J Korean Neuropsychiatr Assoc.  2016 May;55(2):75-88. 10.4306/jknpa.2016.55.2.75.

Effects of Early-Life Stress on the Structural and Functional Development of Central Nervous System : A Review of the Studies Focusing on Animal Models

• Kim MJ
• Kim JS
• Seok JH

• KMID: 2164997
• DOI: http://doi.org/10.4306/jknpa.2016.55.2.75

Abstract

Early-life stress (ELS), a complex traumatic stress including abuse, neglect and bullying during childhood or adolescence, is closely related to the development of psychiatric disorders. Conduct of a prospective study on the effect of ELS in human subjects is difficult due to ethical issues and limitations, and animal model study can be a reasonable alternative. Articles regarding structural and functional changes in the animal brain associated with ELS have been reviewed in this study. An up-to-date literature search on the effect of ELS on animal brain was performed ; keywords included ELS, central nervous system (CNS), and animal study using PubMed. A total of 623 articles were found and important articles were reviewed. First, we summarized the neurobiological changes in CNS associated with ELS, and then the effects of ELS on emotional and cognitive function and behavioral characteristics were recapped. ELS can induce overreactivity of the hypothalamus-pituitary-adrenal axis and cortical-subcortical structural changes including prefrontal cortex, hippocampus, and amygdala. These changes may be associated with neuroendocrine, cognitive, and emotional dysfunctions and related behavioral changes. Although most animal model studies used a single mode of stress, ELS tends to be experienced with complex types in human-life. Design of a new animal model examining the effects of complex trauma during early-life is important. Studies on the association between complex trauma and brain development can provide important insights regarding the pathogenetic mechanism of complex psychiatric disorders such as personality disorder and treatment-resistant depression.

Keyword

Early-life stress; Central nervous system; Animal model

MeSH Terms

Adolescent
Amygdala
Animals*
Brain
Bullying
Central Nervous System*
Cognition
Depression
Ethics
Hippocampus
Humans
Models, Animal*
Personality Disorders
Prefrontal Cortex
Prospective Studies

Reference

1. Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology (Berl). 2011; 214:55–70.

2. Committee on Integrating the Science of Early Childhood Development, Board on Children, Youth, and Families, Institute of Medicine, Division of Behavioral and Social Sciences and Education. From neurons to neighborhoods: the science of early childhood development. Washington, DC: National Academies Press;2000.

3. Taylor SE. Mechanisms linking early life stress to adult health outcomes. Proc Natl Acad Sci U S A. 2010; 107:8507–8512.

4. Kaufman J. Depressive disorders in maltreated children. J Am Acad Child Adolesc Psychiatry. 1991; 30:257–265.

5. Jumper SA. A meta-analysis of the relationship of child sexual abuse to adult psychological adjustment. Child Abuse Negl. 1995; 19:715–728.

6. Huynh NN, McIntyre RS. What are the implications of the STAR*D trial for primary care? A review and synthesis. Prim Care Companion J Clin Psychiatry. 2008; 10:91–96.

7. Salzer S, Cropp C, Streeck-Fischer A. Early intervention for borderline personality disorder: psychodynamic therapy in adolescents. Z Psychosom Med Psychother. 2014; 60:368–382.

8. Schmidt MV, Wang XD, Meijer OC. Early life stress paradigms in rodents: potential animal models of depression? Psychopharmacology (Berl). 2011; 214:131–140.

9. Wyrwoll CS, Holmes MC. Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways. Neuroendocrinology. 2012; 95:47–55.

10. Maccari S, Darnaudery M, Morley-Fletcher S, Zuena AR, Cinque C, Van Reeth O. Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci Biobehav Rev. 2003; 27:119–127.

11. Enthoven L, Schmidt MV, Cheung YH, van der Mark MH, de Kloet ER, Oitzl MS. Ontogeny of the HPA axis of the CD1 mouse following 24 h maternal deprivation at pnd 3. Int J Dev Neurosci. 2010; 28:217–224.

12. Branchi I, D'Andrea I, Cirulli F, Lipp HP, Alleva E. Shaping brain development: mouse communal nesting blunts adult neuroendocrine and behavioral response to social stress and modifies chronic antidepressant treatment outcome. Psychoneuroendocrinology. 2010; 35:743–751.

13. Wang XD, Rammes G, Kraev I, Wolf M, Liebl C, Scharf SH, et al. Forebrain CRF1 modulates early-life stress-programmed cognitive deficits. J Neurosci. 2011; 31:13625–13634.

14. Fuentes S, Carrasco J, Armario A, Nadal R. Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats. Horm Behav. 2014; 66:475–486.

15. McEwen BS. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology. 2000; 22:108–124.

16. De Kloet ER, Derijk R. Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance. Ann N Y Acad Sci. 2004; 1032:14–34.

17. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009; 5:374–381.

18. Dallman MF, Akana SF, Laugero KD, Gomez F, Manalo S, Bell ME, et al. A spoonful of sugar: feedback signals of energy stores and corticosterone regulate responses to chronic stress. Physiol Behav. 2003; 79:3–12.

19. Heim C, Binder EB. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol. 2012; 233:102–111.

20. Maccari S, Darnaudery M, Morley-Fletcher S, Zuena AR, Cinque C, Van Reeth O. Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci Biobehav Rev. 2003; 27:119–127.

21. Henry C, Kabbaj M, Simon H, Le Moal M, Maccari S. Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. J Neuroendocrinol. 1994; 6:341–345.

22. O'Regan D, Kenyon CJ, Seckl JR, Holmes MC. Glucocorticoid exposure in late gestation in the rat permanently programs genderspecific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab. 2004; 287:E863–E870.

23. Brunton PJ, Russell JA. Prenatal social stress in the rat programmes neuroendocrine and behavioural responses to stress in the adult offspring: sex-specific effects. J Neuroendocrinol. 2010; 22:258–271.

24. Liu D, Caldji C, Sharma S, Plotsky PM, Meaney MJ. Influence of neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinepherine release in the hypothalamic paraventricular nucleus. J Neuroendocrinol. 2000; 12:5–12.

25. Koksma JJ, van Kesteren RE, Rosahl TW, Zwart R, Smit AB, Lüddens H, et al. Oxytocin regulates neurosteroid modulation of GABA(A) receptors in supraoptic nucleus around parturition. J Neurosci. 2003; 23:788–797.

26. Stone DJ, Walsh JP, Sebro R, Stevens R, Pantazopolous H, Benes FM. Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. Hippocampus. 2001; 11:492–507.

27. Seok JH. Diagnostic implications of hypothalamic-pituitary-adrenal axis changes in major depressive disorder. J Korea Soc Depress Bipolar Disord. 2014; 12:15–18.

28. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53:865–871.

29. Aksić M, Radonjić NV, Aleksić D, Jevtić G, Marković B, Petronijević N, et al. Long-term effects of the maternal deprivation on the volume and number of neurons in the rat neocortex and hippocampus. Acta Neurobiol Exp (Wars). 2013; 73:394–403.

30. Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EM, et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci. 2010; 30:6635–6645.

31. Wang XD, Rammes G, Kraev I, Wolf M, Liebl C, Scharf SH, et al. Forebrain CRF1 modulates early-life stress-programmed cognitive deficits. J Neurosci. 2011; 31:13625–13634.

32. Leventopoulos M, Rüedi-Bettschen D, Knuesel I, Feldon J, Pryce CR, Opacka-Juffry J. Long-term effects of early life deprivation on brain glia in Fischer rats. Brain Res. 2007; 1142:119–126.

33. Giovanoli S, Weber L, Meyer U. Single and combined effects of prenatal immune activation and peripubertal stress on parvalbumin and reelin expression in the hippocampal formation. Brain Behav Immun. 2014; 40:48–54.

34. Hoeijmakers L, Lucassen PJ, Korosi A. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function. Front Mol Neurosci. 2015; 7:103.

35. Padival MA, Blume SR, Rosenkranz JA. Repeated restraint stress exerts different impact on structure of neurons in the lateral and basal nuclei of the amygdala. Neuroscience. 2013; 246:230–242.

36. Kaplan GA, Turrell G, Lynch JW, Everson SA, Helkala EL, Salonen JT. Childhood socioeconomic position and cognitive function in adulthood. Int J Epidemiol. 2001; 30:256–263.

37. Mueller SC, Maheu FS, Dozier M, Peloso E, Mandell D, Leibenluft E, et al. Early-life stress is associated with impairment in cognitive control in adolescence: an fMRI study. Neuropsychologia. 2010; 48:3037–3044.

38. Aksić M, Radonjić NV, Aleksić D, Jevtić G, Marković B, Petronijević N, et al. Long-term effects of maternal deprivation on the neuronal soma area in the rat neocortex. Biomed Res Int. 2014; 2014:235238.

39. Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maślanka I, Hess G, et al. Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci. 2013; 38:2089–2107.

40. Miyagawa K, Tsuji M, Fujimori K, Saito Y, Takeda H. Prenatal stress induces anxiety-like behavior together with the disruption of central serotonin neurons in mice. Neurosci Res. 2011; 70:111–117.

41. Muneoka K, Mikuni M, Ogawa T, Kitera K, Kamei K, Takigawa M, et al. Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring. Am J Physiol. 1997; 273(5 Pt 2):R1669–R1675.

42. Van den Hove DL, Lauder JM, Scheepens A, Prickaerts J, Blanco CE, Steinbusch HW. Prenatal stress in the rat alters 5-HT1A receptor binding in the ventral hippocampus. Brain Res. 2006; 1090:29–34.

43. Smythe JW, Rowe WB, Meaney MJ. Neonatal handling alters serotonin (5-HT) turnover and 5-HT2 receptor binding in selected brain regions: relationship to the handling effect on glucocorticoid receptor expression. Brain Res Dev Brain Res. 1994; 80:183–189.

44. Arborelius L, Hawks BW, Owens MJ, Plotsky PM, Nemeroff CB. Increased responsiveness of presumed 5-HT cells to citalopram in adult rats subjected to prolonged maternal separation relative to brief separation. Psychopharmacology (Berl). 2004; 176:248–255.

45. Gartside SE, Johnson DA, Leitch MM, Troakes C, Ingram CD. Early life adversity programs changes in central 5-HT neuronal function in adulthood. Eur J Neurosci. 2003; 17:2401–2408.

46. Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci. 2008; 28:9055–9065.

47. McArthur S, McHale E, Gillies GE. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology. 2007; 32:1462–1476.

48. Belay H, Burton CL, Lovic V, Meaney MJ, Sokolowski M, Fleming AS. Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats. Behav Neurosci. 2011; 125:150–160.

49. Moreau JL. Simulating the anhedonia symptom of depression in animals. Dialogues Clin Neurosci. 2002; 4:351–360.

50. Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005; 177:245–255.

51. Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005; 29:571–625.

52. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004; 29:1765–1781.

53. Holmes A. Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci Biobehav Rev. 2001; 25:261–273.

54. D'Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001; 36:60–90.

55. Sharma S, Rakoczy S, Brown-Borg H. Assessment of spatial memory in mice. Life Sci. 2010; 87:521–536.

56. Maei HR, Zaslavsky K, Teixeira CM, Frankland PW. What is the most sensitive measure of water maze probe test performance? Front Integr Neurosci. 2009; 3:4.

57. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993; 361:31–39.

58. Nagano M, Ozawa H, Suzuki H. Prenatal dexamethasone exposure affects anxiety-like behaviour and neuroendocrine systems in an age-dependent manner. Neurosci Res. 2008; 60:364–371.

59. Welberg LA, Seckl JR, Holmes MC. Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. Neuroscience. 2001; 104:71–79.

60. Alonso SJ, Damas C, Navarro E. Behavioral despair in mice after prenatal stress. J Physiol Biochem. 2000; 56:77–82.

61. Laloux C, Mairesse J, Van Camp G, Giovine A, Branchi I, Bouret S, et al. Anxiety-like behaviour and associated neurochemical and endocrinological alterations in male pups exposed to prenatal stress. Psychoneuroendocrinology. 2012; 37:1646–1658.

62. Morley-Fletcher S, Rea M, Maccari S, Laviola G. Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. Eur J Neurosci. 2003; 18:3367–3374.

63. Vallée M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci. 1997; 17:2626–2636.

64. Vallée M, MacCari S, Dellu F, Simon H, Le Moal M, Mayo W. Longterm effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat. Eur J Neurosci. 1999; 11:2906–2916.

65. Mairesse J, Silletti V, Laloux C, Zuena AR, Giovine A, Consolazione M, et al. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. Int J Neuropsychopharmacol. 2013; 16:323–338.

66. Maccari S, Krugers HJ, Morley-Fletcher S, Szyf M, Brunton PJ. The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations. J Neuroendocrinol. 2014; 26:707–723.

67. Zuena AR, Mairesse J, Casolini P, Cinque C, Alemà GS, Morley-Fletcher S, et al. Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats. PLoS One. 2008; 3:e2170.

68. Van Waes V, Enache M, Zuena A, Mairesse J, Nicoletti F, Vinner E, et al. Ethanol attenuates spatial memory deficits and increases mGlu1a receptor expression in the hippocampus of rats exposed to prenatal stress. Alcohol Clin Exp Res. 2009; 33:1346–1354.

69. Levine S. Infantile experience and resistance to physiological stress. Science. 1957; 126:405.

70. Levine S, Alpert M, Lewis GW. Infantile experience and the maturation of the pituitary adrenal axis. Science. 1957; 126:1347.

71. Maniam J, Morris MJ. Palatable cafeteria diet ameliorates anxiety and depression-like symptoms following an adverse early environment. Psychoneuroendocrinology. 2010; 35:717–728.

72. Millstein RA, Holmes A. Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 2007; 31:3–17.

73. Durand M, Sarrieau A, Aguerre S, Mormède P, Chaouloff F. Differential effects of neonatal handling on anxiety, corticosterone response to stress, and hippocampal glucocorticoid and serotonin (5-HT)2A receptors in Lewis rats. Psychoneuroendocrinology. 1998; 23:323–335.

74. Rüedi-Bettschen D, Zhang W, Russig H, Ferger B, Weston A, Pedersen EM, et al. Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats. Eur J Neurosci. 2006; 24:2879–2893.

75. Hilakivi-Clarke LA, Turkka J, Lister RG, Linnoila M. Effects of early postnatal handling on brain beta-adrenoceptors and behavior in tests related to stress. Brain Res. 1991; 542:286–292.

76. Levine S. Primary social relationships influence the development of the hypothalamic--pituitary--adrenal axis in the rat. Physiol Behav. 2001; 73:255–260.

77. Lambás-Señas L, Mnie-Filali O, Certin V, Faure C, Lemoine L, Zimmer L, et al. Functional correlates for 5-HT(1A) receptors in maternally deprived rats displaying anxiety and depression-like behaviors. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33:262–268.

78. El Khoury A, Gruber SH, Mørk A, Mathé AA. Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30:535–540.

79. Rüedi-Bettschen D, Pedersen EM, Feldon J, Pryce CR. Early deprivation under specific conditions leads to reduced interest in reward in adulthood in Wistar rats. Behav Brain Res. 2005; 156:297–310.

80. Macrì S, Laviola G. Single episode of maternal deprivation and adult depressive profile in mice: interaction with cannabinoid exposure during adolescence. Behav Brain Res. 2004; 154:231–238.

81. Cao X, Huang S, Cao J, Chen T, Zhu P, Zhu R, et al. The timing of maternal separation affects morris water maze performance and long-term potentiation in male rats. Dev Psychobiol. 2014; 56:1102–1109.

82. Vivinetto AL, Suárez MM, Rivarola MA. Neurobiological effects of neonatal maternal separation and post-weaning environmental enrichment. Behav Brain Res. 2013; 240:110–118.

83. Macrì S, Laviola G, Leussis MP, Andersen SL. Abnormal behavioral and neurotrophic development in the younger sibling receiving less maternal care in a communal nursing paradigm in rats. Psychoneuroendocrinology. 2010; 35:392–402.

84. Rice CJ, Sandman CA, Lenjavi MR, Baram TZ. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology. 2008; 149:4892–4900.

85. Neal CR Jr, Weidemann G, Kabbaj M, Vázquez DM. Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat. Am J Physiol Regul Integr Comp Physiol. 2004; 287:R375–R385.

86. Walker FR, Knott B, Hodgson DM. Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress. J Psychiatr Res. 2008; 42:1094–1103.

87. Harré EM, Galic MA, Mouihate A, Noorbakhsh F, Pittman QJ. Neonatal inflammation produces selective behavioural deficits and alters N-methyl-D-aspartate receptor subunit mRNA in the adult rat brain. Eur J Neurosci. 2008; 27:644–653.

88. Lucchina L, Carola V, Pitossi F, Depino AM. Evaluating the interaction between early postnatal inflammation and maternal care in the programming of adult anxiety and depression-related behaviors. Behav Brain Res. 2010; 213:56–65.

89. Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2014; 17:89–96.

90. Braun K, Champagne FA. Paternal influences on offspring development: behavioural and epigenetic pathways. J Neuroendocrinol. 2014; 26:697–706.

91. Avital A, Richter-Levin G. Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. Int J Neuropsychopharmacol. 2005; 8:163–173.

92. Kendler KS, Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry. 2001; 158:587–593.

93. Piccinelli M, Wilkinson G. Gender differences in depression. Critical review. Br J Psychiatry. 2000; 177:486–492.

94. Horovitz O, Tsoory MM, Yovell Y, Richter-Levin G. A rat model of pre-puberty (juvenile) stress-induced predisposition to stress-related disorders: sex similarities and sex differences in effects and symptoms. World J Biol Psychiatry. 2014; 15:36–48.

95. Horovitz O, Tsoory MM, Hall J, Jacobson-Pick S, Richter-Levin G. Post-weaning to pre-pubertal ('juvenile') stress: a model of induced predisposition to stress-related disorders. Neuroendocrinology. 2012; 95:56–64.

96. Conrad CD, LeDoux JE, Magariños AM, McEwen BS. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci. 1999; 113:902–913.

97. Rao U, Chen LA, Bidesi AS, Shad MU, Thomas MA, Hammen CL. Hippocampal changes associated with early-life adversity and vulnerability to depression. Biol Psychiatry. 2010; 67:357–364.

98. Sheridan MA, Fox NA, Zeanah CH, McLaughlin KA, Nelson CA 3rd. Variation in neural development as a result of exposure to institutionalization early in childhood. Proc Natl Acad Sci U S A. 2012; 109:12927–12932.

99. Mehta MA, Golembo NI, Nosarti C, Colvert E, Mota A, Williams SC, et al. Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the English and Romanian Adoptees study pilot. J Child Psychol Psychiatry. 2009; 50:943–951.

100. Tottenham N, Hare TA, Quinn BT, McCarry TW, Nurse M, Gilhooly T, et al. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Dev Sci. 2010; 13:46–61.

101. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, et al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch Gen Psychiatry. 2000; 57:1115–1122.

102. Adolphs R. Neural systems for recognizing emotion. Curr Opin Neurobiol. 2002; 12:169–177.

103. Bergman K, Sarkar P, Glover V, O'Connor TG. Maternal prenatal cortisol and infant cognitive development: moderation by infant-mother attachment. Biol Psychiatry. 2010; 67:1026–1032.

104. Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K, Sandman CA. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proc Natl Acad Sci U S A. 2012; 109:E1312–E1319.

105. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008; 455:894–902.

106. Morley-Fletcher S, Mairesse J, Soumier A, Banasr M, Fagioli F, Gabriel C, et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl). 2011; 217:301–313.

107. Darnaudéry M, Perez-Martin M, Bélizaire G, Maccari S, Garcia-Segura LM. Insulin-like growth factor 1 reduces age-related disorders induced by prenatal stress in female rats. Neurobiol Aging. 2006; 27:119–127.