目的 观察不同慢性束缚方案与青春期小鼠抑郁行为及学习记忆能力的相关性,探讨瘦素对慢性束缚应激造成的情绪障碍和学习记忆的影响及相关受体机制。方法 选取出生后3~4周龄健康雄性C57小鼠70只,连续10d低强度(2h)/高强度(4h)束缚应激,筛选理想的束缚模型,腹腔注射瘦素(LP),矿场实验(OFT)观察小鼠抑郁行为,Morris水迷宫检测小鼠的学习记忆能力,酶联免疫法检测血清LP水平,Western blotting实验检测海马和内侧前额叶皮层(mPFC) N-甲基D-天冬氨酸受体1(NMDAR1)和γ氨基丁酸受体(GABAR)的表达。结果 OFT实验中,高强度束缚(HCRS)组小鼠的中央区停留时间低于对照组[HCRS组:(95.2±17.3)s,对照组:(157.1±25.5)s,P<0.01]。HCRS+盐水组小鼠的中央区停留时间低于假手术组(分别为97.7±25.1和148.6±24.8;P<0.01),HCRS+高浓度LP(H-LP,0.05mg/kg)组小鼠在中央区停留时间与假手术组小鼠接近。Morris水迷宫定位航行实验中,HCRS小鼠在四个象限的逃避潜伏期均低于对照组,HCRS+H-LP小鼠与假手术小鼠差异无统计学意义。Morris水迷宫空间探索实验的平均穿越站台次数,HCRS小鼠低于对照组(HCRS组:2.1±0.9, 对照组:4.2±1.9;P<0.05),HCRS+H-LP小鼠与sham小鼠差异无统计学意义。血清LP水平检测显示,HCRS组(4.2±1.3)低于对照组(10.4±2.9;P<0.01),HCRS+ H-LP组与假手术组差异无统计学意义。蛋白质印迹法结果显示,HCRS组小鼠的mPFC NMDR1表达水平低于对照组。应用高浓度LP后NMDR1表达水平接近正常水平。结论 HCRS可以造成青春期小鼠的情绪和学习记忆障碍,全身慢性应用高浓度LP能够改善HCRS导致的青春期小鼠抑郁样行为和学习记忆障碍,这可能与瘦素抑制mPFC NMDAR1表达水平降低有关。
Abstract
Objective To analyze the correlation of different chronic restrained programs with depressive behavior and learning and memory ability in adolescent mice, in order to discuss the effects of leptin (LP) on depression, learning and memory disorders induced by chronic restrained stress, and its related receptor mechanism. Methods Totally 70 healthy male C57 mice aged 3 to 4 weeks after birth were subjected to low-intensity (2h)/high-intensity (4h) chronic restrained stress for 10 consecutive days. Then the ideal bondage model was chosen. LP was injected intraperitoneally, and the depressive behavior of the mice was observed by open field test (OFT). Morris water maze was used to detect their learning and memory abilities. ELISA was used to determine the expression of serum LP. The expression of NMDAR1 and GABAR in the hippocampus and medial prefrontal cortex (mPFC) was detected by Western blotting. Results In OFT, the residence time in the central region of HCRS mice was significantly lower than that in control group[HCRS:(95.2±17.3)s, control:(157.1±25.5)s, P<0.01], which in HCRS + saline group was significantly lower than that of sham group[(97.7±25.1)s vs. (148.6±24.8)s, P<0.01]. The central area residence time of HCRS + H-LP group was close to that of sham group. In the navigation experiment of Morris water maze, the escape latency of HCRS mice in four quadrants was lower than that of control group, which had no statistical difference between HCRS+H-LP and sham mice. The average number of station crossings in Morris water maze was lower in HCRS group than that of control group (HCRS: 2.1±0.9, control: 4.2±1.9, P<0.05), and there was no statistical difference between HCRS+H-LP and sham group. Serum LP level in HCRS group (4.2±1.3) was significantly lower than that in control group (10.4±2.9, P<0.01), and there was no statistical difference between the HCRS+H-LP and sham group. The expression level of NMDR1 in mPFC in HCRS group was significantly lower than that in control group. After high LP injection, the expression level of NMDR1 was close to normal group. Conclusions High chronic restrained stress can cause mood, learning and memory disorders in adolescent mice. Chronic systemic application of high concentration LP can improve these disorders, which may be related to the decreased expression level of NMDAR1 in mPFC.
关键词
抑郁 /
学习记忆 /
瘦素 /
慢性束缚应激
Key words
depression /
learning and memory /
leptin /
chronic restrained stress
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Barha CK, Brummelte S, Lieblich SE, et al. Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats[J]. Hippocampus, 2011, 21(11):1216-1227.
[2] 刘子钰,邓格,王菲迪,等. 慢性束缚应激对小鼠痛经的影响[J]. 国外医学(医学地理分册), 2019,40(2):124-125.
Liu ZY, Deng G, Wang FD, et al. Effect of chronic restraint stress on dysmenorrhea in mice [J]. Foreign Medicine (Medical Geography), 2019,40(2):124-125.(in Chinese)
[3] Watanabe T, Sakamoto K. Meta-analysis of cognitive and behavioral tests in leptin- and leptin receptor-deficient mice [J]. Neuroscience Research, 2021, 170:217-235.
[4] 陈璐,拓明花,胡金萍,等. 瘦素与产后抑郁症状的相关性研究[J]. 中国神经精神疾病杂志, 2019,45(6):340-345.
Chen L,Tuo MH, Hu JP, et al. Study on the correlation between leptin and postpartum depression [J]. Chinese Journal of Neuropsychiatric Diseases, 2019,45(6):340-345.(in Chinese)
[5] Ur E, Wilkinson DA, Morash BA, et al. Leptin immunoreactivity is localized to neurons in rat brain [J]. Neuroendocrinology, 2002, 75:264-272.
[6] Li XL,Aou S,Oomura Y,et al. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents [J]. Neuroscience, 2002, 113(3):607-615.
[7] Esteban M, Danae RS, Vicent TM, et al. Effects of acute stress on the oscillatory activity of the hippocampus-amygdala-prefrontal cortex network [J]. Neuroscience, 2021, 476:72-89.
[8] Waltrick A, Silva A, Carvalho M, et al. Preventive treatment with fish oil facilitates the antidepressant-like effect of antidepressant drugs in type-1 diabetes mellitus rats:Implication of serotonergic system[J]. Neuroscience Letters, 2022, 772:136477.
[9] Zhao J, Jung YH, Jin Y, et al. A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression [J]. Scientific Reports,2019, 9:7566.
[10] Lissner LJ, Wartchow KM, Toniazzo AP, et al. Object recognition and Morris water maze to detect cognitive impairment from mild hippocampal damage in rats:A reflection based on the literature and experience[J]. Pharmacology Biochemistry and Behavior, 2021, 210:173273.
[11] Aspesi D, Pinna G. Animal models of post-traumatic stress disorder and novel treatment targets [J]. Behav Pharmacol, 2019,30(2-3):130-150.
[12] Eiland L, Ramroop J, Hill MN. Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats [J]. Psychoneuroendocrinology, 2012,37(1):39-47.
[13] Sufyan A, Rishikesh N. Stores, channels, glue, and trees:Active glial and active dendritic physiology [J]. Molecular Neurobiology, 2019, 56:2278-2299.
[14] Yoshida-Komiya H,Takano K,Fujimori K, et al. Plasma levels of leptin in reproductive-aged women with mild depressive and anxious states [J]. Psychiatry Clin Neurosci, 2014,68(7):574-581.
[15] 王盛花,贾雪梅,柯红林,等. 瘦素在大鼠学习记忆中枢的分布[J]. 安徽医科大学学报, 2005,40(2):108-110.
Wang SH,Jia XM, Ke HL, et al. Distribution of leptin in the learning and memory centers of rats [J]. Journal of Anhui Medical University, 2005,40(2):108-110.(in Chinese)
[16] 王怀志, 胡建. 血清瘦素与酒精依赖患者认知功能的关系[J]. 神经疾病与精神卫生, 2019, 19(2):4-5.
Wang HuZ, Hu J. The relationship between serum leptin and cognitive function of alcohol dependent patients [J]. Neuropathy and Mental Health, 2019, 19(2):4-5.(in Chinese)
基金
陕西省自然科学基金(2020JM-054);陕西省软科学研究计划项目(2020KRM060)
PDF(1128 KB)
