Prenatal stress alters the pattern of corticoid secretion and affects transplacentally the fetus hypothalamic-pituitary-adrenal axis (HPA) in different animal models. Early postnatal stimulation or handling results in an increase in maternal care to the offspring what reverts the effects of prenatal stress on the alterations produced in the HPA axis. In this revision article we describe and discuss the underlying mechanism present and discuss the mechanisms leading to causing imbalance produced by prenatal stress and how it is related to immune system disorders. The general effects that postnatal early stimulation has on the parameters altered by prenatal stress and the attenuation produced on prenatal stress immune system negative effects will also be discussed.

Keywords: handling, stress, immune system, hypothalamic-pituitary-adrenocortical axis

The prenatal and early postnatal life stages are both dynamic and vulnerable phases during mammalian development. Exposure to adverse factors that interfere with this critical sequence of events places the exposed individual to a higher risk of developing various disorders in adult life.^1–3 For instance, high blood glucocorticoids concentration in pregnant stressed females crossing the placenta and the fetal blood-brain barriers,⁴ can affect brain development, birth weight and HPA axis function in offspring.⁵

In mammals, the mother is not only the source of infant nutrition but also thermal, olfactory, visual and auditory stimuli⁶ and a complex bidirectional communication between the mother and offspring is established immediately after parturition. For instance, arched back nursing behavior and milk ejection in the rat are dependent on the combined suckling stimulus of several neonatal pups.⁷ Numerous studies demonstrated that prenatal stress-induced alterations can be reverted by handling.⁸ Using the rat as model organism, Zhang et al.⁹ demonstrated that neonatal handling could improve the spatial learning and memory ability previously impaired by prenatal stress.

In this review, we describe effects of prenatal stress on different aspects of animal physiology and analyze the possible mechanisms underlying prenatal stress-associated alterations, in particular on immune system function. Then, the general effects that postnatal early stimulation has on the parameters altered by prenatal stress and finally, the attenuation that handling produced on prenatal stress immune system negative effects.

Early life stress triggers hypothalamic-pituitary-adrenocortical (HPA) axis activation and the associated neurochemical reactions following glucocorticoid (GC) release are accompanied by a rapid physiological response. An excessive response may affect the developed of different organs/systems such as the brain, resulting in neurobehavioral and neurochemical changes which are evident in later life.¹⁰ The embryo and fetus are highly responsive and vulnerable to the gestational environment. Glucocorticoids represent a major class of developmental cues and are crucial for normal brain development. In animal models, GC exposure during early development has been associated with transcriptomic and epigenomic changes that influence behavior, HPA function and growth.¹¹ Repeated exposure to high levels of GC during pregnancy suppresses 5α-reductase expression and allopregnanolone levels in the fetus and results in reduced myelination. Both fetal growth restriction and prenatal maternal stress lead to increased cortisol concentrations in the maternal and fetal circulation. As a consequence, prenatal stress results in reduced expression of γ-aminobutyric acid (GABAA) receptor subunits that normally enhance neural cells sensitivity.¹²

A defense mechanism against high hormone levels is the expression of 11β-hydroxysteroid dehydrogenase type-2 (11β-HSD2) that catalyzes the conversion of corticosterone into inactive metabolite, 11-dehydrocorticosterone,¹³ limiting in this way fetal exposure to maternal GC. Repeated exposition to stressors during pregnancy significantly reduces the placental expression of 11β-HSD2 and its activity,^14,15 potentially increasing the exposure of the fetuses to maternal GC. Similarly, Fujioka et al.¹⁶ demonstrated that adrenal glands from 16-day old rat fetuses can secrete corticosterone. Moreover, rat fetuses exposed to prenatal stress exhibited decreased body, adrenal, pancreas and testis weights. These alterations were associated with reduced plasma levels of glucose, growth hormone and ACTH, whereas insulin, IGF-1 and plasma corticosteroid binding globulin levels were unaffected.¹⁴ Contrary to these results, it was reported that increased peripheral sympathetic nerve activity may contribute to the attenuation of glucose uptake and thus reduce insulin sensitivity.¹⁷ Del Cerro et al.¹⁸ found that prenatal stressed rats had higher ACTH values than that in the unstressed controls.

In the reaction of an organism to stress situations, multiple are the factors involved in the actions produced to the maintenance of body homeostasis. There are evidences that elevated levels of circulating maternal catecholamines could impair fetal development indirectly through placental vasoconstriction that reduces oxygen and nutrient supply to the fetus/es.^19,20 Romanini et al.²¹ concluded that the chronically stressed rats had activated the sympathetic-medullary-adrenal axis and increased the levels of catecholamine metabolite, acid 3-metoxi 4-hidroximandélico, in urines at the beginning of pregnancy. Also, high concentrations of corticotropin-releasing hormone (CRH) are found in growth-retarded fetuses and elevated maternal CRH levels are associated with decreased gestational length and increased risk of preterm delivery.²² Conversely, other authors found no effect of prenatal stress on CRH levels.^23,24

In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, the effect on sexual steroid level differs among species studied.²⁵ When immobilization stress is applied to pregnant rats, Mayer et al.²⁶ observed that basal corticosterone and glucose levels were higher in prenatally stressed animals, in agreement with results reported by Vallée et al.²⁷ A group of rats with immobilization stress showed a hyperactive hypothalamic-pituitary-gonadal axis,^15,28 alterations in plasmatic LH and testosterone plasmatic levels, testis with reduced weight and higher apoptosis caused by the prenatal stress.²⁹

In humans, exposure of the developing brain to various types of environmental stressors during intrauterine life increases the susceptibility to neuropsychiatric disorders such as autism, attention deficit, hyperactivity disorder and schizophrenia.³⁰ In the same way, likelihood of developing anxiety, depression and learning deficits that are associated with structural alterations in the offspring hippocampus were observed in animals exposed to prenatal stress.³¹ Chronic social stress during adolescence has been shown to significantly increase basal corticosterone secretion with a flattened circadian rhythm of secretion and enlarged adrenal glands along with a decreased thymus weight. Furthermore, stressed animals display an increased anxiety-like behavior in the elevated plus maze and the novelty induced suppression of feeding test. Hippocampal mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) mRNA levels were significantly downregulated.³² Adult prenatally stressed rats showed high anxiety-like behavior, as indicated by an escape behavior to novelty correlated with high secretion of corticosterone in response to stress.³³ Also, prenatal restraint stress modified reactive and predictive adaptation by altering circadian rhythmicity.³⁴ In the same way, treated rats had greater levels of corticosterone at the end of the light period and especially female animals increased corticosterone values over the diurnal cycle.³⁵

Prenatal stress has been associated with a significant decrease in placental 11β-HSD2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a and increased DNA methylation at specific sites within the hsd11b2 gene promoter.³⁶ Additionally, rats that were stressed across generations increased placental microRNA-181a, a marker of human preterm birth.³⁷ Also, in prenatal stress rats, the expression of glucose transporter (GLUT) type 1 was decreased, whereas GLUT type 3 and type 4 were slightly increased.¹⁴

The immune response involves a complex and well-orchestrated series of events aimed to protect the host against disease-causing organisms, toxins and malignant cells.³⁸ Most studies coincide that immune suppression is invariably associated with stress situations regardless of animal model or type of stress elicited.

Pregnancy is known to induce a transient depression of maternal cell mediated immunity to prevent rejection of the fetus which is considered an allograft, while at the same time it keeps adequate maternal humoral defense mechanisms to fight infections. It was found that pregnancy appears to be associated with depressed cell immunity, as evidenced by a significant inhibition of lymphocyte proliferation.³⁹ Couret et al.⁴⁰ found that prenatal stress did not affect the levels of IgG of piglets but decreased the total numbers of white blood cells, lymphocytes and granulocytes, CD4⁺/CD8⁺ T cell ratio and lipopolysaccharide (LPS) induced-tumor necrosis factor-α (TNFα) production. Another study conducted by Coussons-Read et al.⁴¹ showed that psychosocial and social stress led to higher maternal levels of the proinflammatory cytokines IL-6 and TNF-α and with low levels of the antiinflammatory cytokine IL-10 in pregnant women. In the same line, Elftman ME et al.⁴² demonstrated that dendritic cells exposed to corticosterone in vivo remained phenotypically and functionally immature after stimulation with LPS with impaired production of interleukin IL-6, IL-12 and TNFα. As a consequence, these effects reduced the ability of dendritic cells to prime naive CD8⁺ T cells. Studies conducted in our laboratory⁴³ showed that leucocyte, lymphocyte and neutrophil levels and lymphocyte T proliferation were negatively affected in prenatally stress male rats compare to control animals.

Immunity depression was also reported for animals exposed to different types of stressor agents. Hu et al.⁴⁴ demonstrated that plasmatic ACTH, epinephrine (EPI), angiotensin-II (ANG-II), and IL-10 concentrations were significantly increased in animals exposed to low temperatures (4 and -12°C). On the other hand, cold exposure caused a reduction of IFN-γ, IL-2 and IL-4, the Toll-like receptor (TLR) 4 plasmatic concentration and the percentage of CD4+ CD25+ Foxp3+ Treg cells.

Pascuan et al.⁴⁵ described that prenatally restraint stressed mice had modified immune homeostasis based on their increased vulnerability to infection and disease. Corticosterone inhibitory effect was higher on lymphocytes from prenatally stress mice, what may be explained at least partially by an increase in protein levels and mRNA expression of GR in lymphoid cells. In the same way, Silberman et al.⁴⁶ suggested that impaired T-cell dependent humoral response in a model of chronic mild stress is correlated with an increased T-cell sensitivity to stress hormones. Moreover, chronic stress was reported to accelerate the natural ageing of the immune system.⁴⁷ Also, Li et al.⁴⁸ described a possible mechanism involved in stress immunosuppression. Corticosterone levels were significantly decreased in TLR 9 deficient mice subjected to chronic stress. When immune parameters were evaluated in this system, they found that TLR9 deficiency blocked the chronic stress induced lymphocyte apoptosis, the imbalance in T helper 1 and T helper 2 cytokine levels. On the contrary, Zhang et al.⁴⁹ demonstrated that TLR4 is activated by a chronic stressor in mice.

Postnatal early stimulation (PS) involves hand picking the pup and isolated from the mother in a small compartment for several minutes. This practice is repeated daily from birth to weaning.⁵⁰ The effect of PS appears to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing hormone (CRH) systems, which regulate the expression of behavioral, endocrine and autonomic responses to stress through activation of forebrain noradrenergic systems.⁵¹ The effect of PS on hippocampal GR expression appears to be mediated by the activation of the pituitary–thyroid system that leads to an increase in activity of serotonergic pathway during the first week of life.⁵² In this way, postnatal stress increases plasma levels of triiodothyronine, which potentiates serotonin turnover in the hippocampus and frontal cortex, areas where GR expression is altered by prenatal stress.^53,54 Thus, these findings suggest that postnatal PS might alter GR gene expression via cyclic AMP - Protein kinase A (cAMP-PKA) pathways involving the activation of nerve growth factor gene (NGFI-A) and activating protein 2 (AP-2), both factors implicated in the regulation of this receptor during development.⁵⁵

Active maternal care and environmental stress exert independent effects on HPA reactivity and fearfulness of the offspring. The results obtained by Macrì & Würbel⁵⁶ suggested that the down regulation of the HPA in response to stressful maternal environments could reflect adaptive developmental plasticity based on the increasing reactivity associated with progressively stressful conditions. Specific experimental manipulations of the rat postnatal environment have been shown to exert robust and marked effects on neurobiological, physiological and behavioral phenotypes in adulthood.⁵⁷ For example, Chen et al.²⁹ demonstrated that postnatal PS returned the levels of LH and testosterone to normal values and reduced apoptotic index observed in male testes from prenatal stressed animals.

Other studies indicates that PS of neonatal rat pups decreased hypothalamic CRH secretion, enhanced hippocampal GR expression in adult animals and reduced the stress hormone response during acute stress.^58,59 Interestingly, PS induces a distinct temporal pattern of gene expression, with reduction in CRH expression from paraventricular nuclei. The same pattern of adult gene expression was induced by postnatal administration of a CRH-receptor antagonist⁶⁰ implicating that CRH gene is a important molecular mechanism in the emergence of early life programming of the HPA axis function. Adult male rats exposed to early PS exhibit lower basal CRF mRNA and CRF levels in the hypothalamus compared to control animals. The remaining amount of CRF in the median eminence (part of the hypothalamus where regulatory hormones are released) after exposure to 20 min of restraint stress was lower in control animals than those in animals of PS group.⁵⁹ Another possible mechanism involved in the disruption of corticosterone levels observed in prenatally stressed rats was the altered parameters of adrenal gland physiology. As Liaudat et al.⁶¹ showed, the cortex:medulla ratio, apoptotic index and caspase 3 expression of adrenal gland returned to control levels when the prenatally stress animals were handled. Figure 1 shows the timeline of experimental events in a research model aimed to evaluate the effects of prenatal stress and PS on endocrine and immune systems.

Figure 1Research strategy to study the effects of prenatal stress and postnatal early stimulations on endocrine and immune systems: timeline of experimental events. Prenatal stress in the rat: a model of early programming of stress-related diseases.43

Studies of behavior characteristics conducted in different laboratories rendered contradictory results. Adult handled rats exhibited low anxiety-like conduct, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. Neither prenatal stress nor PS changed spatial learning or memory performance.³³ Moreover, Colman et al.⁶² demonstrated that variations in the neonatal environment affect both behavioral responses and amygdala neuroadaptation to acute withdraw from a palatable diet. Millstein & Holmes⁶³ concluded that in all mice strains studied, maternal separation produced an increase in pups maternal care. The data demonstrated that the maternal separation did not provide a robust model of early life stress effects on the anxiety and depression related behaviors in the mouse strains tested.

On the other hand, Cannizzaro et al.⁶⁴ reported that long-lasting PS in adult male rats was able to over compensate the increased behavioral stress reactivity induced by the prenatal exposure to diazepam and alprazolam.

There is experimental evidence that supports that the response of the immune system to conditions of chronic stress is associated with increased corticosterone secretion.⁶⁵ Although Different researcher analyzed the immune parameters altered by PS but the effects produced by this treatment on immune system are currently poorly defined.

One of the first reports was published by Lown & Dutka⁶⁶ These authors showed that preweaning handling significantly enhanced B- and T-cell proliferative responses. Similarly, our research group has demonstrated that postnatal PS treatment reversed the effect of prenatal stress on leukocyte total numbers as well as lymphocyte and neutrophil percentages. Moreover, when prenatally stressed animals were postnatally handled, the lymphocyte T proliferation was reverted to control levels.⁴³

Another model of early stimulation showed that mild maternal separation in early life increased the stress-resistant phenotype of adult female BALB/c mice which shows reduced repeated stress-induced immune suppression and weight loss. These findings were linked to reduced release of GC after stress exposure.⁶⁷ Additionally, Milde et al.⁶⁸ described that brief maternal separation had a protective effect on adult stress exposure and protects the animals from chemically induced colitis. They also observed that handling protects the animals from dextran sulfate sodium induced colitis. Table 1 summarizes the effect of prenatal stress and postnatal handling on selected endocrine and immune physiological parameters.

It is well known that prenatal stress causes long term modifications in the HPA axis as well as physiological and behavioral alterations in offspring. In particular, immune suppression associated to prenatal stress has been demonstrated by many groups. Interestingly, treatments such as early stimulation or handling during the first week of life were able to induce a long lasting reduction of stress responses in laboratory animal models. For the majority of parameters studied, handling of offspring was able to revert the alterations triggered by prenatal stress; however a few studies were unable to demonstrate a positive effect of handling. Based on the enormous impact of stress-associated diseases in modern life, there is great interest in pinpointing the underlying molecular mechanism of stress. This understanding would lead to development of strategies to prevent and/or treat stress-associated disorders. Information gathered from animals models of prenatal stress may prove to be valuable to identifying interventions, like handling, to reduce the impact of intrauterine stress on physiology and behavior during adult life.

None.

The author declares no conflict of interest.

1. Chang HY, Suh DI, Yang SI, et al. Prenatal maternal distress affects atopic dermatitis in offspring mediated by oxidative stress. J Allergy Clin Immunol. 2016;138(2):468–475.
2. Nolvi S, Karlsson L, Bridgett DJ, et al. Maternal prenatal stress and infant emotional reactivity six months postpartum. J Affect Disord. 2016;199:163–170.
3. Moloney RD, Johnson AC, O'Mahony SM, et al. Stress and the microbiota-gut-brain axis in visceral pain: relevance to Irritable bowel syndrome. CNS Neurosci Ther. 2016;22(2):102–117.
4. Zarrow MX, Philpott JE, Denenberg VH. Passage of 14-C-4 Corticosterone from the rat mother to the fetus and neonate. Nature. 1970;226(5250):1058–1059.
5. Su Q, Zhang H, Zhang Y, et al. Maternal stress in gestation: birth outcomes and stress-related hormone response of the neonates. Pediatr Neonatol. 2015;56(6):376–381.
6. Novak LR, Gitelman DR, Schuyler B, et al. Olfactory-visual integration facilitates perception of subthreshold negative emotion. Neuropsychologia. 2015;77:288–297.
7. Stern JM. Somato sensation and maternal care in Norway rats. In: Rosenblatt JS, Snowdon CT, editors. Parental care: evolution, mechanisms, and adaptive significance. San Diego: Academic Press; 1996:243–294.
8. de Los Angeles GA, Del Carmen RO, Wendy PM, et al. Tactile stimulation effects on hippocampal neurogenesis and spatial learning and memory in prenatally stressed rats. Brain Res Bull. 2016;124:1–11.
9. Zhang Z, Zhang H, Du B, et al. Neonatal handling and environmental enrichment increase the expression of GAP-43 in the hippocampus and promote cognitive abilities in prenatally stressed rat offspring. Neurosci Lett. 2012;522(1):1–5.
10. Silberman DM, Acosta GB, Zorrilla Zubilete MA. Long-term effects of early life stress exposure: Role of epigenetic mechanisms. Pharmacol Res. 2016;109:64–73.
11. Constantinof A, Moisiadis VG, Matthews SG. Programming of stress pathways: A transgenerational perspective. J Steroid Biochem Mol Biol. 2016;160:175–180.
12. Hirst JJ, Cumberland AL, Shaw JC, et al. Loss of neurosteroid-mediated protection following stress during fetal life. J Steroid Biochem Mol Biol. 2016;160:181–188.
13. Benediktsson R, Calder AA, Edwards CR, et al. Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clin Endocrinol (Oxf). 1997;46(2):161–166.
14. Mairesse J, Lesage J, Breton C, et al. Maternal stress alters endocrine function of the feto-placental unit in rats. Am J Physiol Endocrinol Metab. 2007;292(6):E1526–E1533.
15. Lesage J, Sebaai N, Leonhardt M, et al. Perinatal maternal undernutrition programs the offspring hypothalamo-pituitary-adrenal (HPA) axis. Stress. 2006;9(4):183–198.
16. Fujioka T, Fujioka A, Endoh H, et al. Materno-fetal coordination of stress-induced Fos expression in the hypothalamic paraventricular nucleus during pregnancy. Neuroscience. 2003;118(2):409–415.
17. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996;334(6):374–381.
18. Del Cerro MC, Ortega E, Gómez F, et al. Environmental prenatal stress eliminates brain and maternal behavioral sex differences and alters hormone levels in female rats. Horm Behav. 2015;73:142–147.
19. Fan JM, Chen XQ, Jin H, et al. Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic-pituitary-adrenal axis and induces anxiety-like behavior in adult male rat offspring. Neuroscience. 2009;159(4):1363–1373.
20. Nunez H, Ruiz S, Soto-Moyano R, et al. Fetal undernutrition induces overexpression of CRH mRNA and CRH protein in hypothalamus and increases CRH and corticosterone in plasma during postnatal life in the rat. Neurosci Lett. 2008;448(1):115–119.
21. Romanini MC, Paz DA, Rodríguez N, et al. Relative concentrations of placental lactogen II and PRL-like protein-A in stressed rats placenta. Int J Morphol. 2007;25(1):85–94.
22. Wadhwa PD, Porto M, Garite TJ, et al. Maternal corticotropinreleasing hormone levels in the early third trimester predict length of gestation in human pregnancy. Am J Obstet Gynecol. 1998;179(4):1079–1085.
23. Williams MT, Davis HN, McCrea AE, et al. Stress during pregnancy alters the offspring hypothalamic, pituitary, adrenal, and testicular response to isolation on the day of weaning. Neurotoxicol Teratol. 1999;21(6):653–659.
24. Jezová D, Skultétyová I, Makatsori A, et al. Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction. Stress. 2002;5(3):177–183.
25. Barrett ES, Swan SH. Stress and androgen activity during fetal development. Endocrinology. 2015;156(10):3435–3441.
26. Mayer N, Greco C, Bertuzzi M, et al. Immobilization stress responses in adult rats exposed in utero to immobilization. Stress Health. 2011;27(2):e1–e10.
27. Vallée M, Mayo W, Maccari S, et al. Long-term effects of prenatal stress and handling on metabolic parameters: relationship to corticosterone secretion response. Brain Res. 1996;712(2):287–292.
28. Schroeder M, Sultany T, Weller A. Prenatal stress effects on emotion regulation differ by genotype and sex in prepubertal rats. Dev Psychobiol. 2013;55:176–192.
29. Chen Cárdenas S, Mayer N, Romanini M, et al. Reproductive response in offspring male rats exposed to prenatal stress and to early postnatal stimulation. Int J Morphol. 2013;31(2):754–764.
30. Ishii S, Hashimoto-Torii K. Impact of prenatal environmental stress on cortical development. Front Cell Neurosci. 2015;9:207.
31. Bogoch Y, Biala YN, Linial M, et al. Anxiety induced by prenatal stress is associated with suppression of hippocampal genes involved in synaptic function. J Neurochem. 2007;101(4):1018–1030.
32. Sterlemann V, Ganea K, Liebl C, et al. Long-term behavioral and neuroendocrine alterations following chronic social stress in mice: implications for stress-related disorders. Horm Behav. 2008;53(2):386–394.
33. Vallée M, Mayo W, Dellu F, et al. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci.1997;1(7):2626–2636.
34. Maccari S, Darnaudery M, Morley-Fletcher S, et al. Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci Biobehav Rev. 2003;27(1-2):119–127.
35. Koehl M, Barbazanges A, Le Moal M, et al. Prenatal stress induces a phase advance of circadian corticosterone rhythm in adult rats which is prevented by postnatal stress. Brain Research. 1997;759(2):317–320.
36. Jensen Peña C, Monk C, Champagne FA. Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS One. 2012;7(6):e39791.
37. Yao Y, Robinson AM, Zucchi FC, et al. Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes. BMC Medicine. 2014;12:121.
38. Hughes MM, Connor TJ, Harkin A. Stress-related immune markers in depression: implications for treatment. Int J Neuropsychopharmacol. 2016.
39. Brazão V, Kuehn CC, dos Santos CD, et al. Endocrine and immune system interactions during pregnancy. Immunobiology. 2015;220(1):42–47.
40. Couret D, Jamin A, Kuntz-Simon G, et al. Maternal stress during late gestation has moderate but long-lasting effects on the immune system of the piglets. Vet Immunol Immunopathol. 2009;131(1-2):17–24.
41. Coussons-Read ME, Okun ML, Schmitt MP, et al. Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy. Psychosom Med. 2005;67(4):625–631.
42. Elftman MD, Norbury CC, Bonneau RH, et al. Corticosterone impairs dendritic cell maturation and function. Immunology. 2007;122(2):279–290.
43. Liaudat AC, Rodríguez N, Vivas A, et al. Effect of Early Stimulation on Some Immune Parameters in a Model of Prenatally Stressed Rats. International Journal of Psychological Studies. 2012;4(3):73–82.
44. Hu GZ, Yang SJ, Hu WX, et al. Effect of cold stress on immunity in rats. Exp Ther Med. 2016;11(1):33–42.
45. Pascuan CG, Rubinstein MR, Palumbo ML, et al. Prenatal stress induces up-regulation of glucocorticoid receptors on lymphoid cells modifying the T-cell response after acute stress exposure in the adult life. Physiol Behav. 2014;128:141–147.
46. Silberman DM, Wald MR, Genaro AM. Acute and chronic stress exert opposing effects on antibody responses associated with changes in stress hormone regulation of T-lymphocyte reactivity. J Neuroimmunol. 2003;144(1-2):53–60.
47. Hawkley LC, Cacioppo JT. Stress and the aging immune system. Brain Behav Immun. 2004;18(2):114–119.
48. Li H, Zhao J, Chen M, et al. Toll-like receptor 9 is required for chronic stress-induced immune suppression. Neuroimmunomodulation. 2014;21(1):1–7.
49. Zhang Y, Woodruff M, Zhang Y, et al. Toll-like receptor 4 mediates chronic restraint stress-induced immune suppression. J Neuroimmunol. 2008;194(1-2):115–122.
50. Levine S. Stimulation in infancy. Sci Am. 1960;202:81–86.
51. Francis DD, Champagne FA, Liu D, et al. Maternal care, gene expression, and the development of individual differences in stress reactivity. Ann N Y Acad Sci. 1999;896:66–84.
52. Meaney M, Diorio J, Widdowson J, et al. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci.1996;18(1-2):49–72.
53. Mitchell JB, Iny LJ, Meaney MJ. The role of serotonin in the development and environmental regulation of hippocampal type II corticosteroid receptors binding in rat hippocampus. Brain Res Dev Brain Res. 1990a;55(2):231–235.
54. Smythe JW, Rowe W, Meaney MJ. Neonatal handling alters serotonin turnover and serotonin type 2 receptor density in selected brain regions. Brain Res Dev Brain Res. 1994;80(1-2):183–189.
55. Meaney MJ, Diorio J, Francis D, et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000;20(10):3926–3935.
56. Macrì S, Würbel H. Developmental plasticity of HPA and fear responses in rats: a critical review of the maternal mediation hypothesis. Horm Behav. 2006;50(5):667–680.
57. Pryce CR, Feldon J. Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev. 2003;27(1-2):57–71.
58. Avishai-Eliner S, Eghbal-Ahmadi M, Tabachnik E, et al. Down- regulation of hypothalamic corticotropin releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA. Endocrinology. 2001;142(1):89–97.
59. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res. 1993;18(3):195–200.
60. Fenoglio KA, Brunson KL, Avishai-Eliner S, et al. Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor. Endocrinology. 2003;146(9):4090–4096.
61. Liaudat AC, Rodríguez N, Chen S, et al. Adrenal response in offspring male rats exposed to prenatal stress and to early postnatal stimulation. Biotech Histochem. 2015;90(6):432–438.
62. Colman JB, Laureano DP, Reis TM, et al. Variations in the neonatal environment modulate adult behavioral and brain responses to palatable food withdrawal in adult female rats. Int J Dev Neurosci. 2015;40:70–75.
63. Millstein RA, Holmes A. Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 2007;31(1):3–17.
64. Cannizzaro C, Martire M, Steardo L, et al. Prenatal exposure to diazepam and alprazolam, but not to zolpidem, affects behavioural stress reactivity in handling-naïve and handling-habituated adult male rat progeny. Brain Res. 2002;953(1-2):170–180.
65. Elenkov IJ, Chrousos GP, Wilder RL. Neuroendocrine regulation of IL-12 and TNF-alpha/IL-10 balance. Clinical implications. Ann N Y Acad Sci. 2000;917:94–105.
66. Lown BA, Dutka ME. Early handling enhances mitogen responses of splenic cells in adult C3H mice. Brain Behav Immun.1987;1(4):356–360.
67. Kiank C, Mundt A, Schuett C. Mild postnatal separation stress reduces repeated stress-induced immunosuppression in adult BALB/c mice. Neuro Endocrinol Lett. 2009;30(6):761–768.
68. Milde AM, Enger Ø, Murison R. The effects of postnatal maternal separation on stress responsivity and experimentally induced colitis in adult rats. Physiol Behav. 2004;81(1):71–84.
69. Weinstock M. Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis? Neurosci Biobehav Rev 1997;21(1):1–10.
70. Smythe JW, McCormick CM, Meaney MJ. Median eminence corticotrophin-releasing hormone content following prenatal stress and neonatal handling. Brain Res Bull. 1996;40(3):195–159.
71. Desplats PA. Perinatal programming of neurodevelopment: epigenetic mechanisms and the prenatal shaping of the brain. Adv Neurobiol. 2015;10:335–336.
72. Pollard I. Prenatal stress effects over two generations in rats. J Endocrinol. 1986;109(2):239–244.
73. García-Cáceres C, Diz-Chaves Y, Lagunas N, et al. The weight gain response to stress during adulthood is conditioned by both sex and prenatal stress exposure. Psychoneuroendocrinology. 2010;35(3):403–413.
74. Rodríguez N, Mayer N, Gauna HF. Effects of prenatal stress on male offspring sexual maturity. Biocell. 31(1):67–74.
75. Dobrakovová M, Kvetnanský R, Oprsalová Z, et al. Specificity of the effect of repeated handling on sympathetic-adrenomedullary and pituitary-adrenocortical activity in rats. Psychoneuroendocrinology. 1993;18(3):163–174.
76. Neeley EW, Berger R, Koenig JI, et al. Strain dependent effects of prenatal stress on gene expression in the rat hippocampus. Physiol Behav. 2011;104(2):334–339.
77. McCormick JA, Lyons V, Jacobson MD, et al. 5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol Endocrinol. 2000;14(4):506–517.
78. Llorente E, Brito ML, Machado P, et al. Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring. J Physiol Biochem. 2002;58(3):143–149.
79. Dhabhar FS. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res. 2014;58(2-3):193–210.
80. Laviola G, Rea M, Morley-Fletcher S, et al. Beneficial effects of enriched environment on adolescent rats from stressed pregnancies. Eur J Neurosci. 2004;20(6):1655–1664.
81. Klein SL, Rager DR. Prenatal stress alters immune function in the offspring of rats. Dev Psychobiol. 1995;28(6):321–336.
82. Kay G, Tarcic N, Poltyrev T, et al. Prenatal stress depresses immune function in rats. Physiol Behav. 1998;63(3):397–402.