目的 探讨大鼠生命早期母婴分离对成年期异常行为、情绪问题及体内催产素及相关分子表达的影响。方法 将新生SD大鼠随机分为对照组和新生期母婴分离组(NMS组),NMS 组新生鼠生后第 1~14 天每天与母鼠分离2 h,6周龄进行行为学测试,包括旷场测试、三厢社交测试、高架十字迷宫和强迫游泳测试。Western blot方法检测大鼠下丘脑组织CD38蛋白表达水平,ELISA检测大鼠血清OXT水平。结果 与对照组相比,NMS大鼠成年后自身梳理时间[(29.19±3.55)s,(55.90±4.03)s,P<0.001]和次数(6.67±0.74,9.53±0.73,P<0.05)均显著增加,提示刻板行为增加;与同伴互动时间减少[(350.40±41.25)s,(260.30±33.43)s, P<0.05],提示社交功能受损;对新环境的探索时长[高架开放臂:(78.15±20.95)s vs.(36.45±5.35)s,P<0.05;旷场中央区:(153.70±34.41)s vs.(13.84±4.80)s,P<0.01]减短、排便次数增多(1.72±0.24,3.25±0.26,P<0.001),提示焦虑样行为增加;强迫游泳试验中首次不动潜伏期缩短[(59.02±8.64)s,(33.97±5.87)s,P<0.05],提示抑郁样行为加重。此外,NMS大鼠下丘脑CD38蛋白表达水平(P<0.01)、血清OXT含量(P<0.05)明显降低。结论 1)生命早期母婴分离可能导致大鼠成年后出现孤独症样行为,焦虑、抑郁样行为。2)母婴分离可能通过降低大鼠下丘脑组织中CD38蛋白表达,进一步引起OXT释放减少,导致相关行为异常。
Abstract
Objective To investigate the effects of neonatal maternal separation on behavior and mental problems in rat,and to explore the effects of maternal separation on oxytocin and related molecules expression and neurodevelopment in rats. Methods Neonatal SD rats were randomly divided into control group and neonatal maternal separation group(NMS group). Rats in NMS group were separated from their mothers for 2 hours from 1 to 14 days after birth. Behavioral tests were performed at the age of 6 weeks old,including open-field tests,three-chambered tests,elevated-plus maze and forced-swimming tests. The expression of CD38 protein in rat hypothalamus was detected by Western blot. The serum OXT level was detected by ELISA. Results In the NMS rats,the time[control vs. NMS:(29. 19±3. 55)s,(55. 90±4. 03)s,P<0. 001]and frequency of self-grooming(6. 67±0. 74 vs. 9. 53±0. 73,P<0. 05) increased significantly,suggesting an increase of stereotyped behavior. And the interaction time with unfamiliar rats was decreased [(350. 40±41. 25)s,(260. 30±33. 43)s,P<0. 05],suggesting that social function of NMS rats was impaired; the decreased time spent in open-arms [(78. 15±20. 95)s vs. (36. 45±5. 35)s,P<0. 05] of elevated-plus-maze in the central area of the open-field [(153. 7±34. 41)s vs. (13. 84±4. 80)s,P<0. 01)] and the increasing frequency of defecation(1. 72±0. 24,3. 25±0. 26,P<0. 001)suggesting the increased anxiety-like behavior of rats; the immobility latency[(59. 02±8. 64)s,(33. 97±5. 87)s,P<0. 05]and the shortened total struggling time in the forced swimming test,suggesting the depressive behavior of NMS rats. In addition,the expression of hypothalamic CD38(P＜0. 01) protein and the serum OXT level(P＜0. 05) were significantly lower in NMS rats. Conclusions 1) Maternal and child isolation in early life may lead to autism-like behavior,anxiety and depression-like behavior in adult rats. 2) Maternal-infant separation may reduce the release of OXT by reducing the expression of CD38 protein in hypothalami,thereby leading to abnormal behaviors.
关键词
新生期母婴分离 /
行为学 /
催产素 /
CD38
Key words
neonatal maternal separation /
behavior development /
oxytocin /
CD38
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] 李亚菲,鲁利群.母爱剥夺与神经行为发育[J].成都医学院学报,2014,9(4):489-492.
[2] 凌辉,张建人,易艳,等.分离年龄和留守时间对留守儿童行为和情绪问题的影响[J].中国临床心理学杂志,2012,20(5):674-678.
[3] 张宇翔,刘建鹏,陈佳欣,等.母婴分离动物研究及其进展[J].海南医学,2017,28(6):943-946.
[4] Odeon MM,Acosta GB.Repeated maternal separation:alcohol consumption,anxious behavior and corticosterone were reversed by a non-pharmacological treatment[J].Prog Neuropsychopharmacol Biol Psychiatry,2019,95:109726.
[5] Jaimes-Hoy L,Romero F,Charli JL,et al.Sex dimorphic responses of the hypothalamus-pituitary-thyroid axis to maternal separation and palatable diet[J].Front Endocrinol (Lausanne),2019,10:445.
[6] 孙鸿燕,朱小霞,董文斌,等.新生期母婴分离对大鼠成年后行为的影响及机制[J].中国妇幼保健,2011,26(19):2984-2986.
[7] Carter CS.Oxytocin pathways and the evolution of human behavior[J].Annu Rev Psychol,2014,65:17-39.
[8] 刘金婷,蔡强,王若菡,等.催产素与人类社会行为[J].心理科学进展,2011,19(10):1480-1492.
[9] Insel TR,Young LJ.The neurobiology of attachment [J].Nat Rev Neurosci,2001,2(2):129-136.
[10] Nelson EE,Panksepp J.Brain substrates of infant-mother attachment:contributions of opioids,oxytocin,and norepinephrine[J].Neurosci Biobehav Rev,1998,22(3):437-452.
[11] Lai X,Wu X,Hou N,et al.Vitamin A deficiency induces autistic-like behaviors in rats by regulating the RARβ-CD38-oxytocin axis in the hypothalamus[J].Mol Nutr Food Res,2018,3:62-65.
[12] 全国妇联课题组.全国农村留守儿童城乡流动儿童状况研究报告[J].中国妇运,2013,6:30-34.
[13] 邬志辉,李静美.农村留守儿童生存现状调查报告[J].中国农业大学学报:社会科学版,2015,32(1):65-74.
[14] Silveira PP,Portella AK,Goldani MZ,et al.Developmental origins of health and disease (DOHaD) [J].J Pediatr (Rio J),2007,83(6):494-504.
[15] Baird J,Jacob C,Barker M,et al.Developmental origins of health and disease:a lifecourse approach to the prevention of non-communicable diseases[J].Healthcare (Basel),2017,5(1):14.
[16] Hanson MA,Gluckman PD.Early developmental conditioning of later health and disease:physiology or pathophysiology[J].Physiol Rev,2014,94(4):1027-1076.
[17] 李凤莲.关于儿童依恋的研究综述[D].长春:东北师范大学,2008.
[18] 江雪华,张敏,陆大祥,等.早期剥夺所致大鼠抑郁样行为与海马BDNF mRNA表达变化[J].心理学报,2010,42(6):695-703.
[19] 薛晓芳,李曼,王玮文,等.母婴分离的动物模型及其神经生物学机制[J].心理科学进展,2013,21(6):990-998.
[20] Aguggia JP,Suárez MM,Rivarola MA.Multiparity dampened the neurobehavioral consequences of mother-pup separation stress in dams[J].Neuroscience,2019,8(1):416.
[21] Lee Y,Han PL.Early-life stress in D2 heterozygous mice promotes autistic-like behaviors through the downregulation of the BDNF-TrkB pathway in the dorsal striatum[J].Exp Neurobiol,2019,28(3):337-351.
[22] 朱熊兆,彭素芳,马秀玲,等.母爱剥夺对成年大鼠情绪及多巴胺转运蛋白基因表达的影响[J].中南大学学报:医学版,2010,35(1):32-37.
[23] Saavedra LM,Fenton Navarro B,Torner L.Early life stress activates glial cells in the hippocampus but attenuates cytokine secretion in response to an immune challenge in rat pups[J].Neuroimmunomodulation,2018,24(4-5):242-255.
[24] Neumann ID,Landgraf R.Balance of brain oxytocin and vasopressin:implications for anxiety,depression,and social behaviors[J].Trends Neurosci,2012,35(11):649-659.
[25] Insel TR,Winslow JT.Central administration of oxytocin modulates the infant rat's response to social isolation[J].Eur J Pharmacol,1991,203(1):149-152.
[26] Jin D,Liu HX,Hirai H,et al.CD38 is critical for social behaviour by regulating oxytocin secretion[J].Nature,2007,446(7131):41-45.
[27] Lamkin TJ,Chin V,Varvayanis S,et al.Retinoic acid-induced CD38 expression in HL-60 myeloblastic leukemia cells regulates cell differentiation or viability depending on expression levels[J].J Cell Biochem,2006,97(6):1328-1338.
[28] Boku S,Toda H,Nakagawa S,et al.Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic Acid receptor gene promoter[J].Biol Psychiatry,2015,77(4):335-344.
[29] 吉园依,张宇,殷菲,等.四川省农村留守儿童抑郁症状及其与自尊及社会支持的关系研究[J].现代预防医学,2017,44(2):239-242.
基金
国家自然科学基金(81771223,81770526);重庆市研究生科研创新项目(CYB 17107)
PDF(1540 KB)
