环境富集对哺乳期母子分离子代行为异常的缓解及其分子机制研究进展

doi:10.11843/j.issn.0366-6964.2025.04.006

摘要/Abstract

摘要：

不良的早期生命经历影响发育中的神经系统，并塑造子代成年后的社会行为模式。母子分离是哺乳期子代常面临的早期生命应激，对其心理和生理发育产生持久影响，能够导致子代神经内分泌系统紊乱，并增加子代成年后异常行为和患精神疾病的风险。环境富集是用于改善圈养动物生活质量，激发动物情感表达，逆转早期应激动物神经损伤或行为异常的治疗策略。早期逆境引起的子代行为可塑性变化可以在生命后期(青春期或成年期)通过环境富集干预来恢复，其中，神经生物学变化和表观遗传修饰是环境富集逆转早期应激子代行为异常的主要分子机制。因此，本文综述了母子分离引起子代行为异常的表现，环境富集缓解母子分离子代行为异常的效应以及参与调控环境富集效应的分子机制。以期为早期生命应激子代行为异常提供有效的干预策略，也为圈养动物福利水平改善提供科学依据。

关键词: 母子分离, 行为异常, 环境富集, 逆转效应, 分子机制

Abstract:

Adverse early life experiences affect the developing nervous system, and shape the offspring's adult social behavior pattern. Maternal separation is an early life stress that lactating offspring often face, which has a lasting impact on their psychological and physiological development and can lead to neuroendocrine system disorders in offspring, and increases the risk of abnormal behavior and mental illness in the offspring's adult. Environmental enrichment is a therapeutic strategy used to improve the quality of life of captive animals, stimulate animal emotional expression, and reverse neurological damage or behavioral abnormalities in early stressed animals. The behavioral plasticity of offspring induced by early stress can be restored by environmental enrichment intervention in later life (adolescence or adulthood). Neurobiological changes and epigenetic modification are the main molecular mechanisms by which environmental enrichment reverses the abnormal behavior of early stressed offspring. Therefore, this paper reviews the abnormal behavior of offspring caused by maternal separation, the effects of environmental enrichment on alleviating the abnormal behavior of maternal separation, and the molecular mechanisms involved in regulating environmental enrichment effects. In order to provide effective intervention strategies for early life stress offspring abnormal behavior, and provide scientific basis for improving the welfare level of captive animals.

Key words: maternal separation, abnormal behavior, environmental enrichment, reversal effect, molecular mechanism

中图分类号:

S811.8

王慧, 王悦尚, 胡希怡, 韩成全, 李富宽, 杨燕, 吕慎金. 环境富集对哺乳期母子分离子代行为异常的缓解及其分子机制研究进展[J]. 畜牧兽医学报, 2025, 56(4): 1527-1539.

WANG Hui, WANG Yueshang, HU Xiyi, HAN Chengquan, LI Fukuan, YANG Yan, LÜ Shenjin. Reversal Effect of Environmental Enrichment on Behavioral Abnormalities in Lactation Maternal Separation Offspring and Its Molecular Mechanism[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(4): 1527-1539.

图/表 1

参考文献 135

1	贾蕊. 发育早期社会环境对棕色田鼠情绪和社会行为的作用及机制研究[D]. 西安: 陕西师范大学, 2009.
	JIA R. Effects and mechanisms of social environment in early development on emotion and social behavior of brown vole[D]. Xi'an: Shaanxi Normal University, 2009. (in Chinese)
2	LAUTARESCUA,CRAIGM C,GLOVERV.Prenatal stress: effects on fetal and child brain development[J].Int Rev Neurobiol,2020,150,17-40.
3	GIMSAU,BRÜCKMANNR,TUCHSCHERERA,et al.Early-life maternal deprivation affects the mother-offspring relationship in domestic pigs, as well as the neuroendocrine development and coping behavior of piglets[J].Front Behav Neurosci,2022,16,980350. doi: 10.3389/fnbeh.2022.980350
4	FRANCISD,DIORIOJ,LIUD,et al.Nongenomic transmission across generations of maternal behavior and stress responses in the rat[J].Science,1999,286(5442):1155-1158. doi: 10.1126/science.286.5442.1155
5	KOCHH,MCCORMACKK,SANCHEZM M,et al.The development of the hypothalamic-pituitary-adrenal axis in rhesus monkeys: effects of age, sex, and early experience[J].Dev Psychobiol,2014,56(1):86-95. doi: 10.1002/dev.21093
6	CHAMPAGNEF A,CURLEYJ P.How social experiences influence the brain[J].Curr Opin Neurobiol,2005,15(6):704-709. doi: 10.1016/j.conb.2005.10.001
7	MAESTRIPIERID.Parenting styles of abusive mothers in group-living rhesus macaques[J].Anim Behav,1998,55(1):1-11. doi: 10.1006/anbe.1997.0578
8	AČG ATERM,MAJDI AČGG.How early maternal deprivation changes the brain and behavior?[J].Eur J Neurosci,2022,55(9-10):2058-2075. doi: 10.1111/ejn.15238
9	KIME G,CHANGW,SHINS,et al.Maternal separation in mice leads to anxiety-like/aggressive behavior and increases immunoreactivity for glutamic acid decarboxylase and parvalbumin in the adolescence ventral hippocampus[J].Korean J Physiol Pharmacol,2023,27(1):113-125. doi: 10.4196/kjpp.2023.27.1.113
10	CIRULLIF,BERRYA,ALLEVAE.Early disruption of the mother-infant relationship: effects on brain plasticity and implications for psychopathology[J].Neurosci Biobehav Rev,2003,27(1-2):73-82. doi: 10.1016/S0149-7634(03)00010-1
11	WEAVERI C G,CERVONIN,CHAMPAGNEF A,et al.Epigenetic programming by maternal behavior[J].Nat Neurosci,2004,7(8):847-854. doi: 10.1038/nn1276
12	胡希怡,王慧,李富宽,等.肠道菌群调控母幼分离子代行为异常的研究进展[J].畜牧兽医学报,2023,54(11):4514-4525. doi: 10.11843/j.issn.0366-6964.2023.11.008
	HUX Y,WANGH,LIF K,et al.Research progress on the regulation of intestinal flora on abnormal behavior of maternal separation in offspring[J].Acta Veterinaria et Zootechnica Sinica,2023,54(11):4514-4525. doi: 10.11843/j.issn.0366-6964.2023.11.008
13	KESSLERR C,MCLAUGHLINK A,GREENJ G,et al.Childhood adversities and adult psychopathology in the WHO world mental health surveys[J].Br J Psychiatry,2010,197(5):378-385. doi: 10.1192/bjp.bp.110.080499
14	GREENJ G,MCLAUGHLINK A,BERGLUNDP A,et al.Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders[J].Arch Gen Psychiatry,2010,67(2):113-123. doi: 10.1001/archgenpsychiatry.2009.186
15	MCLAUGHLINK A,GREENJ G,GRUBERM J,et al.Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents[J].Arch Gen Psychiatry,2012,69(11):1151-1160. doi: 10.1001/archgenpsychiatry.2011.2277
16	TEICHERM H,GORDONJ B,NEMEROFFC B.Recognizing the importance of childhood maltreatment as a critical factor in psychiatric diagnoses, treatment, research, prevention, and education[J].Mol Psychiatry,2021,27(3):1331-1338.
17	HUGHESK,BELLISM A,HARDCASTLEK A,et al.The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis[J].Lancet Public Health,2017,2(8):e356-e366. doi: 10.1016/S2468-2667(17)30118-4
18	HANC Q,LIM,LIF K,et al.Temporary sensory separation of lamb groups from ewes affects behaviors and serum levels of stress-related indicators of small-tailed Han lambs[J].Physiol Behav,2024,277,114504. doi: 10.1016/j.physbeh.2024.114504
19	TOINONC,WAIBLINGERS,PALMER,et al.Long-term effects of early maternal deprivation on goat social behaviour[J].Animal,2023,17(5):100814. doi: 10.1016/j.animal.2023.100814
20	BROOMD M.Broom and Fraser's domestic animal behaviour and welfare[M].6th ed. Wallingford:CABI,2022.
21	CHENGZ,ZHOUS T,ZHANGX H,et al.Effects of early intermittent maternal separation on behavior, physiological, and growth performance in piglets[J].J Anim Sci,2023,101,skad122. doi: 10.1093/jas/skad122
22	BARNARDS,MATTHEWSL R,MESSORIS,et al.Behavioural reactivity of ewes and lambs during partial and total social isolation[J].Appl Anim Behav Sci,2015,163,89-97. doi: 10.1016/j.applanim.2014.11.016
23	WEARICK-SILVAL E,MARSHALLP,VIOLAT W,et al.Running during adolescence rescues a maternal separation-induced memory impairment in female mice: potential role of differential exon-specific BDNF expression[J].Dev Psychobiol,2017,59(2):268-274. doi: 10.1002/dev.21487
24	HANY,ZHANGL J,WANGQ Z,et al.Minocycline inhibits microglial activation and alleviates depressive-like behaviors in male adolescent mice subjected to maternal separation[J].Psychoneuroendocrinology,2019,107,37-45.
25	AMBESKOVICM,ROSEBOOMT J,METZG A S.Transgenerational effects of early environmental insults on aging and disease incidence[J].Neurosci Biobehav Rev,2020,117,297-316. doi: 10.1016/j.neubiorev.2017.08.002
26	LARRONDOC,ORIHUELAA,STRAPPINIA,et al.Provision of straw and the presence of undocked lambs reduce the behavioural and physiological expressions of pain and stress associated with tail docking in lambs: a preliminary study[J].Anim Prod Sci,2021,61(4):423-431. doi: 10.1071/AN20237
27	ORIHUELAA,MOTA-ROJASD,VELARDEA,et al.Environmental enrichment to improve behaviour in farm animals[J].CAB Rev,2018,13,1-25.
28	张倩,崔燕,余四九,等.初生及成年牦牛大脑皮质的转录组分析[J].畜牧兽医学报,2023,54(11):4605-4614. doi: 10.11843/j.issn.0366-6964.2023.11.016
	ZHANGQ,CUIY,YUS J,et al.Transcriptome analysis of the cerebral cortex in newborn and adult yaks (Bos grunniens)[J].Acta Veterinaria et Zootechnica Sinica,2023,54(11):4605-4614. doi: 10.11843/j.issn.0366-6964.2023.11.016
29	MENEZESJ,SOUTO DAS NEVESB H,GONÇALVESR,et al.Maternal deprivation impairs memory and cognitive flexibility, effect that is avoided by environmental enrichment[J].Behav Brain Res,2020,381,112468. doi: 10.1016/j.bbr.2020.112468
30	ZHANGW J,ZHANGY L,ZHENGY J,et al.Progress in research on brain development and function of mice during weaning[J].Curr Protein Pept Sci,2019,20(7):705-712. doi: 10.2174/1389203720666190125095819
31	GERRITSENR,SOEDEN M,LANGENDIJKP,et al.The intermittent suckling regimen in pigs: consequences for reproductive performance of sows[J].Reprod Domest Anim,2008,43(Suppl 5):29-35.
32	VANDAELEM,VAN KERSCHAVERC,DEGROOTEJ,et al.Piglet performance and colostrum intake in litters either or not split-suckled during the first day or during the first three days of life[J].Livest Sci,2020,241,104265. doi: 10.1016/j.livsci.2020.104265
33	BERKEVELDM,LANGENDIJKP,BOLHUISJ E,et al.Intermittent suckling during an extended lactation period: effects on piglet behavior[J].J Anim Sci,2007,85(12):3415-3424. doi: 10.2527/jas.2007-0223
34	WEARYD M,APPLEBYM C,FRASERD.Responses of piglets to early separation from the sow[J].Appl Anim Behav Sci,1999,63(4):289-300. doi: 10.1016/S0168-1591(99)00021-0
35	TURPIND L,LANGENDIJKP,CHENT Y,et al.Intermittent suckling causes a transient increase in cortisol that does not appear to compromise selected measures of piglet welfare and stress[J].Animals,2016,6(3):24. doi: 10.3390/ani6030024
36	MORAP,MOTAD,ARCH-TIRADOE,et al.Behavior of lambs at different ages during brief periods of increased sensorial isolation from their mothers[J].J Vet Behav,2017,22,29-34. doi: 10.1016/j.jveb.2017.09.004
37	HOFFMANR M,KRONFELDD S,HOLLANDJ L,et al.Preweaning diet and stall weaning method influences on stress response in foals[J].J Anim Sci,1995,73(10):2922-2930. doi: 10.2527/1995.73102922x
38	ERBERR,WULFM,ROSE-MEIERHÖFERS,et al.Behavioral and physiological responses of young horses to different weaning protocols: a pilot study[J].Stress,2012,15(2):184-194. doi: 10.3109/10253890.2011.606855
39	HENRYS,SIGURJÓNSDÓTTIRH,KLAPPERA,et al.Domestic foal weaning: need for re-thinking breeding practices?[J].Animals,2020,10(2):361. doi: 10.3390/ani10020361
40	STěHULOVÁI,LIDFORSL,ŠPINKAM.Response of dairy cows and calves to early separation: effect of calf age and visual and auditory contact after separation[J].Appl Anim Behav Sci,2008,110(1-2):144-165. doi: 10.1016/j.applanim.2007.03.028
41	SANTON K,KÖNIG VON BORSTELU,SIROVNIKJ.The influence of maternal contact on activity, emotionality and social competence in young dairy calves[J].J Dairy Res,2020,87(S1):138-143. doi: 10.1017/S0022029920000527
42	PÉREZL I,ORIHUELAA,GALINAC S,et al.Effect of different periods of maternal deprivation on behavioral and cortisol responses at weaning and subsequent growth rate in zebu (Bos indicus) type cattle[J].Livest Sci,2017,197,17-21. doi: 10.1016/j.livsci.2016.12.006
43	BIEBERA,WALKENHORSTM,EPPENSTEINR,et al.Effects of twice a day teat bucket feeding compared to twice a day mother suckling on behaviour, health traits and blood immune parameters in dairy calves and immune parameters in cow's milk[J].Appl Anim Behav Sci,2022,252,105644. doi: 10.1016/j.applanim.2022.105644
44	GETHINJ A,LYTHEK E,WORKMANC I,et al.Early life stress explains reduced positive memory biases in remitted depression[J].Eur Psychiatry,2017,45,59-64. doi: 10.1016/j.eurpsy.2017.06.011
45	GOMESF V,ZHUX Y,GRACEA A.Stress during critical periods of development and risk for schizophrenia[J].Schizophr Res,2019,213,107-113. doi: 10.1016/j.schres.2019.01.030
46	TAYLORS E,WAYB M,SEEMANT E.Early adversity and adult health outcomes[J].Dev Psychopathol,2011,23(3):939-954. doi: 10.1017/S0954579411000411
47	SÁNCHEZM M,LADDC O,PLOTSKYP M.Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models[J].Dev Psychopathol,2001,13(3):419-449. doi: 10.1017/S0954579401003029
48	TALGEN M,NEALC,GLOVERV.Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?[J].J Child Psychol Psychiatry,2007,48(3-4):245-261. doi: 10.1111/j.1469-7610.2006.01714.x
49	LADDC O,HUOTR L,THRIVIKRAMANK V,et al.Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation[J].Biol Psychiatry,2004,55(4):367-375. doi: 10.1016/j.biopsych.2003.10.007
50	HUOTR L,PLOTSKYP M,LENOXR H,et al.Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats[J].Brain Res,2002,950(1-2):52-63. doi: 10.1016/S0006-8993(02)02985-2
51	AISAB,TORDERAR,LASHERASB,et al.Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats[J].Neuroscience,2008,154(4):1218-1226. doi: 10.1016/j.neuroscience.2008.05.011
52	AKHTARS.The mother and her child: clinical aspects of attachment, separation, and loss[M].Lanham:Jason Aronson,2012.
53	AMINI-KHOEIH,HAGHANI-SAMANIE,BEIGIM,et al.On the role of corticosterone in behavioral disorders, microbiota composition alteration and neuroimmune response in adult male mice subjected to maternal separation stress[J].Int Immunopharmacol,2019,66,242-250. doi: 10.1016/j.intimp.2018.11.037
54	AISAB,TORDERAR,LASHERASB,et al.Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats[J].Psychoneuroendocrinology,2007,32(3):256-266. doi: 10.1016/j.psyneuen.2006.12.013
55	VIVINETTOA L,SUÁREZM M,RIVAROLAM A.Neurobiological effects of neonatal maternal separation and post-weaning environmental enrichment[J].Behav Brain Res,2013,240,110-118. doi: 10.1016/j.bbr.2012.11.014
56	FRANKOLAK A,FLORAA L,TORRESA K,et al.Effects of early rearing conditions on cognitive performance in prepubescent male and female rats[J].Neurobiol Learn Mem,2010,94(1):91-99. doi: 10.1016/j.nlm.2010.04.005
57	LEEJ H,KIMH J,KIMJ G,et al.Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation[J].Neurosci Res,2007,58(1):32-39. doi: 10.1016/j.neures.2007.01.008
58	MARAISL,VAN RENSBURGS J,VAN ZYLJ M,et al.Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus[J].Neurosci Res,2008,61(1):106-112. doi: 10.1016/j.neures.2008.01.011
59	JIAR,TAIF D,ANS C,et al.Effects of neonatal paternal deprivation or early deprivation on anxiety and social behaviors of the adults in mandarin voles[J].Behav Process,2009,82(3):271-278. doi: 10.1016/j.beproc.2009.07.006
60	CASTRO-ZAVALAA,MARTÍN-SÁNCHEZA,MONTALVO-MARTÍNEZL,et al.Cocaine-seeking behaviour is differentially expressed in male and female mice exposed to maternal separation and is associated with alterations in AMPA receptors subunits in the medial prefrontal cortex[J].Prog Neuropsychopharmacol Biol Psychiatry,2021,109,110262. doi: 10.1016/j.pnpbp.2021.110262
61	LUNDBERGS,MARTINSSONM,NYLANDERI,et al.Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats[J].Horm Behav,2017,87,137-144. doi: 10.1016/j.yhbeh.2016.11.016
62	LÉVYF,MELOA I,GALEF JRB G,et al.Complete maternal deprivation affects social, but not spatial, learning in adult rats[J].Dev Psychobiol,2003,43(3):177-191. doi: 10.1002/dev.10131
63	ZIMMERBERGB,SAGESERK A.Comparison of two rodent models of maternal separation on juvenile social behavior[J].Front Psychiatry,2011,2,39.
64	SHEPHERDSOND J.Environmental enrichment: past, present and future[J].Int Zoo Yearb,2003,38(1):118-124. doi: 10.1111/j.1748-1090.2003.tb02071.x
65	TAROUL R,BASHAWM J.Maximizing the effectiveness of environmental enrichment: suggestions from the experimental analysis of behavior[J].Appl Anim Behav Sci,2007,102(3-4):189-204. doi: 10.1016/j.applanim.2006.05.026
66	李洪志,傅善江.环境富集对猪行为、生理和生产性能的影响[J].中国饲料,2020(18):17-20.
	LIH Z,FUS J.Effects of environmental richness on behavior, physiology and production performance of pigs[J].China Feed,2020(18):17-20.
67	ARAÚJO DO NASCIMENTOA P,MARTINS CASTROM S,DE SOUSA OLIVEIRAD,et al.Environmental enrichment in dairy goats in a semi-arid region: thermoregulatory and behavioral responses[J].J Therm Biol,2022,106,103248. doi: 10.1016/j.jtherbio.2022.103248
68	SMAILM A,SMITHB L,NAWREENN,et al.Differential impact of stress and environmental enrichment on corticolimbic circuits[J].Pharmacol Biochem Behav,2020,197,172993. doi: 10.1016/j.pbb.2020.172993
69	RULEL,YANGJ,WATKINH,et al.Environmental enrichment rescues survival and function of adult-born neurons following early life stress[J].Mol Psychiatry,2021,26(6):1898-1908. doi: 10.1038/s41380-020-0718-4
70	韦凤美. 早期饲养环境影响成年小鼠社交行为的作用及机制研究[D]. 兰州: 兰州大学, 2021.
	WEI F M. A study of the effects and mechanisms of early life environment on social behaviors of adult mice[D]. Lanzhou: Lanzhou University, 2021. (in Chinese)
71	KOKRASN,SOTIROPOULOSI,BESINISD,et al.Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes[J].Eur Neuropsychopharmacol,2019,29(1):1-15. doi: 10.1016/j.euroneuro.2018.11.1107
72	MORA-GALLEGOSA,FORNAGUERAJ.The effects of environmental enrichment and social isolation and their reversion on anxiety and fear conditioning[J].Behav Process,2019,158,59-69. doi: 10.1016/j.beproc.2018.10.022
73	JOUSHIS,TAHERIZADEHZ,ESMAEILPOURK,et al.Environmental enrichment and intranasal oxytocin administration reverse maternal separation-induced impairments of prosocial choice behavior[J].Pharmacol Biochem Behav,2022,213,173318. doi: 10.1016/j.pbb.2021.173318
74	NEUMANNI D,MALOUMBYR,BEIDERBECKD I,et al.Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice[J].Psychoneuroendocrinology,2013,38(10):1985-1993. doi: 10.1016/j.psyneuen.2013.03.003
75	LIY,SHID D,WANGZ.Adolescent nonpharmacological interventions for early-life stress and their mechanisms[J].Behav Brain Res,2023,452,114580. doi: 10.1016/j.bbr.2023.114580
76	KOEA S,ASHOKANA,MITRAR.Short environmental enrichment in adulthood reverses anxiety and basolateral amygdala hypertrophy induced by maternal separation[J].Transl Psychiatry,2016,6(2):e729. doi: 10.1038/tp.2015.217
77	MCCREARY J K, ERICKSON Z T, BABENKO A, et al. Environmental enrichment reverses transgenerational programming by early trauma[C]//Proceedings of International Behavioural Neuroscience Society Annual Meeting. Victoria, 2015.
78	AMDIC,LAHRMANNH P,OXHOLML C,et al.Pen-Mate directed behaviour in Ad libitum fed pigs given different quantities and frequencies of straw[J].Livest Sci,2015,171,44-51. doi: 10.1016/j.livsci.2014.11.005
79	VARGASL B,CALDARAF R,DE CASTRO LIPPII C,et al.Environmental enrichment strategies for weaned pigs: welfare and behavior[J].J Appl Anim Welf Sci,2023,26(2):205-217. doi: 10.1080/10888705.2021.1967753
80	BLACKIEN,DE SOUSAM.The use of garlic oil for olfactory enrichment increases the use of ropes in weaned pigs[J].Animals,2019,9(4):148. doi: 10.3390/ani9040148
81	TEIXEIRAD L,MIRANDA-DE LA LAMAG C,VILLARROELM,et al.Lack of straw during finishing affects individual and social lamb behavior[J].J Vet Behav,2014,9(4):177-183. doi: 10.1016/j.jveb.2014.02.008
82	STRAPPINIA C,MONTIG,SEPÚLVEDA-VARASP,et al.Measuring calves' usage of multiple environmental enrichment objects provided simultaneously[J].Front Vet Sci,2021,8,698681. doi: 10.3389/fvets.2021.698681
83	BULENS A, VAN BEIRENDONCK S, CAN THIELEN J, et al. The effect of environmental enrichment on the behaviour of beef calves[C]//Proceedings of the 6th International Conference on the Assessment of Animal Welfare at the Farm and Group Level. France: Wageningen Academic, 2014.
84	BOLTS L,GEORGEA J.The use of environmental enrichment on farms benefits animal welfare and productivity[J].Livestock,2019,24(4):183-188. doi: 10.12968/live.2019.24.4.183
85	GATTJ M,NEMEROFFC B,DOBSON-STONEC,et al.Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety[J].Mol Psychiatry,2009,14(7):681-695. doi: 10.1038/mp.2008.143
86	PILLAIA G,ARPM,VELZINGE,et al.Early life stress determines the effects of glucocorticoids and stress on hippocampal function: electrophysiological and behavioral evidence respectively[J].Neuropharmacology,2018,133,307-318. doi: 10.1016/j.neuropharm.2018.02.001
87	ARCEGOD M,BUSCHDORFJ P,O'TOOLEN,et al.A glucocorticoid-sensitive hippocampal gene network moderates the impact of early-life adversity on mental health outcomes[J].Biol Psychiatry,2024,95(1):48-61. doi: 10.1016/j.biopsych.2023.06.028
88	WANGR,WANGW,XUJ J,et al.Jmjd3 is involved in the susceptibility to depression induced by maternal separation via enhancing the neuroinflammation in the prefrontal cortex and hippocampus of male rats[J].Exp Neurol,2020,328,113254. doi: 10.1016/j.expneurol.2020.113254
89	LIUC H,HAOS,ZHUM H,et al.Maternal separation induces different autophagic responses in the hippocampus and prefrontal cortex of adult rats[J].Neuroscience,2018,374,287-294. doi: 10.1016/j.neuroscience.2018.01.043
90	MUHAMMADA,CARROLLC,KOLBB.Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex[J].Neuroscience,2012,216,103-109. doi: 10.1016/j.neuroscience.2012.04.041
91	MONROYE,HERNÁNDEZ-TORRESE,FLORESG.Maternal separation disrupts dendritic morphology of neurons in prefrontal cortex, hippocampus, and nucleus accumbens in male rat offspring[J].J Chem Neuroanat,2010,40(2):93-101. doi: 10.1016/j.jchemneu.2010.05.005
92	JIANGZ J,ZHUZ M,ZHAOM Y,et al.H3K9me2 regulation of BDNF expression in the hippocampus and medial prefrontal cortex is involved in the depressive-like phenotype induced by maternal separation in male rats[J].Psychopharmacology,2021,238(10):2801-2813. doi: 10.1007/s00213-021-05896-7
93	RÉCAMIER-CARBALLOS,ESTRADA-CAMARENAE,LÓPEZ-RUBALCAVAC.Maternal separation induces long-term effects on monoamines and brain-derived neurotrophic factor levels on the frontal cortex, amygdala, and hippocampus: differential effects after a stress challenge[J].Behav Pharm,2017,28(7):545-557. doi: 10.1097/FBP.0000000000000324
94	TENKUMOC,OHTAK I,SUZUKIS,et al.Repeated maternal separation causes transient reduction in BDNF expression in the medial prefrontal cortex during early brain development, affecting inhibitory neuron development[J].Heliyon,2020,6(8):e04781. doi: 10.1016/j.heliyon.2020.e04781
95	LIM,XUEX F,SHAOS,et al.Cognitive, emotional and neurochemical effects of repeated maternal separation in adolescent rats[J].Brain Res,2013,1518,82-90. doi: 10.1016/j.brainres.2013.04.026
96	SIERRA-FONSECAJ A,HAMDANJ N,COHENA A,et al.Neonatal maternal separation modifies proteostasis marker expression in the adult hippocampus[J].Front Mol Neurosci,2021,14,661993. doi: 10.3389/fnmol.2021.661993
97	MAJCHER-MAŚLANKAI,SOLARZA,CHOCYKA.Maternal separation disturbs postnatal development of the medial prefrontal cortex and affects the number of neurons and glial cells in adolescent rats[J].Neuroscience,2019,423,131-147. doi: 10.1016/j.neuroscience.2019.10.033
98	IRLESC,NAVA-KOPPA T,MORÁNJ,et al.Neonatal maternal separation up-regulates protein signalling for cell survival in rat hypothalamus[J].Stress,2014,17(3):275-284. doi: 10.3109/10253890.2014.913017
99	PARKH J,KIMS K,KANGW S,et al.Increased activation of synapsin 1 and mitogen-activated protein kinases/extracellular signal-regulated kinase in the amygdala of maternal separation rats[J].CNS Neurosci Ther,2014,20(2):172-181. doi: 10.1111/cns.12202
100	TODAH,BOKUS,NAKAGAWAS,et al.Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala[J].PLoS One,2014,9(5):e97421. doi: 10.1371/journal.pone.0097421
101	KEMPERMANNG.Environmental enrichment, new neurons and the neurobiology of individuality[J].Nat Rev Neurosci,2019,20(4):235-245.
102	CANDEMIRE,POSTA,DISCHINGERU S,et al.Limited effects of early life manipulations on sex-specific gene expression and behavior in adulthood[J].Behav Brain Res,2019,369,111927. doi: 10.1016/j.bbr.2019.111927
103	FRANCISD D,DIORIOJ,PLOTSKYP M,et al.Environmental enrichment reverses the effects of maternal separation on stress reactivity[J].J Neurosci,2002,22(18):7840-7843. doi: 10.1523/JNEUROSCI.22-18-07840.2002
104	BHANSALIP,DUNNINGJ,SINGERS E,et al.Early life stress alters adult serotonin 2C receptor pre-mRNA editing and expression of the α subunit of the heterotrimeric G-protein Gq[J].J Neurosci,2007,27(6):1467-1473. doi: 10.1523/JNEUROSCI.4632-06.2007
105	YANGJ L,HOUC L,MAN,et al.Enriched environment treatment restores impaired hippocampal synaptic plasticity and cognitive deficits induced by prenatal chronic stress[J].Neurobiol Learn Mem,2007,87(2):257-263. doi: 10.1016/j.nlm.2006.09.001
106	XUH F,LIB Z,LIL,et al.Environmental enrichment mitigates PTSD-like behaviors in adult male rats exposed to early life stress by regulating histone acetylation in the hippocampus and amygdala[J].J Psychiatr Res,2022,155,120-136. doi: 10.1016/j.jpsychires.2022.07.067
107	BREDYT W,HUMPARTZOOMIANR A,CAIND P,et al.Partial reversal of the effect of maternal care on cognitive function through environmental enrichment[J].Neuroscience,2003,118(2):571-576. doi: 10.1016/S0306-4522(02)00918-1
108	BREDYT W,ZHANGT Y,GRANTR J,et al.Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression[J].Eur J Neurosci,2004,20(5):1355-1362. doi: 10.1111/j.1460-9568.2004.03599.x
109	CUIM H,YANGY,YANGJ L,et al.Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress[J].Neurosci Lett,2006,404(1-2):208-212. doi: 10.1016/j.neulet.2006.05.048
110	DO PRADOC H,NARAHARIT,HOLLANDF H,et al.Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress[J].Dev Psychobiol,2016,58(4):482-491. doi: 10.1002/dev.21390
111	CORDIERJ M,AGUGGIAJ P,DANELONV,et al.Postweaning enriched environment enhances cognitive function and brain-derived neurotrophic factor signaling in the hippocampus in maternally separated rats[J].Neuroscience,2021,453,138-147. doi: 10.1016/j.neuroscience.2020.09.058
112	MOHAMMADIANJ,NAJAFIM,MILADI-GORJIH.Effect of enriched environment during adolescence on spatial learning and memory, and voluntary consumption of morphine in maternally separated rats in adulthood[J].Dev Psychobiol,2019,61(4):615-625. doi: 10.1002/dev.21808
113	JEFFERYK J.The hippocampus: from memory, to map, to memory map[J].Trends Neurosci,2018,41(2):64-66. doi: 10.1016/j.tins.2017.12.004
114	YOUSSEFM,ATSAKP,CARDENASJ,et al.Early life stress delays hippocampal development and diminishes the adult stem cell pool in mice[J].Sci Rep,2019,9(1):4120. doi: 10.1038/s41598-019-40868-0
115	FENOGLIOK A,BRUNSONK L,BARAMT Z.Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects[J].Front Neuroendocrinol,2006,27(2):180-192. doi: 10.1016/j.yfrne.2006.02.001
116	HUIJ J,ZHANGZ J,LIUS S,et al.Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study[J].Behav Brain Res,2011,217(1):122-127. doi: 10.1016/j.bbr.2010.10.014
117	RASMUSONS,OLSSONT,HENRIKSSONB G,et al.Environmental enrichment selectively increases 5-HT1A receptor mRNA expression and binding in the rat hippocampus[J].Brain Res,1998,53(1-2):285-290.
118	MOHAMMEDA H,HENRIKSSONB G,SÖDERSTRÖMS,et al.Environmental influences on the central nervous system and their implications for the aging rat[J].Behav Brain Res,1993,57(2):183-191. doi: 10.1016/0166-4328(93)90134-C
119	ESCORIHUELAR M,FERNANDEZTERUELA,TOBENAA,et al.Early environmental stimulation produces long-lasting changes on β-adrenoceptor transduction system[J].Neurobiol Learn Mem,1995,64(1):49-57. doi: 10.1006/nlme.1995.1043
120	YANGS S,MACKN R,SHUY S,et al.Prefrontal GABAergic interneurons gate long-range afferents to regulate prefrontal cortex-associated complex behaviors[J].Front Neural Circuits,2021,15,716408. doi: 10.3389/fncir.2021.716408
121	MEANEYM J,SZYFM.Maternal care as a model for experience-dependent chromatin plasticity?[J].Trends Neurosci,2005,28(9):456-463. doi: 10.1016/j.tins.2005.07.006
122	BOERSMAG J,TAMASHIROK L.Individual differences in the effects of prenatal stress exposure in rodents[J].Neurobiol Stress,2015,1,100-108. doi: 10.1016/j.ynstr.2014.10.006
123	ZOCHERS,OVERALLR W,LESCHEM,et al.Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus[J].Nat Commun,2021,12(1):3892. doi: 10.1038/s41467-021-23993-1
124	KOLB B, METZ G A. Animal models of brain plasticity and behavioral change[M]//GRAFMAN J, ROBERTSON I H. Handbook of Neuropsychology. Amsterdam: Elsevier, 2003: 139-152.
125	PRICEJ L.Comparative aspects of amygdala connectivity[J].Ann N Y Acad Sci,2003,985(1):50-58. doi: 10.1111/j.1749-6632.2003.tb07070.x
126	ÖNGÜRD,PRICEJ L.The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans[J].Cereb Cortex,2000,10(3):206-219. doi: 10.1093/cercor/10.3.206
127	MCKIBBENL A,DWIVEDIY.Early life and adult stress promote sex dependent changes in hypothalamic miRNAs and environmental enrichment prevents stress-induced miRNA and gene expression changes in rats[J].BMC Genomics,2021,22(1):701. doi: 10.1186/s12864-021-08003-4
128	LUPIENS J,MCEWENB S,GUNNARM R,et al.Effects of stress throughout the lifespan on the brain, behaviour and cognition[J].Nat Rev Neurosci,2009,10(6):434-445. doi: 10.1038/nrn2639
129	MCEWENB S,NASCAC,GRAYJ D.Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex[J].Neuropsychopharmacology,2016,41(1):3-23. doi: 10.1038/npp.2015.171
130	VAN BODEGOMM,HOMBERGJ R,HENCKENSM J A C.Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure[J].Front Cell Neurosci,2017,11,87.
131	HALLB S,MODAR N,LISTONC.Glucocorticoid mechanisms of functional connectivity changes in stress-related neuropsychiatric disorders[J].Neurobiol Stress,2015,1,174-183. doi: 10.1016/j.ynstr.2014.10.008
132	MEANEYM J,SZYFM,SECKLJ R.Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health[J].Trends Mol Med,2007,13(7):269-277. doi: 10.1016/j.molmed.2007.05.003
133	KRONTIRAA C,CRUCEANUC,BINDERE B.Glucocorticoids as mediators of adverse outcomes of prenatal stress[J].Trends Neurosci,2020,43(6):394-405. doi: 10.1016/j.tins.2020.03.008
134	GAPPK,BOHACEKJ,GROSSMANNJ,et al.Potential of environmental enrichment to prevent transgenerational effects of paternal trauma[J].Neuropsychopharmacology,2016,41(11):2749-2758. doi: 10.1038/npp.2016.87
135	MCCREARYJ K,ERICKSONZ T,HAOY X,et al.Environmental intervention as a therapy for adverse programming by ancestral stress[J].Sci Rep,2016,6,37814. doi: 10.1038/srep37814

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