Pediatrics & Neonatology
Volume 52, Issue 3 , Pages 122-129, June 2011

Effects of Early Life Stress on Neuroendocrine and Neurobehavior: Mechanisms and Implications

  • Ming-Chi Lai

      Affiliations

    • Department of Pediatrics, Chi Mei Medical Center, Yong Kang Campus, Tainan, Taiwan
    • ,
  • Li-Tung Huang

      Affiliations

    • Department of Pediatrics, Chang Gung Memorial Hospital—Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
    • Corresponding Author InformationCorresponding author. Department of Pediatrics, Chang Gung Memorial Hospital—Kaohsiung Medical Center, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien 833, Taiwan.

Received 10 August 2010; received in revised form 30 November 2010; accepted 23 December 2010. published online 14 April 2011.

Article Outline

Evidence continues to mount that adverse experiences early in life have an impact on brain functions. Early life stress can program the development of the hypothalamic-pituitary-adrenal axis and cause alterations of neurochemistry and signaling pathways involved in regulating neuroplasticity, with resultant neurobehavioral changes. Early life experiences and genetic factors appear to interact in determining the individual vulnerability to mental health disorders. We reviewed the effects of early life stress on neuroendocrine regulation and the relevance to neurobehavioral development.

Key Words: early life stress, epileptogenesis, hypothalamic-pituitary-adrenal axis, learning and memory, psychiatric disorders

 

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1. Introduction 

An adverse environment in early life has been demonstrated to be one of the most important factors affecting long life health. In humans, early adverse experiences, such as abuse, neglect, or loss of a parent, have an impact on cardiometabolic risk profile and increase the risk of developing mental health disorders, including attention deficit/hyperactivity disorder, conduct disorders, anxiety, depression, suicide, drug abuse, and posttraumatic stress disorder.1, 2, 3 Talge et al2 revealed a large body of research relating stress to health and found an attributable load of emotional/behavioral problems and language delay because of prenatal stress and/or anxiety in approximately 15% of subjects. Animal studies have also suggested that exposure to stressors or steroids during early life alters the programming of neuroendocrine and neuroimmune systems.4 For example, maternal separation of rodent pups during the first 2 weeks of life has been shown to induce alterations in behavior and hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress that persists throughout life. The long-term effects of early life stress on vulnerability to neurological events, such as seizures or stroke, are well documented.5, 6 These findings provide evidence that early life stress modifies the development of the HPA axis, brain function, and neurobehavior.7, 8, 9, 10, 11, 12, 13, 14, 15, 16

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2. The Concept of Stress 

A generally accepted concept of stress is still elusive; however, a useful operational definition is anything that induces activation of the autonomic nervous system and HPA axis and promotes catabolism.12, 17 Stress response aims to restore homeostatic control and facilitate adaptation. When encountering acute physical or psychological stress, input to the higher brain centers is connected synaptically with the hypothalamus to increase the production of hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin. CRH is transported by means of the hypophyseal portal system to the pituitary, where it elicits the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary gland, which finally stimulates the secretion of glucocorticoids (GCs), principally cortisol in humans and corticosterone (CORT) in rodents, from the adrenal glands. GCs then interact with their receptors in multiple target tissues, including the HPA axis and hippocampus, where they exert an inhibitory negative feedback effect over the synthesis of hypothalamic releasing factors for ACTH, notably CRH and vasopressin (Figure 1).18, 19, 20, 21 The neuroendocrine system acts in close cooperation with vegetative centers in the brain and in regulating metabolism, psychical and physical development, and the necessary adaptations in the performance of the organism, and the internal milieu (homeostasis).20 The increase in circulating levels of both catecholamines and GCs also promotes the increase in cardiovascular tone, and these reactions serve to enhance the availability and distribution of energy substrates to meet the metabolic demands posed by the stressor. However, these responses to stress are a double-edged sword. Elevated GCs actually help to terminate fight/flight physiological and behavioral responses. However, when the elevation of GCs and/or CRH remains for a prolonged period, it threatens neuronal viability and increases the risk of stress-related disorders. Relevant studies have shown that individuals with long-term or frequent stress-induced exaggeration of HPA activity and sympathetic reaction are at risk of vulnerability to diseases over a life span, including cognitive dysfunction, hypertension, diabetes, anxiety, depression, and drug addiction.13, 22

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  • Figure 1 

    Response of the hypothalamus-pituitary-adrenal axis to stress and negative feedback. CRH is transported by means of the hypophyseal portal system to the pituitary gland, where it elicits the release of ACTH from the anterior lobe of the pituitary gland, which finally stimulates the secretion of glucocorticoids from the adrenal glands. In each of these steps, the original signal can not only be amplified but can also undergo modulation, e.g., feedback regulation. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle. CRH = corticotrophin-releasing hormone; ACTH = adrenocorticotropic hormone.

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3. Spectrum of Early Life Stress 

Early life stress in humans can originate from prenatal stress, including negative birth perception, provider disaffirmation, perinatal trauma symptoms, or postnatal stress, including premature steroid use, maternal postpartum depression, family conflict, or childhood physical/sexual abuse, usually involving economic hardship, marital strife, and a lack of social and emotional support.1, 2, 23, 24, 25, 26, 27, 28, 29 Relevant animal research has mostly investigated the effects of restraint stress,3, 30 maternal separation (neonatal isolation),31, 32, 33, 34 and infant paired odor-shock conditioning.35 These findings, in particular, indicate the importance of parental care as a mediator of the effects of early environmental adversity on neural development.

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4. Early Life Programming of Neuroendocrine System 

The hypothalamus is intimately connected with the limbic system, formatio reticularis, and (by means of the thalamus) cerebral cortex. Hormone balance is thus not only concerned with purely vegetative regulation but is also connected with the sleeping-waking rhythm and with psychic-emotional factors. The end hormone, GC, not only acts on target cells but also inhibits the HPA axis. In each of these steps, the original signal can be amplified and also undergoes modulation (e.g., feedback regulation), and the hippocampus, a region rich in glucocorticoid receptors (GRs), has been strongly implicated in GC negative feedback regulation.36, 37 Exposure of the developing brain to severe and/or prolonged stress can result in enduring hyperactivation of the HPA axis: upregulation of CRH mRNA expression in the hypothalamus and amygdala,38, 39, 40, 41 reduced GR gene expression in the hippocampus, and increased CORT release in response to acute stress.11, 32

4.1. Effects during the stress hyporesponsive period 

Previous studies in rodents have demonstrated that during the first 2 weeks of life, normal maternal behavior ensures a quiescent stress response in the pup, the so-called stress hyporesponsive period (SHRP), when neonatal rats have very low basal levels of CORT, and the CORT response to stressors is blunted.8, 16, 42 An important question is which factor contributes substantially to the stress hyporesponsiveness of the HPA axis during the SHRP—central inhibition or peripheral inhibition of HPA axis activity? Although the expression of CRH in the paraventricular nucleus (PVN) of the hypothalamus is high, CRH expression decreases at the end of the SHRP when basal CORT levels increase, indicating very sensitive negative feedback regulation of CRH gene expression in the neonate.43, 44 GR expression in the hippocampus is low at birth but increases significantly during the SHRP, with the highest level at a postnatal age (P) of 12 days in rat pups.45 The animals with GR knockouts have massive basal CORT levels during the first postnatal week, and the homozygous knockout offspring ultimately die.46 Furthermore, Levine et al47 demonstrated a smaller increase in CORT secretion after ACTH secretion in neonatal pups compared with older animals outside the SHRP. Taken together, these results suggest an important role of peripheral inhibition at the level of the pituitary gland by means of a high GR feedback signal and the adrenal gland by means of a low sensitivity to ACTH during the SHRP.48

4.2. Influences of maternal care 

Based on the fact that mother is a substantial provider of psychosocial stimulation for infants, normal mother-infant interaction appears to be a key regulator during SHRP. Different maternal separation paradigms have been demonstrated to influence the sympatho-adrenal system, as well as long-term physiological and behavioral consequences for the offspring. For example, 24-hour isolation of rat pups from the dam (neonatal isolation) can result in a 40% decline in heart rate, and repeated daily 1-hour neonatal isolation from P2 to P9 can increase CORT release after seizure without changing baseline circulating levels of CORT. Regarding the central effects of maternal separation, prior studies have also demonstrated an increase in c-fos expression in the PVN in P12 rat pups after 24-hour maternal deprivation, indicating an activation of the PVN cells,49 and downregulated expressions of GR and mineralocorticoid receptors (MRs) in the hippocampus in maternally deprived pups at P9.50, 51 In contrast, compared with nonhandled rats, postnatally handled animals showed a decrease of mRNA and immunoreactivity for CRH and vasopressin in the hypothalamus, as well as an increase of hippocampal GR gene expression, which is considered to mediate the enhanced GC negative feedback sensitivity of the handling effect on the HPA axis. The most intriguing question is how maternal care or early life stress affects long-term HPA responses to stress. Weaver et al16 demonstrated that maternal behavior produces enduring alterations of DNA methylation at the GR gene promoter (GR exon 17 promoter) and that the adult offspring of less licking-grooming dams showed a decrease of GR gene expression in the hippocampus and an increase of plasma CORT in response to acute stress. Cross-fostering reverses the differences in the methylation of the GR exon 17 promoter. Accordingly, epigenetic modifications in GR gene promoters in response to environmental demands may contribute to the dynamic regulation that mediates persistent changes in neurobiology and behavior through life.52

4.3. Roles of GCs 

The elevation of GCs is thought to be the primary candidate for programming of the fetal HPA axis during early life experience.10 GCs operate in concert with other humoral and nervous signals that mediate the stress response. In general, stress is assumed to cause initial acute effects through the actions of monoamines (noradrenaline, dopamine, and serotonin) and peptides (CRH and vasopressin). The latter effects are mainly mediated by GRs acting as regulators of gene transcription53 and by CRH receptor 2 signaling, which exerts inhibition on the initial stress effects for restoring allostasis.54, 55, 56 The actions of GCs depend on the functionality of the balance of MRs and GRs in the brain and their effects involve interactions with other neurochemical systems, including serotonin, γ-aminobutyric acid (GABA), and excitatory amino acids (mainly glutamate). GRs have lower affinity compared with MRs, thus GRs are more occupied as CORT increases. The MR:GR balance is altered by gene variants of these receptor complexes and experience-related factors, which can induce lasting epigenetic changes in the expression of these receptors.16, 52, 57

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5. Effects on Neuroplasticity in Later Life 

The term “neuroplasticity” refers to the ability of the nervous system to adapt its structural and functional organization to altered circumstances arising from developmental or environmental changes.58 Psychological stressors primarily engage stress mediators in their preferred brain regions that subserve emotion (the amygdala and prefrontal cortex), learning and memory (the hippocampus), and decision making (the prefrontal cortex), and the functional contributions to the stress response act through convergence on interconnected networks.5 Because of the importance of the limbic system in the regulation of HPA axis responses to psychological stressors, limbic-HPA axis is usually used in discussions of the stress response system. Activation of the HPA axis to psychological stressors involves the amygdala, whereas inhibition of the HPA response involves the hippocampus and medial prefrontal cortex. Several lines of evidence suggest that early life stress has detrimental effects on the developing central nervous system and destabilizes homeostatic neurosynaptic plasticity on the hippocampus and amygdala in particular.12, 59, 60 Chronically, early life stress can suppress dentate gyrus neurogenesis, induce dendritic remodeling in CA3 and mossy fiber sprouting, and lead to an abnormal abundance of mossy fiber terminals in CA3 and marked dendritic atrophy of CA1 pyramidal cells.12, 39, 61 The adult offspring of abundant maternal care (high levels of licking and grooming and arched-back nursing) have been shown to have an increased expression of N-methyl-d-aspartic acid (NMDA) receptor subunits and brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, suggesting increased synapse formation,62 whereas neonatal isolation from the dam has been shown to cause decreased BDNF and synaptophysin mRNA density in the hippocampus and lower neural cell adhesion molecule expression after water maze learning.63

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6. Effects on Neurobehavior in Later Life 

Early life stress appears to disrupt the HPA axis and the limbic system (mainly the hippocampus and amygdala), both of which are considered as critical mediators of early life stress on compromised mental health in humans and animal models in later life, such as fear reaction (amygdala hyperfunction),13, 64 impaired spatial learning and memory (hippocampal function–dependent task),9, 12, 63 and increased seizure vulnerability (Figure 2).5, 31, 32, 33

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  • Figure 2 

    Long-term effects of early life stress on neurobehavior. The early environment modifies the interplay between the limbic system and hypothalamic-pituitary-adrenal axis and influences long-term neurobehavioral development (modified from Fig. 1 in Ref. 65). LHPA = limbic-hypothalamic-pituitary-adrenal axis.

6.1. Effects on learning and memory in later life 

The major concern is how hippocampus-dependent memory and synaptic plasticity are modulated by stress hormone. Stress modulates intrinsic hippocampal excitability and activity-dependent synaptic plasticity, which are involved in transferring immediate or short-term memories into long-term memories. If a stressor is physical or cognitive, the central nervous system mediates the synergistic activation of the neuroendocrine and autonomic nervous systems. In doing so, it optimizes physiological parameters that help subserve short-term coping needs, e.g., gluconeogenesis, enhanced oxygen delivery, increased heart rate, and effective vigilance. The limbic forebrain circuits are activated to immediately cope with the threat stressors. Prominent in the stress circuitry of the brain are the amygdala, for regulation of emotional responses and modulating the consolidation of memory,66 and the hippocampus, for context memory in terms of time and place.67, 68 However, inappropriate stress or GC exposure impairs spatial learning and memory,63 contextual fear conditioning (hippocampus implicated)69 and fear conditioning (amygdala implicated).35, 70 Likewise, early life stress or exposure to GCs can result in long-term alterations of several molecules important to synaptic plasticity during memory processing, such as a decrease in hippocampal BDNF63 and pCREBSer-133,71 pivotal in the switch from short-term to long-term memory,72 and an alteration in hippocampal NMDA receptor expression.73, 74

6.2. Effects on emotional reactivity in later life 

Early life perturbations induce persistent changes in the CRH system, including increased CRH expression in the PVN and the amygdala and alterations of CRH receptor levels, increased α2 adrenoreceptor density in the locus ceruleus, as well as decreased GABAA/benzodiazepine receptor binding in the basolateral and central nuclei of the amygdala and in the locus ceruleus. Considering the importance of the amygdala for the behavioral responses to stress, particularly the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus and the anxiolytic actions of GABAA/benzodiazepine receptors, such effects may contribute to the enhanced stress-related behavior, such as open-field exposure, and fearfulness in response to novelty.64 Inappropriately increased exposure to CORT or stress alters specific gene patterns, with the greatest implication on the 5-hydroxytryptamine 1A receptor system.75, 76, 77 In one study, disruption of the 5-hydroxytryptamine 1A receptor gene in early postnatal life produced a more anxious mouse, an effect not observed when mutagenesis was postponed until adulthood.53Furthermore, prior work has also demonstrated a critical role of BDNF in mediating the effects of early life stress in mood disorders.15, 78 BDNF is involved in adaptive brain plasticity, in particular neuronal growth, differentiation, and synaptogenesis, and is highly expressed in the neocortex and hippocampus, critical to HPA axis activity, as well as being involved in mood disorders. It is reasonable to speculate that BDNF plays an important role in the modulation of neural plasticity changes in the pathogenesis of psychiatric disorders after early life stress. Roceri et al15 showed long-term depression of BDNF gene expressions in the prefrontal cortex and hippocampus after early maternal deprivation.

6.3. Effects on increased incidence of epileptogenesis 

Seizures are one of the most common pediatric emergencies with the highest incidence in the first year of life. Notwithstanding the higher susceptibility to seizures, the immature brain is less vulnerable to seizure-induced injuries than the mature brain.79, 80 However, temporal lobe epilepsy, the most common focal intractable epilepsy, is thought to be a multistage process of increasing epileptogenesis commencing in early life, and epidemiological data implicate early life stress in the aggravation of limbic epilepsy.81 Epileptogenesis is a process by which a normal brain develops epilepsy, and the hippocampus is implicated in the pathogenesis of both the initiation phase and propagation phase. Seizure-induced neural injuries are a kind of excitotoxicity, mainly mediated by excessive calcium influx into cells by means of overactivation of excitatory neurotransmitter (glutamate) receptors (NMDA receptor and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor) and subsequent activation of a number of enzymes, including phospholipase, endonucleases, and proteases. These enzymes go on to damage cell structures. Excessive GCs increase extracellular glutamate levels,82, 83 calcium conductance, either voltage- or ligand-gated,82 and alter expressions of NMDA receptor subunits,84 as well as reduce the uptake of glutamate by glia (Figure 3).65, 85 It is reasonable to speculate that stress or excessive GC exposure will potentiate the excitotoxic effect of concurrent neurological insults.22, 65 Several lines of evidence have demonstrated that early life stress impacts on epileptogenesis by accelerating kindling epileptogenesis,86 changing seizure propensity,87, 88 and potentiating early life seizure-induced epileptogenesis.33 Prior steroid treatment has been shown to result in an acceleration of seizure behavior and a significant increase in the amplitude of voltage-gated Ca2+ currents in kindled rats89 and increases in the magnitude of the glutamate response to kainic acid-induced seizures, exacerbating NMDA receptor-mediated toxicity.90, 91 Repeated parental separation has been shown to result in an elevated excitatory spine density,92 and alteration of numbers of hippocampal GABAergic neuronal subpopulations, reflecting reduced inhibitory activity in the CA1 region.93 Frye et al87 demonstrated that prenatal stress reduces the effectiveness of the neurosteroid 3α,5α-tetrahydroprogesterone, a GABA-active metabolite of progesterone, to prevent kainic acid-induced seizures. Thus, early life stress changes the balance of excitatory and inhibitory synaptic connectivity in the hippocampus, a critical region for epileptogenesis.

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  • Figure 3 

    Model of glucocorticoid effects on excitotoxicity. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and activates both ionotropic receptors and G protein-coupled (mGlu) receptors. Activation of these receptors evokes cellular responses by means of increased iCa2+ and is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as LTP and LTD. The iCa2+ level varies with Ca2+ influx through both the glutamate-operated Ca2+ channel and VSCC and with the mGlu receptor-mediated calcium release from intracellular stores. However, high concentrations of glutamate cause cell death through the excessive activation of these receptors. Overactivation at NMDA receptors triggers an excessive entry of Ca2+, initiating a series of cytoplasmic and nuclear processes that promote neuronal cell death, such as activating NOS, lipases, proteases, and endonucleases. All these mechanisms, together with enhanced oxidative stress can induce cell death through necrosis as well as apoptosis. Glucocorticoids seem to enhance the postsynaptic response by inhibiting the glutamate uptake by glial cells and by preferentially stimulating the genomic expression of the NMDA receptor subunit, NR2B, that increases Ca2+ influx. Furthermore, glucocorticoid receptor activation increases Ca2+ current through VSCCs65, 82, 83, 84, 85 (modified from Fig. 2 in Ref. 65). VSCC = voltage-sensitive Ca2+ channel; NMDA = N-methyl-d-aspartic acid; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; iCa2+ = intracellular Ca2+; mGlu = metabotropic glutamate; LTP = long-term potentiation; LTD = long-term depression; NOS = nitric oxide synthase.

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7. Conclusions 

Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health. Stress can elicit an immediate response mode to protect an individual against threats, and a slower mode, which facilitates behavioral adaptation, promotes recovery, and reestablishes homeostasis. GC hormones are implicated in both system modes. As highlighted in this review, adverse experiences during development contribute to deficits in the maturity of stress response systems. Early life stress programs HPA axis development and exerts profound effects on neural plasticity, with resultant long-term influences on neurobehavior. In humans, early life stress, including persistent emotional neglect, family conflict, or excessive exposure to steroids, is one of the most robust risks for mental illness and increases vulnerability to diseases throughout life.

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Acknowledgments 

This work was supported by grant 99-2314-B-182A-003-MY3 from the National Science Council, Taiwan to Dr Li-Tung Huang, and by grants of 96CM-KMU-03 and 96CM-KMU-04 to Ming-Chi Lai.

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References 

  1. Buchmann AF, Kopf D, Westphal S, et al. Impact of early parental child-rearing behavior on young adults’ cardiometabolic risk profile: a prospective study. Psychosom Med. 2010;72:156–162
  2. Talge NM, Neal C, Glover V. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?. J Child Psychol Psychiatry. 2007;48:245–261
  3. Taylor SE. Mechanisms linking early life stress to adult health outcomes. Proc Natl Acad Sci U S A. 2010;107:8507–8512
  4. Meagher MW, Sieve AN, Johnson RR, et al. Neonatal maternal separation alters immune, endocrine, and behavioral responses to acute Theiler’s virus infection in adult mice. Behav Genet. 2010;40:233–249
  5. Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–466
  6. Craft TK, Zhang N, Glasper ER, Hurn PD, Devries AC. Neonatal factors influence adult stroke outcome. Psychoneuroendocrinology. 2006;31:601–613
  7. Francis DD, Diorio J, Plotsky PM, Meaney MJ. Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci. 2002;22:7840–7843
  8. Levine S. Maternal behavior as a mediator of pup adrenocortical function. Ann NY Acad Sci. 1994;746:260–275
  9. Liu D, Diorio J, Tannenbaum B, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997;277:1659–1662
  10. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab. 2002;13:373–380
  11. McCormick CM, Kehoe P, Kovacs S. Corticosterone release in response to repeated, short episodes of neonatal isolation: evidence of sensitization. Int J Dev Neurosci. 1998;16:175–185
  12. McEwen BS. Effects of adverse experiences for brain structure and function. Biol Psychiatry. 2000;48:721–731
  13. Meaney MJ. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci. 2001;24:1161–1192
  14. 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. Mol Brain Res. 1993;18:195–200
  15. Roceri M, Cirulli F, Pessina C, Peretto P, Racagni G, Riva MA. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry. 2004;55:708–714
  16. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–854
  17. Heuser I, Lammers CH. Stress and the brain. Neurobiol Aging. 2003;24(S1):S69–S76
  18. Imaki T, Nahan JL, Rivier C, Sawchenko PE, Vale W. Differential regulation of corticotropin-releasing factor mRNA in rat brain regions by glucocorticoids and stress. J Neurosci. 1991;11:585–599
  19. Plotsky PM, Sawchenko PE. Hypophysial-portal plasma levels, median eminence content, and immunohistochemical staining of corticotropin-releasing factor, arginine vasopressin, and oxytocin after pharmacological adrenalectomy. Endocrinology. 1987;120:1361–1369
  20. Silbernagl S, Despopoulos A. Color Atlas of Physiology (Basic Sciences). 6th edition. Stuttgart/New York: Thieme; 2009;pp. 268–333
  21. von Bardeleben U, Holsboer F. Human corticotropin releasing hormone: clinical studies in patients with affective disorders, alcoholism, panic disorder and in normal controls. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:S165–S187
  22. Sapolsky RM. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress. 1996;1:1–19
  23. Eisenberg L. Social policy and child health. Acta Paediatr Suppl. 1994;394:7–13
  24. Eisenberg L, Belfer M. Prerequisites for global child and adolescent mental health. J Child Psychol Psychiatry. 2009;50:26–35
  25. Linnet KM, Dalsgaard S, Obel C, et al. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am J Psychiatry. 2003;160:1028–1040
  26. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58:542–548
  27. Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. 2003;29:381–390
  28. Scher MS, Hamid MY, Steppe DA, Beggarly ME, Painter MJ. Ictal and interictal electrographic seizure durations in preterm and term neonates. Epilepsia. 1993;34:284–288
  29. Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med. 2004;350:1304–1313
  30. Barbazanges A, Piazza PV, Le Moal M, Maccari S. Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci. 1996;16:3943–3949
  31. Huang LT, Holmes GL, Lai MC, et al. Maternal deprivation stress exacerbates cognitive deficits in immature rats with recurrent seizures. Epilepsia. 2002;43:1141–1148
  32. Lai MC, Holmes GL, Lee KH, et al. Effect of neonatal isolation on outcome following neonatal seizures in rats: the role of corticosterone. Epilepsy Res. 2006;68:123–136
  33. Lai MC, Lui CC, Yang SN, Wang JY, Huang LT. Epileptogenesis is increased in rats with neonatal isolation and early-life seizure and ameliorated by MK-801: a long-term MRI and histological study. Pediatr Res. 2009;66:441–447
  34. Lai MC, Yang SN, Huang LT. Neonatal isolation enhances anxiety-like behavior following early-life seizure in rats. Pediatr Neonatol. 2008;49:19–25
  35. Sevelinges Y, Sullivan RM, Messaoudi B, Mouly AM. Neonatal odor-shock conditioning alters the neural network involved in odor fear learning at adulthood. Learn Mem. 2008;15:649–656
  36. de Kloet ER. Steroids, stability and stress. Front Neuroendocrinol. 1995;16:416–425
  37. de Kloet ER, Reul JM, Sutanto W. Corticosteroids and the brain. J Steroid Biochem Mol Biol. 1990;37:387–394
  38. Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)?. Trends Neurosci. 2002;25:518–524
  39. Brunson KL, Eghbal-Ahmadi M, Bender R, Chen Y, Baram TZ. Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc Natl Acad Sci USA. 2001;98:8856–8861
  40. Hatalski CG, Guirguis C, Baram TZ. Corticotropin releasing factor mRNA expression in the hypothalamic paraventricular nucleus and the central nucleus of the amygdala is modulated by repeated acute stress in the immature rat. J Neuroendocrinol. 1998;10:663–669
  41. Wadhwa PD, Sandman CA, Garite TJ. The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res. 2001;133:131–142
  42. Sapolsky RM, Meaney MJ. Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res. 1986;39:64–76
  43. Grino M, Burgunder JM, Eskay RL, Eiden LE. Onset of glucocorticoid responsiveness of anterior pituitary corticotrophs during development is scheduled by corticotropin-releasing factor. Endocrinology. 1989;124:2686–2692
  44. Walker CD, Akana SF, Cascio CS, Dallman MF. Adrenalectomy in the neonate: adult-like adrenocortical system responses to both removal and replacement of corticosterone. Endocrinology. 1990;127:832–842
  45. Schmidt MV, Enthoven L, van der Mark M, Levine S, de Kloet ER, Oitzl MS. The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse. Int J Dev Neurosci. 2003;21:125–132
  46. Erdmann G, Schütz G, Berger S. Loss of glucocorticoid receptor function in the pituitary results in early postnatal lethality. Endocrinology. 2008;149:3446–3451
  47. Levine S, Huchton DM, Wiener SG, Rosenfeld P. Time course of the effect of maternal deprivation on the hypothalamic-pituitary-adrenal axis in the infant rat. Dev Psychobiol. 1991;24:547–558
  48. Schmidt MV. Molecular mechanisms of early life stress: lessons from mouse models. Neurosci Biobehav Rev. 2010;34:845–852
  49. Smith MA, Kim SY, van Oers HJ, Levine S. Maternal deprivation and stress induce immediate early genes in the infant rat brain. Endocrinology. 1997;138:4622–4628
  50. Avishai-Eliner S, Hatalski CG, Tabachnik E, Eghbal-Ahmadi M, Baram TZ. Differential regulation of glucocorticoid receptor messenger RNA (GR-mRNA) by maternal deprivation in immature rat hypothalamus and limbic regions. Brain Res Dev Brain Res. 1999;114:265–268
  51. Schmidt MV, Oitzl MS, Levine S, de Kloet ER. The HPA system during the postnatal development of CD1 mice and the effects of maternal deprivation. Brain Res Dev Brain Res. 2002;139:39–49
  52. Weaver IC. Epigenetic effects of glucocorticoids. Semin Fetal Neonatal Med. 2009;14:143–150
  53. Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol. 2009;300:7–16
  54. Coste SC, Kesterson RA, Heldwein KA, et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet. 2000;24:403–409
  55. Chen Y, Bender RA, Brunson KL, et al. Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proc Natl Acad Sci U S A. 2004;101:15782–15787
  56. Chen Y, Bender RA, Frotscher M, Baram TZ. Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci. 2001;21:7171–7181
  57. Oitzl MS, Champagne DL, van der Veen R, de Kloet ER. Brain development under stress: hypotheses of glucocorticoid actions revisited. Neurosci Biobehav Rev. 2010;34:853–866
  58. Leuner B, Gould E. Structural plasticity and hippocampal function. Annu Rev Psychol. 2010;61:111–140C1–3
  59. Karst H, Joëls M. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J Neurophysiol. 2005;94:3479–3486
  60. Rich MM, Wenner P. Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci. 2007;30:119–125
  61. Fenoglio KA, Brunson KL, Baram TZ. Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front Neuroendocrinol. 2006;27:180–192
  62. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci. 2000;3:799–806
  63. Aisa B, Elizalde N, Tordera R, Lasheras B, Del Río J, Ramírez MJ. Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: implications for spatial memory. Hippocampus. 2009;19:1222–1231
  64. Diorio J, Meaney MJ. Maternal programming of defensive responses through sustained effects on gene expression. J Psychiatry Neurosci. 2007;32:275–284
  65. Kim JJ, Yoon KS. Stress: metaplastic effects in the hippocampus. Trends Neurosci. 1998;21:505–509
  66. McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci. 2004;27:1–28
  67. Foster JA, Burman MA. Evidence for hippocampus-dependent contextual learning at postnatal day 17 in the rat. Learn Mem. 2010;17:259–266
  68. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci. 1992;106:274–285
  69. Matsumoto M, Yoshioka M, Togashi H. Early postnatal stress and neural circuit underlying emotional regulation. Int Rev Neurobiol. 2009;85:95–107
  70. Sevelinges Y, Moriceau S, Holman P, et al. Enduring effects of infant memories: infant odor-shock conditioning attenuates amygdala activity and adult fear conditioning. Biol Psychiatry. 2007;62:1070–1079
  71. Musholt K, Cirillo G, Cavaliere C, et al. Neonatal separation stress reduces glial fibrillary acidic protein- and S100 beta-immunoreactive astrocytes in the rat medial precentral cortex. Dev Neurobiol. 2009;69:203–211
  72. Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci. 1998;21:127–148
  73. Owen D, Matthews SG. Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs. J Physiol. 2007;578:249–257
  74. Son GH, Geum D, Chung S, et al. Maternal stress produces learning deficits associated with impairment of NMDA receptor-mediated synaptic plasticity. J Neurosci. 2006;26:3309–3318
  75. Gross C, Zhuang X, Stark K, et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature. 2002;416:396–400
  76. Datson NA, van der Perk J, de Kloet ER, Vreugdenhil E. Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. Eur J Neurosci. 2001;14:1–17
  77. Feldker DE, Datson NA, Veenema AH, Meulmeester E, de Kloet ER, Vreugdenhil E. Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice. Eur J Neurosci. 2003;17:379–387
  78. Cirulli F, Berry A, Bonsignore LT, et al. Early life influences on emotional reactivity: evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels. Neurosci Biobehav Rev. 2010;34:808–820
  79. Dubé C, Boyet S, Marescaux C, Nehlig A. Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp Neurol. 2001;167:227–241
  80. Schmid R, Tandon P, Stafstrom CE, Holmes GL. Effects of neonatal seizures on subsequent seizure-induced brain injury. Neurology. 1999;53:1754–1761
  81. Koe AS, Jones NC, Salzberg MR. Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?. Front Behav Neurosci. 2009;3:1–16
  82. Nair SM, Werkman TR, Craig J, Finnell R, Joels M, Eberwine JH. Corticosteroid regulation of ion channel conductances and mRNA levels in individual hippocampal CA1 neurons. J Neurosci. 1998;18:2685–2696
  83. Venero C, Borrell J. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci. 1999;11:2465–2473
  84. Lee PR, Brady D, Koenig JI. Corticosterone alters N-methyl-D-aspartate receptor subunit mRNA expression before puberty. Brain Res Mol Brain Res. 2003;115:55–62
  85. Virgin CE, Ha TP, Packan DR, et al. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity. J Neurochem. 1991;57:1422–1428
  86. Taher TR, Salzberg M, Morris MJ, Rees S, O’Brien TJ. Chronic low-dose corticosterone supplementation enhances acquired epileptogenesis in the rat amygdala kindling model of TLE. Neuropsychopharmacology. 2005;30:1610–1616
  87. Frye CA, Rhodes ME, Raol YH, Brooks-Kayal AR. Early postnatal stimulation alters pregnane neurosteroids in the hippocampus. Psychopharmacology (Berl). 2006;186:343–350
  88. Salzberg M, Kumar G, Supit L, et al. Early postnatal stress confers enduring vulnerability to limbic epileptogenesis. Epilepsia. 2007;48:2079–2085
  89. Karst H, de Kloet ER, Joels M. Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state. Eur J Neurosci. 1999;11:889–898
  90. Mulholland PJ, Self RL, Harris BR, Littleton JM, Prendergast MA. (−)-Nicotine ameliorates corticosterone’s potentiation of N-methyl-D-aspartate receptor-mediated cornu ammonis 1 toxicity. Neuroscience. 2004;125:671–682
  91. Stein-Behrens BA, Lin WJ, Sapolsky RM. Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem. 1994;63:596–602
  92. Seidel K, Helmeke C, Poeggel G, Braun K. Repeated neonatal separation stress alters the composition of neurochemically characterized interneuron subpopulations in the rodent dentate gyrus and basolateral amygdala. Dev Neurobiol. 2008;68:1137–1152
  93. Anand KJ. Effects of perinatal pain and stress. Prog Brain Res. 2000;122:117–129

PII: S1875-9572(11)00039-8

doi:10.1016/j.pedneo.2011.03.008

Pediatrics & Neonatology
Volume 52, Issue 3 , Pages 122-129, June 2011

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