This week we'll be reading this article by Lupien et al. 2009
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Every day, parents observe the growing behavioural repertoires of their infants and young children, and the corresponding changes in cognitive and emotional functions. These changes are thought to relate to normal brain development, particularly the development of the hippocampus, the amygdala and the frontal lobes, and the complex circuitry that connects these brain regions. At the other end of the age spectrum, we observe changes in cognition that accompany aging in our parents. These changes are related to both normal and pathological brain processes associated with aging.
Studies in animals and humans have shown that during both early childhood and old age the brain is particularly sensitive to stress, probably because it undergoes such important changes during these periods. Furthermore, research now relates exposure to early-life stress with increased reactivity to stress and cognitive deficits in adulthood, indicating that the effects of stress at different periods of life interact.
Stress triggers the activation of the hypothalamus- pituitary-adrenal (HPA) axis, culminating in the pro- duction of glucocorticoids by the adrenals (FIG. 1). Receptors for these steroids are expressed throughout the brain; they can act as transcription factors and so regulate gene expression. Thus, glucocorticoids can have potentially long-lasting effects on the functioning of the brain regions that regulate their release.
This Review describes the effects of stress during pre- natal life, infancy, adolescence, adulthood and old age on the brain, behaviour and cognition, using data from ani- mal (BOX 1) and human studies. Here, we propose a model
that integrates the effects of stress across the lifespan, along with future directions for stress research.
Prenatal stress Animal studies. In animals, exposure to stress early in life has ‘programming’ effects on the HPA axis and the brain1. A single or repeated exposure of a pregnant female to stress2 or to glucocorticoids3 increases mater- nal glucocorticoid secretion. A portion of these gluco- corticoids passes through the placenta to reach the fetus, increasing fetal HPA axis activity and modifying brain development4. In rats prenatal stress leads to long-term increases in HPA axis activity 5. Controlling glucocor- ticoid levels in stressed dams by adrenalectomy and hormone replacement prevents these effects, indicating that elevations in maternal glucocorticoids mediate the prenatal programming of the HPA axis6.
Glucocorticoids are important for normal brain maturation: they initiate terminal maturation, remodel axons and dendrites and affect cell survival7; both sup- pressed and elevated glucocorticoid levels impair brain development and functioning. For example, admin- istration of synthetic glucocorticoids to pregnant rats delays the maturation of neurons, myelination, glia and vasculature in the offspring, significantly altering neuronal structure and synapse formation and inhibit- ing neurogenesis4. Furthermore, juvenile and adult rats exposed to prenatal stress have decreased numbers of mineralocorticoid receptors (MRs) and glucocorticoid recep- tors (GRs) in the hippocampus, possibly because of epi- genetic effects on gene transcription8. The hippocampus
*Université de Montréal, Mental Health Research Centre, Fernand Seguin Hôpital Louis‑H Lafontaine, Montreal, Quebec, H1N 3V2, Canada. ‡Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA. §Institute of Child Development, University of Minnesota, Minneapolis, Minnesota 55455, USA. ||Department of Psychiatry, Emory University, 101 Woodruff Circle, Suite 4000, Atlanta, Georgia 30307, USA. Correspondence to S.J.L. e‑mail: [email protected] umontreal.ca doi:10.1038/nrn2639 Published online 29 April 2009
Programming When an environmental factor that acts during a sensitive developmental period affects the structure and function of tissues, leading to effects that persist throughout life.
Effects of stress throughout the lifespan on the brain, behaviour and cognition Sonia J. Lupien*, Bruce S. McEwen‡, Megan R. Gunnar § and Christine Heim||
Abstract | Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.
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Nature Reviews | Neuroscience
MRs and GRs
Mineralocorticoid receptor A receptor that is activated by mineralocorticoids, such as aldosterone and deoxycorti- costerone, as well as glucocorticoids, such as cortisol and cortisone. It also responds to progestins.
Glucocorticoid receptor A receptor that is activated by cortisol, corticosterone and other glucocorticoids and is expressed in almost every cell in the body. It regulates genes controlling development, metabolism and the immune response.
inhibits HPA axis activity (FIG. 1), and a prenatal stress- induced reduction in hippocampal MRs and GRs could decrease this inhibition, with a resulting increase in basal and/or stress-induced glucocorticoid secretion. In rhe- sus monkeys, prenatal treatment with the synthetic GR agonist dexamethasone causes a dose-dependent degen- eration of hippocampal neurons, leading to a reduced hippocampal volume at 20 months of age9.
Effects on other brain regions are also apparent. Rats exposed to stress during the last week of gestation have significantly decreased dendritic spine density in the anterior cingulate gyrus and orbitofrontal cortex10. Furthermore, prenatal exposure to glucocorticoids leads to increased adult corticotropin-releasing hormone (CRH) levels in the central nucleus of the amygdala, a key region in the regulation of fear and anxiety11.
Exposure to prenatal stress has three major effects on adult behaviour: learning impairments, especially in aging rats12; enhanced sensitivity to drugs of abuse13; and increases in anxiety- and depression-related behav- iours14. The impaired learning is thought to result from the effects of prenatal stress on hippocampal function15, whereas the effects on anxiety are thought to be medi- ated by prenatal stress-induced increases in CRH in the amygdala11. Prenatal glucocorticoid exposure affects the developing dopaminergic system, which is involved in reward- or drug-seeking behaviour16, and it has been
suggested that the increased sensitivity to drugs of abuse is related to the interaction between prenatal stress, glucocorticoids and dopaminergic neurons16.
Human studies. In agreement with animal data, findings from retrospective studies on children whose mothers experienced psychological stress or adverse events or received exogenous glucocorticoids during pregnancy suggest that there are long-term neurodevelopmental effects17. First, maternal stress or anxiety18, depression19 and glucocorticoid treatment during pregnancy17 have been linked with lower birthweight or smaller size (for gestational age) of the baby. More importantly, mater- nal stress, depression and anxiety have been associated with increased basal HPA axis activity in the offspring at different ages, including 6 months20, 5 years21 and 10 years22.
Disturbances in child development (both neurologi- cal and cognitive) and behaviour have been associated with maternal stress23 and maternal depression dur- ing pregnancy 24, and with fetal exposure to exogenous gluco corticoids in early pregnancy 25. These behavioural alterations include unsociable and inconsiderate behav- iours, attention deficit hyperactivity disorder and sleep disturbances as well as some psychiatric disorders, including depressive symptoms, drug abuse and mood and anxiety disorders. Very few studies have measured
Figure 1 | The stress system. When the brain detects a threat, a coordinated physiological response involving autonomic, neuroendocrine, metabolic and immune system components is activated. A key system in the stress response that has been extensively studied is the hypothalamus-pituitary-adrenal (HPA) axis. Neurons in the medial parvocellular region of the paraventricular nucleus of the hypothalamus release corticotropin- releasing hormone (CRH) and arginine vasopressin (AVP). This triggers the subsequent secretion of adrenocortico- tropic hormone (ACTH) from the pituitary gland, leading to the production of glucocorticoids by the adrenal cortex. In addition, the adrenal medulla releases catecholamines (adrenaline and noradrenaline) (not shown). The responsiveness of the HPA axis to stress is in part determined by the ability of glucocorticoids to regulate ACTH and CRH release by binding to two corticosteroid receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Following activation of the system, and once the perceived stressor has subsided, feedback loops are triggered at various levels of the system (that is, from the adrenal gland to the hypothalamus and other brain regions such as the hippocampus and the frontal cortex) in order to shut the HPA axis down and return to a set homeostatic point. By contrast, the amygdala, which is involved in fear processing142, activates the HPA axis in order to set in motion the stress response that is necessary to deal with the challenge. Not shown are the other major systems and factors that respond to stress, including the autonomic nervous system, the inflammatory cytokines and the metabolic hormones. All of these are affected by HPA activity and, in turn, affect HPA function, and they are also implicated in the pathophysiological changes that occur in response to chronic stress, from early experiences into adult life.
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changes in the brain as a function of prenatal stress in humans. However, a recent study showed that low birth- weight combined with lower levels of maternal care was associated with reduced hippocampal volume in adult- hood26. This finding is consistent with evidence that effects of prenatal stress in humans are often moderated by the quality of postnatal care, which in turn is consist- ent with the protracted postnatal development of the human brain.
Postnatal stress Animal studies. Although in rodents the postnatal period is relatively hyporesponsive to stress (BOX 2), one of the most potent stressors for pups is separation from the dam. long separation periods (3 h or more each day) activate the pups’ HPA axis, as evidenced by increased plasma levels of adrenocorticotropic hormone and glucocorticoids27. Protracted maternal separation also reduces pituitary CRH binding sites28, and low levels of maternal care reduce GR levels in the hippocampus29.
The effects of maternal deprivation extend beyond the HPA axis. Early prolonged maternal separation in rats increases the density of CRH binding sites in the prefrontal cortex, amygdala, hypothalamus, hippo- campus and cerebellum, as measured post-infancy28. In the hippocampus CRH mediates stress-related loss of branches and spines30, and in the amygdala and hypotha- lamus elevated CRH levels are associated with increased anxiety and HPA axis activity, respectively31. Thus, the increase in CRH-binding sites induced by maternal sep- aration might have negative effects over time. The long- term effects of prolonged separation depend on the age
of the pup and the duration of the deprivation, with the effects noted above generally being greater when these separations occur earlier in infancy and last for longer durations32.
Although the rodent work provides a rich frame- work for conceptualizing the impact of early-life stress, the fact that the rodent brain is much less developed at birth than the primate brain makes translation of the findings to humans somewhat challenging (BOX 3). non- human primates have more human-like brain matura- tion at birth and patterns of parent–offspring relations, and so provide an important bridge in the translation of the rodent findings. Studies in monkeys have shown that repeated, unpredictable separations from the mother33, unpredictable maternal feedings34 or spontaneous mater- nal abusive behaviour35 increases CRH concentrations in the cerebrospinal fluid and alters the diurnal activity of the HPA axis for months or even years after the period of adversity: cortisol levels are lower than normal early in the morning (around wake-up) and slightly higher than normal later in the day, an effect that seems to reverse over time in the absence of continued, ongoing psy- chosocial stress35. These diurnal effects have not been noted in rodents, but the effects on higher brain regions seem to be comparable to the rodent findings and include heightened fear behaviour36, exaggerated startle responses33, hippocampal changes such as an increase in the intensity of non-phosphorylated neurofilament pro- tein immunoreactivity in the dentate gyrus granule cell layer37, and atypical development of prefrontal regions involved in emotion and behaviour control38.
Human studies. A human equivalent of the rodent maternal separation paradigms might be studies of children who attend full-day, out-of-home day care centres. Studies have reported that glucocorticoid levels rise in these children over the day, more so in toddlers than in older preschool-aged children39,40. However, it is important to note that the elevated glucocorticoid levels observed are less pronounced than those observed in rodents and monkeys exposed to maternal separation. Moreover, although age accounts for most of the varia- tion in the rise in glucocorticoid levels by late afternoon, the quality of care is also important, with less supportive care producing larger increases, especially for children who are more emotionally negative and behaviour- ally disorganized39. So far, there is no evidence that the elevated glucocorticoid levels associated with being in day care affect development; however, children who are exposed to poor care for long hours early in develop- ment have an increased risk of behaviour problems later in development41.
Parent–child interactions and the psychological state of the mother also influence the child’s HPA axis activity. Beginning early in the first year, when the HPA system of the infant is quite labile, sensitive parenting is associ- ated with either smaller increases in or less prolonged activations of the HPA axis to everyday perturbations42. Maternal depression often interferes with sensitive and supportive care of the infant and young child; there is increasing evidence that offspring of depressed mothers,
Box 1 | Models to study stress in animals and humans
The hypothalamus-pituitary-adrenal axis can be activated by a wide variety of stressors. Some of the most potent are psychological or processive stressors (that is, stressors that involve higher-order sensory cognitive processing), as opposed to physiological or systemic stressors. Many psychological stressors are anticipatory in nature — that is, they are based on expectation as the result of learning and memory (for example, conditioned stimuli in animals and the anticipation of threats, real or implied, in humans) or on species-specific predispositions (for example, avoidance of open space in rodents or the threat of social rejection and negative social evaluations in humans).
Animal studies allow the development of experimental protocols in which animals are submitted to acute and/or chronic stress and the resulting effects on brain and behaviour are studied. Experimental stressful ‘early-life’ manipulations in animals can be broadly split into prenatal and postnatal manipulations. Prenatal manipulations involve maternal stress, exposing the mother to synthetic glucocorticoids or maternal nutrient restriction. Postnatal manipulations include depriving the animal of maternal contact, modifying maternal behaviour and exposing the animal to synthetic glucocorticoids. In these protocols, the cause–effects relationship between stress and its impact on the brain can be demonstrated. By contrast, and because of ethical issues, the cause–effects impact of stress on the brain cannot be studied in humans, and most human studies are correlational by nature. However, there are some ‘experiments of nature’ that can be used to inform scientists about the effects of chronic exposure to early adversity on brain development and of adulthood and late-life stress effects on the brain. Intrauterine under-growth and low birth weight are considered indices of prenatal stress (including malnutrition) in humans. In terms of postnatal stress, low socio-economic status, maltreatment and war are considered adverse events. In adults and older adults, studies of chronic caregivers (spouses of patients with brain degenerative disorders, parents of chronically sick children and health-care professionals) provide a human model of the impact of chronic stress on the brain, behaviour and cognition.
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especially those who were clinically depressed in the child’s early years, are at risk of heightened activity of the HPA axis43 or of developing depression during ado- lescence (controlling for maternal depression during adolescence)44. However, it should be noted that it can be difficult to exclude potentially confounding genetic factors in such studies. Furthermore, preschool-aged children of depressed mothers exhibit electroencephalo- graphic alterations in frontal lobe activity that corre- late with diminished empathy and other behavioural problems45.
In contrast to findings of elevated glucocorticoid lev- els in conditions of low parental care, studies in human children exposed to severe deprivation (for example, in orphanages or other institutions), neglect or abuse report lower basal levels of glucocorticoids, similar to what has been observed in primates39. one proposed mechanism for the development of hypocortisolism is downregulation of the HPA axis at the level of the pitui- tary in response to chronic CRH drive from the hypoth- alamus46, whereas a second possible mechanism is target tissue hypersensitivity to glucocorticoids47. Importantly, this hypocortisolism in humans in response to severe stress may not be permanent: sensitive and supportive care of fostered children normalizes their basal gluco- corticoid levels after only 10 weeks48. Another impor- tant finding comes from a recent study which showed that exposure to early adversity is associated with epi- genetic regulation of the GR receptor, as measured in the post-mortem brains of suicide victims49.
Stress in adolescence Animal studies. In rodents the period of adolescence has three stages: a prepubescent or early adolescent period from day 21 to 34, a mid-adolescent period from day 34 to 46 and a late adolescent period from day 46 to 59
(ReF. 50). In humans, adolescence is often considered to demarcate the period of sexual maturation (that is, starting with menarche in girls).
Although adolescence is a time of significant brain development, particularly in the frontal lobe51, there has been relatively little research on stress during this period in rodents. In adolescent rodents, HPA function is char- acterized by a prolonged activation in response to stres- sors compared with adulthood. Moreover, prepubertal rats have a delayed rise of glucocorticoid levels and prolonged glucocorticoid release in response to several types of stressors compared with adult rats52, owing to incomplete maturation of negative-feedback systems53.
In contrast to adult rats, which show a habituation of the stress response with repeated exposure to the same stressor 54, juvenile rats have a potentiated release of adrenocorticotropic hormone and glucocorticoids after repeated exposure to stress55, suggesting that the HPA axis responses to acute and chronic stress depend on the developmental stage of the animal. Compared with exposure to stress in adulthood alone, exposure to stress as both a juvenile and an adult increases basal anxiety levels in the adult 56. Moreover, exposure to juvenile stress results in greater HPA axis activation than a dou- ble exposure to stress during adulthood56, and this effect is long-lasting. These results suggest that repeated stress in adolescence leads to greater exposure of the brain to glucocorticoids than similar experiences in adulthood.
The fact that the adolescent brain undergoes vigor- ous maturation and the fact that, in rats, the hippocam- pus continues to grow until adulthood suggest that the adolescent brain may be more susceptible to stressors and the concomitant exposure to high levels of gluco- corticoids than the adult brain. Consistent with this hypothesis are findings that increased glucocorticoid levels before but not after puberty alter the expression of genes for nMDA (N-methyl-d-aspartate) receptor sub- units in the hippocampus57. In addition, chronic, vari- able stress during the peripubertal juvenile period results in reduced hippocampal volume in adulthood, which is accompanied by impairments in Morris water maze navigation and delayed shutdown of the HPA response to acute stress58. These differences became evident only in adulthood58, suggesting that stress in adolescence reduces hippocampal growth. Finally, the effects of juve- nile stress are long-lasting: adult rats exposed to juvenile stress exhibit reduced exploratory behaviour and poor avoidance learning 59. Moreover, stress in adolescence increases susceptibility to drugs of abuse during the adolescent period60 and in adulthood61.
Human studies. Interestingly, studies in human adoles- cents also suggest that the adolescent period is associ- ated with heightened basal and stress-induced activity of the HPA axis62. This could be related to the dramatic changes in sex steroid levels during this period, as these steroids influence HPA axis activity50. However, studies of stress in adolescent rats cannot be translated directly to humans because the brain areas that are undergoing development during adolescence differ between rats and humans: although the rodent hippocampus continues to
Box 2 | The stress hyporesponsive period: from animals to humans
Despite there being clear evidence that corticotropin-releasing hormone-containing neurons are present in the fetal rat139, in rodents noxious stimuli evoke only a subnormal hypothalamus-pituitary-adrenal (HPA) axis response during the first 2 weeks of life140. During this so-called stress hyporesponsive period (SHRP), baseline plasma glucocorticoid levels are lower than normal and are only minimally increased by exposure to a noxious stressor140. The SHRP is due to a rapid regression of the HPA axis after birth140 and may have evolved in rodents to protect the rapidly developing brain from the impact of elevated glucocorticoids.
Evidence is accumulating that in children there may be a comparable hyporesponsive period that emerges in infancy and extends throughout most of childhood141. At birth, glucocorticoid levels increase sharply in response to various stressors, such as a physical examination or a heel lance. However, over the course of the first year the HPA axis becomes more insensitive to stressors. No study has assessed the exact period over which this human SHRP may occur, but in adolescents glucocorticoid levels can become elevated in response to a psychosocial stressor141, which suggests that the SHRP could extend throughout childhood.
In rodents the SHRP is maintained primarily by maternal care (that is, the presence of the dam seems to suppress HPA axis activity); indeed, maternal separation is a potent inducer of a stress response, even during the SHRP. Similarly, in humans the apparent hyporesponsivity of the HPA axis might reflect the fact that during the first year of life the HPA axis comes under strong social regulation or parental buffering141. Here again, stressors that involve a lack of parental care or social contact can induce a stress response in children.
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develop well into adulthood, in humans it is fully devel- oped by 2 years of age63. The frontal cortex and amygdala continue to develop in both species, but humans have larger ontogenic bouts of development in frontal regions than do rodents (BOX 3).
There are indications that the adolescent human brain might be especially sensitive to the effects of elevated levels of glucocorticoids and, by extension, to stress. Recent studies on the ontogeny of MR and GR expres- sion show that GR mRnA levels in the prefrontal cortex are high in adolescence and late adulthood compared with in infancy, young adulthood and senescence64. This suggests that the cognitive and emotional processes that are regulated by these brain areas might be sensitive to GR-mediated regulation by glucocorticoids in an age- dependent manner. Various forms of psychopathology, including depression and anxiety, increase in prevalence in adolescence65,66. Periods of heightened stress often precede the first episodes of these disorders, raising the possibility that heightened HPA reactivity during adoles- cence increases sensitivity to the onset of stress-related mental disorders.
Adolescence is also a period in which the long- lasting effects of earlier exposures to stress become evi- dent. Adolescents who grew up in poor economic condi- tions have higher baseline glucocorticoid levels67, as do adolescents whose mothers were depressed in the early postnatal period44. High early-morning glucocorticoid levels that vary markedly from day to day during the transition to adolescence are not associated with depres- sive symptoms at that time, but they predict increased risk for depression by age 16 (ReF. 44).
Although early-life stress impairs hippocampal devel- opment in rodents, there is currently little evidence
of comparable effects in humans. Children exposed to physical or sexual abuse early in life do not exhibit reduced hippocampal volume (relative to whole-brain size) as adolescents, although adults with these histo- ries do show volume reductions68. This finding holds even when the abused children have been selected for chronic post-traumatic stress disorder (PTSD), and even though in some cases they exhibit overall reductions in brain volume69. By contrast, alterations in grey matter volume and the neuronal integrity of the frontal cortex, and reduced size of the anterior cingulate cortex, have been reported in adolescents exposed to early (and con- tinued) adversity70. Together, these results suggest that in humans the frontal cortex, which continues to develop during adolescence, might be particularly vulnerable to the effects of stress during adolescence. By contrast, the hippocampus, which develops mainly in the first years of life, might be less affected by exposure to adversity in adolescence.
Stress in adulthood Animal studies. Studies on adult stress in rodents have delineated the effects of acute versus chronic stress on brain and behaviour. The impact of acute stressors depends on the level of glucocorticoid elevations, with small increases resulting in enhanced hippocampus- mediated learning and memory, and larger, prolonged elevations impairing hippocampal function71. The inverted-u-shaped effects of acute glucocorticoid ele- vations might serve adaptive purposes by increasing vigilance and learning processes during acute challenges.
The mechanism that underlies the acute bipha- sic actions of glucocorticoids on cognition involves the adrenergic system in the basolateral nucleus of the amygdala. By enhancing noradrenergic function in the amygdala, glucocorticoids have a permissive effect on the priming of long-term potentiation in the den- tate gyrus by the basolateral nucleus72. This modulation of noradrenergic function by glucocorticoids has been linked to the enhanced memory for emotional events that occur under stress73.
Chronic stress or chronic exogenous administration of glucocorticoids in rodents causes dendritic atrophy in hippocampal CA3 pyramidal neurons74. However, these changes take several weeks to …
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