Effects of Early Life Stress on Neuroendocrine and Neurobehavior: Mechanisms and Implications
2011; Elsevier BV; Volume: 52; Issue: 3 Linguagem: Inglês
10.1016/j.pedneo.2011.03.008
ISSN2212-1692
Autores Tópico(s)Birth, Development, and Health
ResumoEvidence 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. 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. 1. IntroductionAn 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.1Buchmann A.F. 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: 156-162Crossref PubMed Scopus (24) Google Scholar, 2Talge N.M. Neal C. Glover V. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?.J Child Psychol Psychiatry. 2007; 48: 245-261Crossref PubMed Scopus (942) Google Scholar, 3Taylor S.E. Mechanisms linking early life stress to adult health outcomes.Proc Natl Acad Sci U S A. 2010; 107: 8507-8512Crossref PubMed Scopus (257) Google Scholar Talge et al2Talge N.M. Neal C. Glover V. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?.J Child Psychol Psychiatry. 2007; 48: 245-261Crossref PubMed Scopus (942) Google Scholar 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.4Meagher M.W. Sieve A.N. Johnson R.R. et al.Neonatal maternal separation alters immune, endocrine, and behavioral responses to acute Theiler's virus infection in adult mice.Behav Genet. 2010; 40: 233-249Crossref PubMed Scopus (37) Google Scholar 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.5Joëls M. Baram T.Z. The neuro-symphony of stress.Nat Rev Neurosci. 2009; 10: 459-466Crossref PubMed Scopus (999) Google Scholar, 6Craft T.K. Zhang N. Glasper E.R. Hurn P.D. Devries A.C. 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Effects of adverse experiences for brain structure and function.Biol Psychiatry. 2000; 48: 721-731Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 17Heuser I. Lammers C.H. Stress and the brain.Neurobiol Aging. 2003; 24: S69-S76Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar 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. 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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.13Meaney M.J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations.Annu Rev Neurosci. 2001; 24: 1161-1192Crossref PubMed Scopus (2072) Google Scholar, 22Sapolsky R.M. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion.Stress. 1996; 1: 1-19Crossref PubMed Scopus (601) Google Scholar3. Spectrum of Early Life StressEarly 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.1Buchmann A.F. 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: 156-162Crossref PubMed Scopus (24) Google Scholar, 2Talge N.M. Neal C. Glover V. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?.J Child Psychol Psychiatry. 2007; 48: 245-261Crossref PubMed Scopus (942) Google Scholar, 23Eisenberg L. Social policy and child health.Acta Paediatr Suppl. 1994; 394: 7-13Crossref PubMed Scopus (2) Google Scholar, 24Eisenberg L. 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Neonatal odor-shock conditioning alters the neural network involved in odor fear learning at adulthood.Learn Mem. 2008; 15: 649-656Crossref PubMed Scopus (42) Google Scholar These findings, in particular, indicate the importance of parental care as a mediator of the effects of early environmental adversity on neural development.4. Early Life Programming of Neuroendocrine SystemThe 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.36de Kloet E.R. Steroids, stability and stress.Front Neuroendocrinol. 1995; 16: 416-425Crossref PubMed Scopus (46) Google Scholar, 37de Kloet E.R. Reul J.M. Sutanto W. Corticosteroids and the brain.J Steroid Biochem Mol Biol. 1990; 37: 387-394Crossref PubMed Scopus (154) Google Scholar 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,38Avishai-Eliner S. Brunson K.L. Sandman C.A. Baram T.Z. Stressed-out, or in (utero)?.Trends Neurosci. 2002; 25: 518-524Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 39Brunson K.L. Eghbal-Ahmadi M. Bender R. Chen Y. Baram T.Z. 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The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse.Int J Dev Neurosci. 2003; 21: 125-132Crossref PubMed Scopus (201) Google Scholar The animals with GR knockouts have massive basal CORT levels during the first postnatal week, and the homozygous knockout offspring ultimately die.46Erdmann G. Schütz G. Berger S. Loss of glucocorticoid receptor function in the pituitary results in early postnatal lethality.Endocrinology. 2008; 149: 3446-3451Crossref PubMed Scopus (28) Google Scholar Furthermore, Levine et al47Levine S. Huchton D.M. Wiener S.G. Rosenfeld P. Time course of the effect of maternal deprivation on the hypothalamic-pituitary-adrenal axis in the infant rat.Dev Psychobiol. 1991; 24: 547-558Crossref PubMed Scopus (262) Google Scholar demonstrated a smaller increase in CORT secretion after ACTH secretion in neonatal pups compared with older animals outside the SHRP. 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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,49Smith M.A. Kim S.Y. van Oers H.J. Levine S. Maternal deprivation and stress induce immediate early genes in the infant rat brain.Endocrinology. 1997; 138: 4622-4628Crossref PubMed Scopus (119) Google Scholar and downregulated expressions of GR and mineralocorticoid receptors (MRs) in the hippocampus in maternally deprived pups at P9.50Avishai-Eliner S. Hatalski C.G. Tabachnik E. Eghbal-Ahmadi M. Baram T.Z. 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: 265-268Crossref PubMed Scopus (58) Google Scholar, 51Schmidt M.V. Oitzl M.S. Levine S. de Kloet E.R. The HPA system during the postnatal development of CD1 mice and the effects of maternal deprivation.Brain Res Dev Brain Res. 2002; 139: 39-49Crossref PubMed Scopus (95) Google Scholar 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 al16Weaver I.C. Cervoni N. Champagne F.A. et al.Epigenetic programming by maternal behavior.Nat Neurosci. 2004; 7: 847-854Crossref PubMed Scopus (4531) Google Scholar 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.52Weaver I.C. 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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.12McEwen B.S. Effects of adverse experiences for brain structure and function.Biol Psychiatry. 2000; 48: 721-731Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 59Karst H. Joëls M. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells.J Neurophysiol. 2005; 94: 3479-3486Crossref PubMed Scopus (142) Google Scholar, 60Rich M.M. Wenner P. 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