NAA/Cr值较模型雄鼠组升高(P<0.01),参芪解郁方雄鼠组右侧前额叶皮质和盐酸氟西汀雄鼠组双侧前额叶皮质的Glu/Cr值均较模型雄鼠组升高(P<0.05)。结果见表7表8

    表7  各组雌鼠和雄鼠左侧前额叶皮质脑代谢物相对值(x¯±sn=6)
    Table 7  The relative value of brain metabolites in the left prefrontal cortex of female and male rats in each group (x¯±s; n=6)
    组别Group剂量DoseNAA/CrCho/CrGlu/CrmI/Cr
    正常雌鼠组Normal female rat group   1.81±0.12 0.85±0.14 0.75±0.08 0.51±0.06
    模型雌鼠组Model female rat group   1.38±0.12○○ 0.90±0.10 0.56±0.20○○ 0.44±0.13
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 1.75±0.13●● 0.83±0.07 0.69±0.09 0.53±0.08
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 1.74±0.24●● 0.81±0.10 0.70±0.08 0.54±0.07
    正常雄鼠组Normal male rat group   1.84±0.10 0.86±0.15 0.75±0.09 0.52±0.07
    模型雄鼠组Model male rat group   1.43±0.12** 0.91±0.04 0.57±0.12** 0.49±0.07
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 1.78±0.07## 0.84±0.10 0.70±0.10 0.52±0.14
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 1.76±0.15## 0.83±0.09 0.71±0.10# 0.53±0.10
    F   9.832 0.702 2.533 0.716
    P   <0.001 0.670 0.030 0.659

    注:与正常雌鼠组比较,○○P<0.01;与模型雌鼠组比较,●P<0.05,●●P<0.01;与正常雄鼠组比较,**P<0.01;与模型雄鼠组比较,#P<0.05,##P<0.01。

    Note:○○P<0.01 compared with the normal female rat group; ●P<0.05, ●●P<0.01 compared with the model female rat group;**P<0.01 compared with the normal male rat group; #P<0.05, ##P<0.01 compared with the model male rat group.

    icon 下载:  CSV icon 下载:  表格图片
    表8  各组雌鼠和雄鼠右侧前额叶皮质脑代谢物相对值(x¯±sn=6)
    Table 8  The relative value of brain metabolites in the right prefrontal cortex of female and male rats in each group (x¯±s; n=6)
    组别Group剂量DoseNAA/CrCho/CrGlu/CrmI/Cr
    正常雌鼠组Normal female rat group   1.82±0.11 0.85±0.08 0.76±0.06 0.53±0.06
    模型雌鼠组Model female rat group   1.37±0.11○○ 0.90±0.18 0.47±0.19○○ 0.50±0.05
    参芪解郁方雌鼠组Shenqi Jieyu Formula female rat group 12.5 g/kg 1.74±0.13●● 0.83±0.10 0.70±0.07●● 0.53±0.04
    盐酸氟西汀雌鼠组Fluoxetine female rat group 2.33 mg/kg 1.75±0.10●● 0.81±0.10 0.68±0.12●● 0.51±0.08
    正常雄鼠组Normal male rat group   1.83±0.15 0.86±0.08 0.76±0.10 0.54±0.05
    模型雄鼠组Model male rat group   1.39±0.12** 0.91±0.14 0.54±0.16** 0.51±0.04
    参芪解郁方雄鼠组Shenqi Jieyu Formula male rat group 12.5 g/kg 1.75±0.17## 0.82±0.11 0.72±0.09# 0.52±0.06
    盐酸氟西汀雄鼠组Fluoxetine male rat group 2.33 mg/kg 1.78±0.13## 0.82±0.12 0.73±0.13# 0.52±0.08
    F   12.861 0.592 4.585 0.212
    P   <0.001 0.758 0.001 0.981

    注:与正常雌鼠组比较,○○P<0.01;与模型雌鼠组比较,●●P<0.01;与正常雄鼠组比较,**P<0.01;与模型雄鼠组比较,#P<0.05,##P<0.01。

    Note:○○P<0.01 compared with the normal female rat group; ●●P<0.01 compared with the model female rat group; **P<0.01 compared with the normal male rat group; #P<0.05, ##P<0.01 compared with the model male rat group.

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    4 讨论

    成年后抑郁的发生多与幼年时的不良经历相关,生命早期是大脑神经系统发育的关键时期,母婴分离作为早期应激会持续影响子代机体生长发育、认知及情绪行为[

    11],母婴分离动物模型模拟了人类在幼儿期和儿童期亲代和子代缺乏联系的养育环境,已广泛应用于早期应激对于子代影响的研究[12]

    本实验中,采用母婴分离制备大鼠模型,结果显示,母婴分离后的各组雌鼠和雄鼠均表现出行为学上的变化。母婴分离降低了子代大鼠体质量的增长速度,这与另一研究[

    13]结果一致。本研究还发现该模型子代雌鼠体质量低于雄鼠体质量。OFT中模型雌鼠和雄鼠组水平得分和垂直得分均降低,说明母婴分离后的子代大鼠对周围环境的探索减少;蔗糖水消耗量减少,表明大鼠对奖赏的快感缺乏,而抑郁症的核心症状之一即是快感缺失;FST不动时间增加、挣扎时间减少,说明母婴分离后诱发出大鼠的绝望行为,且雌鼠的不动时间较雄鼠更长,说明母婴分离后雌性大鼠对精神疾病更具易感性[14];EPM进入开放臂的时间和探索开放臂的次数均减少,说明模型组大鼠的焦虑水平较正常组升高。行为学结果说明模型制备成功,母婴分离大鼠子代成年后均出现了抑郁样行为,在一定程度上还伴有焦虑表现,且子代雌性更易诱发精神疾病。母鼠在哺乳期经参芪解郁方干预后,其子代大鼠在行为学上有所改善,可以缓解仔鼠的抑郁、焦虑情绪,减轻早期应激对仔鼠神经系统发育的不良影响。

    Papez环路和情感体验与情感表达密切相关[

    15]。环路中的海马具有情绪调控、记忆存储等重要功能,前额叶皮质内有许多传入、传出纤维与Papez环路相联系,参与Papez环路相关脑区的情感传导,而其在发育早期极易受到不良刺激的影响[16]。有研究发现,经历早期应激后的子代存在海马和前额叶皮质区神经元的损伤[17]。MRS能够在早期观察脑区神经代谢物含量的变化,一般检测的脑组织代谢物主要包括NAA、Cr、Cho、Glu、mI等。Cr在各种病理状态下的含量相对稳定,常作为参考值来对比其他脑内代谢物的变化。

    本实验中,对母婴分离子代成年后大鼠的海马和前额叶皮质进行MRS检测。结果显示,模型雌鼠和雄鼠组双侧海马和前额叶皮质的NAA/Cr、Glu/Cr值降低,模型雌鼠组右侧海马Cho/Cr值升高。NAA主要存在于神经元,是神经元密度及活力的测量指标,其降低提示模型雌鼠和雄鼠组的神经元完整性遭到破坏[

    18],从而导致神经环路信号传递受损,诱发抑郁。Glu是脑内重要的兴奋性神经递质,其含量变化可反映星形胶质细胞和谷氨酸能神经元的功能[19],Glu/Cr值的降低说明模型雌鼠和雄鼠组脑内星形胶质细胞完整性受损,导致谷氨酸代谢紊乱,以及神经元功能的异常,使其调节情绪的功能失衡,这与其他研究[20-21]结果相似。Cho是细胞膜磷脂代谢状态的潜在生物标志物,模型雌鼠组右侧海马Cho/Cr值升高,而左侧海马未见明显异常,这可能与检测的脑区不同有关,既往研究[22]也有类似发现。右侧海马Cho/Cr值升高说明右侧海马的细胞更新及细胞内信号转导功能异常,且可能存在左右半球不同等的变化。研究发现,抑郁患者前额叶皮质Cho/Cr值存在高低不同的变化[23],这可能与患者年龄、经历不同有关。本研究中模型雌鼠和雄鼠组双侧前额叶皮质Cho/Cr值未见明显异常,这提示早期的不良刺激可能导致了前额叶皮质的低反应性,使其应激反应被抑制[24],其机制有待进一步研究探索。mI由神经胶质细胞产生,参与细胞膜磷脂代谢过程,可调节细胞渗透压、营养细胞,mI的代谢水平和抑郁严重程度存在着相关性[23],各组雌鼠和雄鼠双侧海马和前额叶皮质的mI/Cr值差异无统计学意义,这可能与子代大鼠处于成年后抑郁早期相关,本研究认为mI/Cr值对预测母婴分离大鼠子代成年后抑郁的易感性无明确相关性。结果显示,应用参芪解郁方的母鼠组,子代雌鼠和雄鼠的海马和前额叶皮质区脑代谢异常得到改善,可使降低的NAA/Cr及Glu/Cr值恢复至接近正常水平,使右侧海马异常的Cho/Cr值下降。说明参芪解郁方可调节海马和前额叶皮质的神经元损伤,促进神经元修复,减少焦虑、抑郁带来的不良反应。

    参芪解郁方是唐启盛教授基于多年临床经验,根据产后“多虚多瘀”的特点,结合黄元御“枢轴理论”拟定而成[

    25],本方以补益心脾、调气祛瘀、颐脑醒神为治法,药以黄芪、党参补脾益气,共为君药;陈皮、佛手理气健脾,共为臣药;当归、山萸肉补益精血,郁金解郁凉血,酸枣仁养心安神,伍为佐使,全方共奏补益心脾、解郁安神之效。临床观察发现,参芪解郁方能改善产后抑郁症患者抑郁症状[26]。课题组前期研究表明,参芪解郁方能有效调节神经-内分泌-免疫网络及Papez环路相关脑区功能[6,9,27-30]。网络药理学研究发现,参芪解郁方可通过多个通路抑制细胞凋亡,减轻神经元损害,并可调节脑内神经递质[31]。本研究从母婴分离大鼠子代成年后脑代谢物的角度出发,发现母鼠哺乳期应用参芪解郁方,可通过乳汁对子代大鼠起到治疗作用,能有效减轻母婴分离早期应激造成的机体发育迟缓和抑郁易感性,并能对子代Papez环路相关脑区海马和前额叶皮质起到神经保护和修复作用。

    综上所述,母婴分离大鼠子代成年后具有较高的抑郁易感性,雌性大鼠更易受到早期应激的不良影响,且子代大鼠Papez环路相关脑区海马和前额叶皮质区存在神经元完整性损伤、谷氨酸代谢紊乱等病理过程。参芪解郁方可促进Papez环路相关脑区的神经元修复,调节神经的兴奋性,改善情感环路的功能完整性,缓解抑郁、焦虑的反应。

    利益冲突

    Conflicts of interest: None of the authors have any conflicts of interest associated with this study, and all the authors have read and approved this manuscript.

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