LupienSJ2005Stresshor

Psychoneuroendocrinology (2005) 30, 225–242 www.elsevier.com/locate/psyneuen 2004 CURT P. RICHTER AWARD WINNER Stress hormones and human memory function across the lifespan Sonia J. Lupien*, Alexandra Fiocco, Nathalie Wan, Francoise Maheu, Catherine Lord, Tania Schramek, Mai Thanh Tu Laboratory of Human Stress Research, Department of Psychiatry, Douglas Hospital Research Center, McGill University, 6875 Boudevard, Lasalle, Verdun, Que., Canada H4H-1R3 KEYWORDS Glucocorticoids; Memory; Cognition; Aged; Adults; Children; Humans Summary In this paper, we summarize the data obtained in our laboratory showing the effects of glucocorticoids on human cognitive function in older adults, young adults and children. We first present data obtained in the aged human population which showed that long-term exposure to high endogenous levels of glucocorticoids is associated with both memory impairments and a 14% smaller volume of the hippocampus. We then report on studies showing that in older adults with moderate levels of glucocorticoids, memory performance can be acutely modulated by pharmacological manipulations of glucocorticoids. In young adults, we present data obtained in our laboratory showing that cognitive processing sustained by the frontal lobes is also sensitive to acute increases of glucocorticoids. We also summarize studies showing that just as in older adults, memory performance in young adults can be acutely modulated by pharmacological manipulations of glucocorticoids. We then present a study in which we showed a differential involvement of adrenergic and glucocorticoid hormones for short- and long-term memory of neutral and emotional information. In the last section of the paper, we present data obtained in a population of young children and teenagers from low and high socioeconomic status (SES), where we showed that children from low SES present significantly higher levels of basal cortisol when compared to children from high SES. We then present new data obtained in this population showing that children and teenagers from low and high SES do not process the plausibility of positive and negative attributes in the same way. Children from low SES tended to process positive and negative attributes on a more negative note than children from high SES, and this type of processing was significantly related to basal cortisol at age 10, 12 and 14. Altogether, the results of these studies show that both bottom–up (effects of glucocorticoids on cognitive function), and top–down (effects of cognitive processing on glucocorticoid secretion) effects exist in the human population. Q 2004 Elsevier Ltd. All rights reserved. 1. Introduction * Corresponding author. Tel.: C1 514 761 6131x3359; fax: C1 514 888 4064. E-mail address: sonia.lupien@mcgill.ca (S.J. Lupien). One of the most important neuroendocrine systems responding to stress in both animals and humans is the hypothalamic–pituitary–adrenal (HPA) 0306-4530/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2004.08.003 226 axis (for an overview, see Francis and Meaney, 1999). It is activated when the homeostasis of the organism is challenged, situations that are commonly referred to as stress. During a perceived physical or psychological threat, a cascade of hormones is released. First, corticotropin releasing factor (CRF) is released from the hypothalamus, which triggers the subsequent release of adrenocorticotropin hormone (ACTH) from the pituitary into the bloodstream. Finally, ACTH stimulates the release of GCs (GCs; cortisol in humans, corticosterone in rats) from the adrenal cortex. Glucocorticoids have a variety of different effects in target systems throughout the organism, which can be summarized as aiming to increase the availability of energy substrates in different parts of the body, and allow for optimal adaptation to changing demands of the environment. While the activation of the HPA axis can be regarded as a basic adaptive mechanism in response to change, prolonged activation of this system presents a health risk to the organism: the highly catabolic GCs antagonize insulin and increase blood pressure, thus increasing the risk for developing diabetes, hypertension, and arterial disease. Also, growth and tissue repair is impaired. Furthermore, activation of the HPA axis suppresses immune functions, which in a chronic state, can be considered harmful for the organism, since it is associated with increased risk of infection (Munck and Guyre, 1991; Derijk and Sternberg, 1994). S.J. Lupien et al. the endogenous hormone occupies more than 90% of MRs, but only 10% of GRs. However, during stress and/or the circadian peak of GC secretion (the AM phase in humans and the PM phase in rats), MRs are saturated, and there is occupation of approximately 67–74% of GRs (Reul and DeKloet, 1985). The second major difference between these two receptor types is related to their distribution in the brain. The MR is exclusively present in the limbic system, with a preferential distribution in the hippocampus, parahippocampal gyrus, entorhinal, and insular cortices. On the contrary, the GR is present in both subcortical (paraventricular nucleus and other hypothalamic nuclei, the hippocampus and parahippocampal gyrus) and cortical structures, with a preferential distribution in the prefrontal cortex (McEwen et al., 1968, 1986; Meaney and Aitken, 1985; Diorio et al., 1993). As we will see in the following sections, the impact of GCs on cognitive function can be best understood in terms of the differential effects of MR and GR activation (for a complete review, see DeKloet et al., 1999) in both the hippocampus and frontal lobes, two brain structures critically involved in cognitive function. 1.2. Glucocorticoids and cognition in the aged human population Although science has managed to increase human longevity over the decades, enhanced life endurance is not necessarily always accompanied by health and independence. For many years, physical and cognitive decline in the elderly has been well documented and accepted as the norm. However, since the recognition of greater cognitive variability in the elderly, compared to young adults, researchers have called into question the concept of ‘normal decline’ (Rowe and Kahn, 1987). Indeed, if the group variance of the elderly population is so high, it must be because some aged individuals show very poor cognitive performance while others show very high levels of performance (Rowe and Kahn, 1987; Lupien and Wan, 2004). Research has thus begun to focus on factors that may contribute to the heterogeneity in cognitive performance in later years (Lupien and Lecours, 1993). Over the past three decades, it has been found that stress exposure over the lifespan, or more specifically, stress hormones, play a significant role in the aging process (Sapolsky et al., 1986) and thus research has increasingly turned to the neuroendocrine system, particularly the activity of the HPA axis, in order to explain some of the variability in cognitive performance in later life. 1.1. Important characteristics of glucocorticoids Under basal conditions, glucocorticoid secretion exhibits a 24-h circadian profile in which glucocorticoid concentrations present a morning maximum in humans (the circadian peak), and slowly declining levels in the late afternoon, evening and nocturnal period (the circadian trough), and an abrupt elevation after the first few hours of sleep. Circulating GCs bind with high affinity to two receptor subtypes; the mineralocorticoid (MR or Type I) and glucocorticoid (GR or Type II) receptors. Although both receptor types have been implicated in mediating GC feedback effects (see Reul and DeKloet, 1985), there are two major differences between MR and GR receptors. First, MRs bind GCs with an affinity that is about 6–10 times higher than that of GRs. This differential affinity results in a striking difference in occupation of the two receptor types under different conditions and time of day. Thus, during the circadian trough (the PM phase in humans and the AM phase in rats), Glucocorticoids and cognition across the human lifespan 1.2.1. The variability of aging Before the 1990s, the majority of human studies performed in order to measure whether basal cortisol levels increase with aging were crosssectional studies. In general, these studies revealed that basal cortisol levels generally do not change across age in healthy subjects (West et al., 1961; Jensen and Blichert-Toft, 1971; Sherman et al., 1985; Waltman et al., 1991), although higher evening levels of plasma cortisol levels (Friedman et al., 1969; Jensen and Blichert-Toft, 1971; Touitou et al., 1982), and lower morning basal plasma cortisol levels (Maes et al., 1994) have been reported in aged subjects, as well as a phase advance in their diurnal rhythm (Drafta et al., 1982; Sherman et al., 1985). This picture was consistent with animal studies indicating that in the rat, increased HPA activity is not a necessary consequence of aging, but is significantly more prevalent in aged rats selected for spatial memory deficits than in cognitively-unimpaired aged rats (Landfield et al., 1978,1981; Issa et al., 1990). However, interpretations of the results of earlier cross-sectional studies in healthy human subjects was somewhat compromised by the fact that HPA activity was often measured only once in young and elderly subjects in order to assess the existence of increased cortisol secretion in elderly subjects as 227 a group. Since increased HPA activity does not seem to be a universal feature of aging, this approach masked the rich individual differences that are common in aged populations and which are predictive of neuropathology in aged rats (McEwen et al., 1986; Sapolsky et al., 1986; Miller et al., 1994). Moreover, the fact that each subject was only measured once might have obscured the agerelated changes in cortisol levels in individual subjects. Indeed, animal data had shown that it is the cumulative exposure of the hippocampus to high levels of stress hormones that proves to be detrimental for an organism, rather than acutely high levels of stress hormones at one points of an individual’s life (Landfield et al., 1978,1981). Considering the importance of this issue, we examined a large sample of aged (60–87 years), healthy controls with hourly 24-hour sampling on a longitudinal basis (ranging from 3 to 6 years; The Douglas Hospital Longitudinal Study of Normal and Pathological Aging; Lupien et al., 1995); (Fig. 1). Seventeen female and 34 male subjects ranging from 60 to 90 years participated in this longitudinal study. The status of the subjects was determined by a complete physical examination including ECG, EEG, CAT Scan, and a battery of laboratory tests for kidney, liver, and thyroid functions, haemogram, vitamin B12, folate levels, Figure 1 Schematic representation of the data obtained in a population of aged human individuals followed over a period of 3 to 6 years for yearly 24-hour cortisol assessment, and memory performance (The Douglas Hospital Longitudinal Study of Normal and Pathological Aging). 228 S.J. Lupien et al. Figure 2 Schematic representation of the modulation of memory performance by pharmacological inhibition of cortisol secretion (Panel A), and by hydrocortisone replacement (Panel B) in aged human participants with chronic secretion of high (Increasing/High cortisol group) and moderate (Increasing/Moderate cortisol group) levels of cortisol over a period of 5 years. as well as a neuropsychological assessment. Every year, all subjects were sampled for a 24-hour period using an indwelling forearm catheter kept patent with a 0.3% heparin saline solution (Fig. 2). In order to have a measure of the change in cortisol levels over years for a particular subject, a simple regression analysis on plasma cortisol levels for each subject was conducted using year as the independent variable and the integrated 24-hour cortisol concentration at each year as the dependent variable. The direction and amplitude of the slope of the regression line then served as Glucocorticoids and cognition across the human lifespan the measure of the cortisol history per subject (thereafter ‘cortisol slope’). Indeed, the direction of the slope [being positive (increasing cortisol levels with years), or negative (decreasing cortisol levels with years)], gave us an indication of the changes in cortisol levels with time. The magnitude of the slope (e.g. 0.4 versus 0.7) gave us an indication of the rapidity of these changes over time. Using this measure, we have found considerable variation in plasma cortisol levels, as well as clear evidence for sub-groups which show either (1) a progressive year to year increase in cortisol levels with currently high levels (a positive cortisol slope over years with current cortisol levels higher than 12.5 mg/dl/h see Lupien et al., 1995 for a complete description and validation of this criterion; ‘Increasing/High’ group) or (2) a progressive year to year increase in cortisol levels with currently moderate levels (current cortisol levels lower then 12.5mg/dl/h; ‘Increasing/Moderate’ group), or (3) a progressive decrease in cortisol levels with currently moderate cortisol levels (current cortisol levels lower than 12.5mg/dl/h; ‘Decreasing/Moderate’ group). We measured the endocrine and metabolic correlates of these subgroups and showed that there was no change in the circadian rhythm nor CBG levels in these three groups of subjects, nor were there any gender differences between men and women with regard to cortisol history or any other variables tested (Lupien et al., 1995). No group differences were observed for weight, height, body mass index, pulse, blood pressure and glucose. However, significant group differences were reported for plasma triglycerides levels as well as high density lipoproteins levels. It was found that when compared to the Increasing/Moderate and Decreasing/Moderate cortisol groups, the Increasing/High cortisol group presented a significant increase in plasma triglycerides levels over the 4-year period of testing. Moreover, the Increasing/ High cortisol group presented higher levels of high density lipoproteins (HDL) then the other two groups at each time of testing. Finally, a positive correlation was observed between systolic blood pressure and the cortisol slope of subjects. Altogether, these results were in agreement with reports showing GC-induced hypertension (Heuser et al., 1994; Miller et al., 1994). Indeed, 70–80% of patients with Cushing’s syndrome develop hypertension and the majority of them show remission of hypertension with successfull treatment (Mantero and Boscaro, 1992). Other reports have shown that endogenous or exogenous GC excess eliminates or reverses circadian blood pressure variation 229 (Imai et al., 1988) and that the hypertension reported in these cases can be inhibited by a GC antagonist such as RU486 (Chrousos et al., 1988; Whitworth, 1987). The relation between systolic blood pressure and cortisol slope observed in this population suggested that GC-induced hypertension may slowly develop in time in aged individuals showing increases in cortisol levels with years. Altogether, the variations in cortisol levels obtained over time in this population of aged subjects followed from 3 to 6 years, were in accordance with results showing that in the rodent, elevated plasma concentrations of corticosterone is not a necessary correlate of aging. This study showed a comparable level of heterogeneity in the aged human population. 1.2.2. Glucocorticoids, and the aging hippocampus If a middle-aged rat is exposed for a long period to high levels of GCs, it will develop memory impairments (Landfield et al., 1978), and hippocampal atrophy (Landfield et al., 1981) similar to those observed in a significant proportion of aged rats (about 30% of aged-rats present GC hypersecretion correlated with memory impairments and hippocampal atrophy; Issa et al., 1990). On the contrary, if a middle-aged rat is adrenalectomized (the adrenal glands secreting GCs are removed and the animal is kept alive with low doses of exogenous GCs), this will prevent the emergence of both memory deficits and hippocampal atrophy observed in old age (Landfield et al., 1981). Such a cause–effect relationship between cumulative exposure to high levels of GCs, memory impairments and hippocampal atrophy has also been observed in humans. Indeed, patients suffering from Cushing’s disease (a disease leading to chronic oversecretion of GCs), and other patients taking exogenous GCs for anti-inflammatory treatment on a chronic basis present both memory impairments and hippocampal atrophy (Ling et al., 1981; Starkman et al., 1992). Altogether, these results have given rise to the ‘glucocorticoidcascade hypothesis’ (Sapolsky et al., 1986) which suggests that there exist a significant relationship between cumulative exposure to high levels of GCs, impaired memory function, and atrophy of the hippocampus. The role of the hippocampal formation in human learning and memory is now well established (for a complete review, see Squire, 1992). More importantly, studies report that the hippocampus is essential for a specific kind of memory, notably declarative (Cohen and Squire, 1980) or explicit memory (Graf and Schacter, 1985). In contrast, 230 the hippocampus is not essential for non-declarative or implicit memory (Schacter, 1987; Butters et al., 1990). Declarative memory refers to conscious or voluntary recollection of previous information, whereas non-declarative memory refers to the fact that experience changes the facility for recollection of previous information without affording conscious access to it. Thus, this somewhat specialized role of the hippocampus could serve as the basis for specific hypotheses regarding the effects of long-term exposure to GCs on human cognition. In order to test the hypothesis that increased levels of GCs during human aging is detrimental to the hippocampus, we first tested the aged population from the Douglas Hospital Longitudinal Study of Normal and Pathological Aging with a broad range of cognitive tests (Lupien et al., 1994). Sensitive neuropsychological measures were used in order to determine whether there were any cognitive deficits related to measures of cortisol in this aged human population and if so, to identify which cognitive components were affected. The second goal of this study was to determine whether a static (single recent measure) or a dynamic measure of cortisol levels (cortisol slope or the general mean across years), would be the best predictor of cognitive deficits. We first postulated that if long-term exposure to progressively elevated titers of GCs (rather than ‘static’ or ‘acutely-’ elevated levels of GCs at one point of an individual’s life) is the major determinant of hippocampal damage, the cortisol slope of subjects would be the better predictor of cognitive deficits. With regard to the nature of these cognitive deficits, we further hypothesized that if long-term HPA dysfunction is selectively associated with hippocampal pathology and not merely with advanced age (Issa et al., 1990), then the cognitive picture related to elevated cortisol slopes would resemble that of the amnesic syndrome, that is, would be only characterized by deficits in declarative memory with no deficits in non-declarative memory or in any other cognitive spheres tested. The results confirmed this hypothesis as we showed that subjects from the Increasing/High cortisol group were significantly impaired in declarative memory performance when compared to subjects from the Increasing/Moderate and Decreasing/Moderate cortisol group. Moreover, there were no group differences for non-declarative memory performance. A negative significant correlation was also found between the cortisol slope of participants and performance on the declarative memory test. No such correlation was found with a more acute measure of cortisol levels, such as S.J. Lupien et al. the cortisol levels obtained on the last year of the study. Note, however, that the current basal cortisol levels were also apparently a contributing factor. The differences in the performance between the Increasing/High and the Increasing/ Moderate cortisol groups suggested that the current basal cortisol levels did affect cognitive performance. In a final set of experiments testing the effects of chronic exposure to high levels of GCs on the human hippocampus, we performed magnetic resonance imaging (MRI) of the brain of a subgroup of subjects from the increasing/high cortisol group, and the decreasing/moderate cortisol group (Lupien et al., 1998). Given the increased variability in cortisol secretion an cognitive function reported to occur during human aging (see Lupien et al., 1994, 1995), we used these two extreme groups in order to assess the magnitude of the difference in hippocampal volume in conditions of normal versus impaired HPA activity during human aging. Given that the hippocampus has also been implicated in performance on several other cognitive tasks (Squire, 1992), particularly on those sensitive to the timelimited (Scolville and Milner, 1957), and spatial (O’Keefe and Nadel, 1978) aspects of memory, we also measured these two groups on performance on immediate versus delayed memory, as well as on a test of spatial memory using a human maze. We postulated that if cumulative exposure to high circulating levels of GCs in later life is related to impaired hippocampal function, elderly subjects from the increasing/high cortisol group should show impairments on delayed and spatial memory tests, as well as a significant reduction in hippocampal volume, when compared to elderly subjects from the decreasing/moderate cortisol group. We confirmed this hypothesis as we showed that aged humans with significant elevations of cortisol levels over years show deficits on hippocampal-dependent memory tasks as well as reduced hippocampal volume when compared to aged humans with normal cortisol levels. Indeed, we showed that subjects from the Increasing/High cortisol groups had a 14% smaller hippocampal volume when compared to subjects from the Decreasing/Moderate cortisol group. Moreover, we showed that the subjects’ hippocampal volume strongly correlated with both the degree of cortisol elevation over time, as well as with current basal cortisol levels. These findings suggest that in humans, elevation of basal cortisol levels is associated with reduced hippocampal volume and impairments on learning and memory tasks which depend upon the integrity of the hippocampus. Glucocorticoids and cognition across the human lifespan 1.2.3. Glucocorticoids as modulators of aged human memory Although our previous results with elderly humans suggested that long-term exposure to increased cortisol levels (cortisol history) was associated with memory impairments, it was not clear whether the memory deficits observed in the Increasing/High cortisol group were related to their acutely high levels of cortisol at the time of testing (current cortisol levels), or to their long-term history of high cortisol levels (cortisol history). Indeed, data obtained in animals and humans suggest that the cognitive impairments associated with increased levels of GCs are both a result of long-term exposure to high levels of GCs (cortisol history), as well as currently high glucocorticoid levels, and that they may interact (Landfield et al., 1978,1981; Sapolsky et al., 1986; Lupien et al., 1994; Seeman et al., 1997; Porter and Landfield, 1998). Studies in rodents report that acute or shortterm variations in glucocorticoid levels exert a concentration-dependent biphasic influence on hippocampal function (Sloviter et al., 1989; McEwen and Gould, 1991; Cameron and McKay, 1999), long-term potentiation (Diamond et al., 1992), and hippocampal-dependent forms of learning and memory (Kovacs et al., 1976). Situations in which GCs are significantly decreased (e.g. after an adrenalectomy), or increased (e.g. acute stress or exogenous administration) are associated with impairments in hippocampal dependent forms of memory (Kirschbaum et al., 1996; Lupien and McEwen, 1997; Newcomer et al., 1999; DeQuervain et al., 2000, 2003). Also, many authors have acutely reversed the detrimental effects of adrenalectomy on animals’ behavior by subsequently administering GCs (a procedure called a hormone removalreplacement protocol), a result that goes along with the existence of an inverted-U shape function between circulating levels of GCs and memory performance (for a review, see Lupien and McEwen, 1997). Using this hormone removal-replacement paradigm, many have reported that pre-training (Micco et al., 1979; Micco and McEwen, 1980; Mitchell and Meaney, 1991), as well as post-training (Bohus and deKloet, 1981; DeKloet et al., 1988; Veldhuis et al., 1985; Mitchell and Meaney, 1991) administration of corticosterone restores an impaired learned behavior or extinction pattern induced by an adrenalectomy. Because acute modulation of cortisol levels gives rise to a concomitant modulation of the learning and memory processes, direct implications of GCs in memory function have been postulated. In order to measure whether the impaired memory performance observed in 231 the Increasing/High cortisol group was related to currently high levels of cortisol rather than to longterm exposure to high levels of GCs, we measured whether memory performance in elderly individuals from the Increasing/High and Increasing/Moderate cortisol groups (similar cortisol history but different acute current cortisol levels) could be modulated by a hormone removal-replacement protocol in which we pharmacologically manipulated circulating levels of cortisol and measured subsequent memory performance (Lupien et al., 2002a). In this protocol, we used a within-subject double-blind experimental protocol in which we first induced a chemical lowering of GC levels by administration of metyrapone, a potent inhibitor of GC synthesis, and then restored baseline circulating GC levels with subsequent infusion of hydrocortisone. Memory performance of participants under each of these conditions was compared to that measured on a placebo day (Lupien et al., 2002a). We postulated that if the baseline memory performance of elderly humans from the Increasing/Moderate cortisol group is related to moderate cortisol levels, then memory performance should be impaired after metyrapone administration, and restored to baseline levels after hydrocortisone replacement. In contrast, if the baseline memory deficit observed in the Increasing/High cortisol group is due to currently high cortisol levels, memory performance should be improved by metyrapone-induced decrease of cortisol levels, and restored to impaired performance after hydrocortisone replacement. However, if the baseline memory deficit in this group is not due to currently high cortisol levels, there should be no modulatory effect of pharmacological manipulation of GCs on memory function. The results confirmed the chronic exposure hypothesis of memory impairments in the Increasing/High cortisol group as we showed that metyrapone treatment did not have any effect on memory performance in this group (see Fig. 2). However, we showed that replacement of baseline GC levels by subsequent infusion of hydrocortisone significantly impaired memory. In contrast, we found that inhibition of cortisol production in the Increasing/ Moderate cortisol group significantly impaired memory, while this pattern of cognitive impairments was completely reversed by subsequent administration of hydrocortisone. The results obtained in the Increasing/Moderate cortisol subjects were strikingly similar to those reported in rodents with adrenalectomy followed by low replacement doses of glucocorticoids (Micco et al., 1979; Micco and McEwen, 1980; Bohus and deKloet, 1981; DeKloet et al., 1982; Veldhuis et al., 232 1985; Mitchell and Meaney, 1991), and pointed to a modulatory influence of cortisol on human memory. In contrast, and based on the results obtained in the Increasing/High cortisol group, we suggested that the memory impairments in this group of older adults are due to a relative loss of MRs, with normal or heightened sensitivity of GRs. A loss of MRs would explain the absence of any metyrapone-induced memory effects in this population, as there are less MRs to bind circulating levels of GCs, thus preventing any significant impact of the absence of GCs on binding to MRs. Less MRs could also lead to a faster saturation of GRs, leading to the increased sensitivity of GRs activation and the induction of significant cognitive impairment after physiological increase in circulating levels of GCs as observed during the hydrocortisone replacement condition. Our hypothesis is also supported by recent rodent (Herman and Spencer, 1998; Lopez et al., 1998; Vazquez et al., 1998) and human (Wetzel et al., 1995) studies showing that levels of MRs rather than GRs are markedly reduced in response to chronic elevations in glucocorticoid levels such as those observed in the aged subjects from the Increasing/ High cortisol group. Altogether, the results of our studies in the aged human population provided three sets of important data. First, we showed the presence of large interindividual differences in basal secretion of cortisol in the aged human population (Lupien et al., 1995). Second, we showed that aged humans with significant elevations of GCs over time present both memory impairments (Lupien et al., 1994), and a 14% smaller volume of the hippocampus (Lupien et al., 1998) when compared to aged humans with moderate increase or decrease of cortisol over time. Third, we showed that in aged humans with moderate levels of cortisol, memory performance can be acutely modulated by pharmacological manipulations of glucocorticoid levels (Lupien et al., 2002a). Altogether, these results suggest that there might exist a time window in human aging during which at-risk aged humans could be amenable to therapeutic interventions in order to prevent GC-induced cognitive impairments. S.J. Lupien et al. recollection of previously learned information, as in free or cued recall of material learned before. In general, the majority of human studies that have measured the impact of GCs on cognitive function report impaired declarative memory function after acute and/or chronic administration of synthetic GCs (for a complete review, see Lupien and McEwen, 1997; Lupien et al., 1999a; Lupien and Lepage, 2001). In the last 5 years, the work from our laboratory has contributed in extending this view in three ways. First, we have shown that the effects of GCs on memory performance are not always negative (Lupien et al., 2002b). Second, we showed that cognitive processing sustained by the frontal lobes is also sensitive to acute variations of GCs (Lupien et al., 1999b). Third, we showed the presence of a differential effect of adrenergic and glucocorticoi hormones on the consolidation of neutral and emotional information (Maheu et al., 2004). 1.3.1. Glucocorticoids: the good guys Many studies performed in rodents have reported that the ratio of MR/GR occupation is a major determinant of the direction of GC-induced cognitive changes (for a review, see De Kloet et al., 1999). For example, long-term potentiation (LTP), a proposed neurobiological substrate of memory formation, has been shown to be optimal when GC levels are mildly elevated, ie. when the ratio of MR/GR occupation is high (see Diamond et al., 1992). In contrast, significant decreases in LTP are observed after adrenalectomy, when MR occupancy is very low (Dubrovsky et al., 1987; Filipini et al., 1991), or after exogenous administration of synthetic GCs (Bennett et al., 1991; Pavlides et al., 1993), which activate GRs and deplete cortisol, again resulting in low occupancy of MRs. In their recent paper, De Kloet et al. (1999) have re-interpreted the well-known inverted-U shape function between circulating levels of GCs and cognitive performance in line with the MR/GR ratio hypothesis. In this view, cognitive function can be enhanced when most of the MRs and only part of the GRs are activated (top of the inverted-U shape function; increased MR/GR ratio). However, when circulating levels of GCs are significantly decreased or increased (extremes of the inverted-U shape function; low MR/GR ratio), cognitive impairments will result. The authors suggested that the negative view of GC actions on human cognitive function could be partly explained by limitations in previous human experimental designs, which did not allow differential manipulation of MR and GR levels. In order to do this, such studies should measure cognitive function when GC occupancy is decreased 1.3. Glucocorticoids and cognition in young human adults In populations of young adults, the effects of GCs on cognitive function have been measured using mainly cognitive tasks assessing declarative memory. In general, declarative memory function can be assessed using tasks involving a conscious Glucocorticoids and cognition across the human lifespan (rather than increased), thus allowing functional measures of MR/GR occupancy on learning and memory. In order to test this hypothesis, we performed two studies in young human populations in which we tested the cognitive impact of GCs in situations of low MR/GR ratio (Lupien et al., 2002b). In the first study, we used the same hormone removal-replacement protocol we previously used with the aged humans from the Douglas Hospital Longitudinal Study of Normal and Pathological Aging. In summary, memory performance of young participants was assessed after administration of metyrapone, and after restoration of baseline cortisol levels using an infusion of hydrocortisone. Memory function was tested after each pharmacological manipulation and compared to performance under appropriate placebo conditions. The results obtained in the young population were similar to those obtained with aged humans from the Increasing/Moderate cortisol group. Indeed, in young population, we observed that metyrapone treatment significantly impaired memory, while hydrocortisone replacement restored performance at placebo level (Lupien et al., 2002b). In the second study, we took advantage of the circadian variation in circulating levels of cortisol and tested the impact of a bolus injection of 35 mg of hydrocortisone on memory performance in the afternoon. The idea behind this experiment was the following. We tested the impact of hydrocortisone in the late afternoon, at a time of very low cortisol concentrations, i.e. at a time of low MR/GR ratio. We postulated that if the ratio of MR/GR activation is involved in GC-induced memory changes, administration of hydrocortisone in the late afternoon should increase the MR/GR ratio, and lead to increased memory performance when compared to placebo. The results obtained on the study confirmed the hypothesis as we showed that administration of hydrocortisone in the afternoon led to significantly faster detection times on the memory test when compared to administration of placebo. Altogether, the results of these two studies suggest that GCs can modulate human memory function through a differential activation of MRs and GRs. Indeed, in the metyrapone condition of the first study, MR occupancy was low, given the significant decrease of cortisol secretion induced by metyrapone. At this point, impairment in memory was observed. In contrast, administration of a 35 mg dose of hydrocortisone at the time of circadian trough in the second study might have led to partial activation of GRs, thus increasing cognitive efficiency in the group of participants who 233 received hydrocortisone, when compared to placebo. This later finding is interesting in line with data obtained by Oitzl and DeKloet (1992) and recently reviewed by DeKloet et al. (1999), suggesting that MRs and GRs mediate different effects of cortisol in different time domains. According to this view, MR activation is involved in behavioral reactivity in response to environmental cues, while GR-mediated effects promote consolidation of acquired information. The significant decrease in reaction times observed after GC administration in the PM phase in our second study are in line with a MR-mediated effect of behavioral reactivity (what we call here ‘cognitive efficiency’; a nonspecific process), while the delayed memory impairment observed after metyrapone administration is in line with a GR-mediated effect of memory consolidation. 1.3.2. The forgotten ones: frontal lobes Following the work by Reul and DeKloet (1985), it was established that in the rodent brain, the MR is present exclusively in the limbic system, with a preferential distribution in the hippocampus, parahippocampal gyrus, entorhinal and insular cortices. On the contrary, the GR is present in both subcortical (paraventricular nucleus and other hypothalamic nuclei, the hippocampus and parahippocampal gyrus) and cortical structures, with a preferential distribution in the prefrontal cortex (McEwen et al., 1968, 1986; Meaney and Aitken, 1985; Diorio et al., 1993). Still, in the rodent brain, the largest concentration of both MRs and GRs was found in the hippocampus, which led to the glucocorticoid-hippocampus link (for a complete review, see Lupien and Lepage, 2001). However, in 2000, two papers were published which described the distribution of MRs and GRs in the primate brain, more closely related to the human brain in terms of neocortex development. These two recent studies mapping both MRs and GRs distribution revealed that in the primate’s brain, there are less GR then originally proposed in the hippocampus, but there are more GR in the frontal lobes than the levels originally described in the rodent literature. These results strongly suggested that extrapolation from rat brain to primate brain may be misleading when discussing the impact of GCs on the hippocampus. The first study was published by Sanchez and collaborators (2000) who reported that, in contrast to its well established distribution in the rat brain, GR mRNA is only weakly detected in the dentate gyrus and Cornu Ammonis of the macaque hippocampus. In contrast, GR mRNA is strongly detected in the pituitary, cerebellum, hypothalamic 234 paraventricular nucleus and prefrontal cortices. In a second study published by Patel et al. (2000), it was reported on an experiment where the authors used a specific squirrel monkey antibody and found that GR receptors were well expressed in the hippocampus, but were more prominently found in the prefrontal cortex. These recent evidences in the primate brain showed that MRs are present in large quantities in the hippocampus and limbic structures, while GRs are present in all these structures and additionally in the frontal regions. This latter finding suggested that in humans, GCs should not only affect the hippocampus, but also the frontal lobes. Neuropsychological evidence suggests that humans with prefrontal damage are impaired in working memory (Luria, 1966; Fuster, 1980). Working memory is the cognitive mechanism that allows us to keep a limited amount of information active for a limited period of time (see Baddeley, 1995). Patients with frontal damage are highly susceptible to cognitive interference and they perform poorly on neuropsychological tests that require response inhibition such as the Wisconsin Card Sorting Test (Stuss et al., 1982; Shimamura, 1995). Moreover, recent neuroimaging data summarized and reviewed by Smith et al. (Smith et al. (1998); see also Dolan and Fletcher, 1997; Ungerleider et al., 1998) show a significant relationship between working memory processing, and activation observed in the prefrontal cortex (Smith et al., 1998; Ungerleider et al., 1998). In 1999, two studies performed in humans reported that working memory is more sensitive than declarative memory to acute and short-term administration of GCs. Young and collaborators (1999) administered 20 mg hydrocortisone for 10 days to young normal male volunteers and measured various cognitive functions in a randomized, placebo control, crossover, within-subject design. They showed that this regimen of GCs led to deficits in cognitive function sensitive to frontal lobe dysfunction (working memory), while it did not impact on cognitive function sensitive to hippocampal damage. Similar results were obtained by our group (Lupien et al., 1999b) using an acute dose–response protocol. In this study, 40 young subjects were infused for 100 min with either hydrocortisone or placebo and declarative and working memory function was tested during the infusion period. The results revealed that performance on the working memory task decreased significantly under the highest dose of hydrocortisone, whereas performance on the declarative memory task remained the same following an acute elevation S.J. Lupien et al. of GCs. Curve fit estimations revealed the existence of a significant quadratic function (U-shape curve) between performance on the working memory task and changes in GC levels after hydrocortisone infusion. The results of these two studies suggested that in young individuals, working memory is more sensitive than declarative memory to an acute elevation of GCs, which goes along with the suggestion that GCs have a significant impact on frontal lobe functions in young humans through activations of GRs in the frontal regions. 1.3.3. Glucocorticoids and emotional memory Although most of the literature on the acute effects of GCs on animal and human cognitive process was reported using the hippocampus and the frontal lobes as models for GC-induced cognitive changes, there is now evidence showing that GCs also act as modulators of the formation of emotional memory in the amygdala. The role of the amygdala in the modulation and/or storage of emotional memory has been demonstrated in various animal models. The amygdala contains both MRs and GRs (Allen and Allen, 1974; Honkaniemi et al., 1992), and the interaction between GCs and the amygdala has recently been demonstrated in humans by the presence of a significantly smaller amygdala volume in children with congenital adrenal hyperplasia, which is a genetic disease where there is a block in cortisol production (Merke et al., 2003). Glucocorticoid receptors in particular nuclei of the amygdala (particularly the central and medial) have been implicated in emotional expression and in neuroendocrine control of emotions (for a recent review, see Roozendaal, 2002). In rodents, Roozendaal et al. (1996) demonstrated that posttraining injections of dexamethasone enhances inhibitory avoidance retention, while inhibition of glucocorticoid synthesis by administration of metyrapone impairs performance on this same task. Although modulatory effects of GCs on emotional memory have been reported in the animal literature, it is important to note here that adrenergic hormones (adrenaline and noradrenaline), which are also secreted in face of an emotion and/or a stressor, have also been implicated in the memoryenhancing effects of emotions. In humans, prelearning blockade of central b-adrenergic receptors inhibits long-term memory for emotionally-arousing material (Cahill et al., 1994; Van Stegeren et al., 1998), while pre- or post-learning stimulation of the noradrenergic system enhances it (O’Carroll et al., 1999; Southwick et al., 2002; Cahill and Alkire, 2003). In the same vein, recent human findings show that the administration of synthetic GCs has Glucocorticoids and cognition across the human lifespan a specific enhancing effect on memory for highly arousing material (Buchanan and Lovallo, 2001). However, these results stand in contrast to other published results showing enhancing effects of synthetic GCs on memory for both emotional and neutral information (Abercrombie et al., 2003). Although a role of adrenergic and glucocorticoid hormones has been suggested for the modulation of emotional memory, there were still two major variables that had not been tested with regard to the shared and/or unique role of each type of hormones for the modulation of emotional memory in human populations. First, in most of the previous studies assessing the effects of adrenergic or glucocorticoid hormones on memory for emotionally-arousing material, short-term memory was not assessed (with the exception of Abercrombie et al., 2003), thus leaving open the question as to whether these two adrenal hormones also had an impact on the early process of consolidation. Second, both types of hormones (adrenergic and glucocorticoid) were never tested in the same protocol in order to assess whether they had the same effect on memory for neutral and/or emotional information, or whether they were involved in particular components of memory processing for neutral and emotional events. Consequently, we performed a study in which was assessed short- and long-term memory of emotionally-arousing and neutral material in humans after pharmacological manipulation of adrenergic or glucocorticoid systems (Maheu et al., 2004). Young men were administered either a blocker of b-adrenergic receptors (propranolol; 80 mg), or an inhibitor of GC synthesis (metyrapone; 2 doses of 750 mg), and short (5 min after learning) and long-term (one week after learning) memory for emotionally-arousing and neutral material was compared to short- and long-term memory measured under a placebo condition. The results of this study showed that administration of propranolol impaired both short- and long-term memory for emotionally-arousing material, while it had no impact on short- and long-term memory of neutral information. In contrast, metyrapone did not impair short-term memory, but impaired longterm memory for both emotionally-arousing and neutral material. The impairing effects of propranolol on shortand long-term memory of emotional information confirmed the specific role of adrenergic hormones on memory for emotionally-arousing material (Cahill et al., 1994; Van Stegeren, et al., 1998), and they further extend the effects of these hormones to short-term memory function. These results go along with previous animal studies 235 showing that activation of b-noradrenergic receptors is necessary to induce both the early (shortterm) and late (long-term) phases of long-term potentiation (LTP) in the hippocampus (Hopkins and Johnston, 1988; Huang and Kanddel, 1996). Longterm potentiation is a form of neuronal plasticity that has been shown to sustain memory consolidation (Bliss and Collingridge, 1993). In chicks, subcutaneous injections of propranolol administered five minutes before and 25 min after training in an avoidance learning paradigm results in shortand long-term memory loss (Gibbs and Summers, 2002). Similarly, intra-cerebral injections of propranolol into the hyperstriatum ventrale of chicks 5 min after training on an avoidance learning task results in memory loss 30 min post-training, and impaired long-term memory consolidation (Gibbs and Summers, 2002). Combined, these findings obtained with emotionally-arousing situations in animals suggest that blockade of adrenergic receptors has a significant impact on both short- and longterm memory of emotionally-arousing information. Our results showing impairing effects of propranolol on both short- and long-term memory go along with this suggestion. In contrast to the results we obtained with administration of propranolol, we showed that inhibition of GC synthesis by administration of metyrapone did not impaired short-term memory of emotionally-arousing and neutral material, although one week later, when GC synthesis was no longer inhibited, long-term memory of both types of material was significantly impaired. These data are in line with animal studies showing impaired long-term consolidation for avoidance learning paradigms following GC depletion due to metyrapone or adrenalectomy (Sandi, 1998; Liu et al., 1999; Roozendaal, 2002), and with human research acknowledging a necessary role for optimal levels of GCs in long-term memory for both emotionally-arousing (Buchanan and Lovallo, 2001; Abercrombie et al., 2003) and neutral material (Abercrombie et al., 2003). Altogether, the results of this study showed that adrenergic and glucocorticoid hormones may be differentially involved in the modulation of neutral and emotional information. Future studies measuring circulating levels of both adrenergic and glucocorticoid hormones, as well as studies using specific agonists and antagonists of adrenergic and glucocorticoid receptors, will be necessary in order to clarify the potential interactions of these two adrenal hormones on memory consolidation for emotionally-arousing material. 236 S.J. Lupien et al. and 10 years old present significantly higher salivary cortisol levels when compared to children from high SES. This difference disappeared at the time of school transition, with no SES differences observed on salivary cortisol levels during high school. Second, we showed that children from low and high SES did not differ with regard to memory, attentional and linguistic functions. Third, we showed that mothers of low SES children reported higher feelings of depression and more unhealthy behaviors, while mothers of high SES children reported higher stress related to work or family transitions. Finally, within the population of children from 6 to 10 years of age, we reported the presence of a significant positive correlation between depressive score of the mother, and her own child’s cortisol levels (Lupien et al., 2000). Interestingly, it has been hypothesized that the child’s response to stress experienced in the early years may have long-term effects upon future development of psychosomatic diseases (Tennes and Kreye, 1985). Although we did not report any differences between SES groups in terms of general cognitive performance, we were also interested in measuring whether SES had a significant impact on the judgment of the children with regard to attribution of plausibility as a function of the valence of an attribute (which we called ‘emotional plausibility’). Here, we were mainly interested in assessing whether children from low and high SES, differing in terms of basal cortisol levels, would also present differences in the ways they process ‘possible’ and ‘impossible’ events. On a more candid note, we were interested in knowing whether children from low SES would state that in general, things are more impossible than possible, which could be an interesting indicator of early development of a pessimistic view about events in low SES children. In order to measure whether children from low and high SES differed with regard to their judgment of negative and positive attributes, we designed a projective test in which children were presented with the name of 20 animals to which we associated a negative or a positive attribute (e.g. ‘a stupid lion’ versus ‘an intelligent giraff’). The task of the child was to state if such an attribute (e.g. ‘a stupid lion’) was ‘possible’ or ‘impossible’. Here, we were mainly interested in assessing whether SES would have an impact on the plausibility judgment (‘impossible’ versus ‘possible’) of the negative (‘stupid’) and positive (‘intelligent’) attributes. The subjects were told that this was not a task in which we measured performance, but that is was a task in which we just wanted to know what they think. For each child, a plausibility score 1.4. Glucocorticoids and cognition in children In populations of children, studies on the effects of GCs on cognitive function have been scarced. Due to obvious ethical reasons, the effects of exogenous administration of GCs on cognitive performance in young normal children have not been performed. Consequently, two types of protocols have been used in order to assess the effects of stress and/or endogenous increases of GCs on cognitive function in children. The first set of experiments showed that children living in noisy areas (Cohen et al., 1973,1980) present a significant increase in blood pressure and they show significant impairments in learning how to discriminate between irrelevant and relevant tasks, which supposes that stress in children may affect selective attention, i.e. the ability to discriminate between relevant and irrelevant information. This is an important finding given the importance of selective attention in memory processing. It is well known that what we encode and remember from an event depends primarily on the attention that is devoted to this event and its components. If you do not pay attention to what you are reading right now, there is less chance for you to remember it at a later time than if you give all your attention to your lecture. This is because the more attention given to an event, the higher the probability that this event will be elaborated (relating the information from this event to other situations and related concepts in memory) at the time of encoding. Research on memory has shown that events that are poorly elaborated (shallow processing) at the time of encoding are less well remembered than events that are deeply elaborated (deep processing) at the time of encoding. The level of attention devoted to an event at the time of encoding will greatly depend on the emotional salience of this event. Consequently, it is possible that the nature of the relevant material to be encoded in memory depends on the environment in which a child lives. In 2000 and 2001, we reported on a study performed in 307 children from low versus high socioeconomic status (SES) splitted across 6 age groups (6, 8, 10, 12, 14, and 16 years old) in whom we measured salivary basal morning cortisol levels as well as cognitive performance (Lupien et al., 2001). The main goal of this study was to assess whether SES acts as a potent environmental stressor on the child, and whether cortisol levels across SES can predict memory performance in these children. The results revealed that low SES children from 6, 8, Glucocorticoids and cognition across the human lifespan 237 Figure 3 Plausibility scores (see text for definition;G sterr) for low and high SES children ranging from 6 to 16 year of age who differ between each others in terms of cortisol secretion. (difference between the number of possible answers minus the number of impossible answers) was calculated for each attribute (positive vs negative), in order to reach a baseline (nothing is more possible than impossible) of zero. Using this scale, a positive score (over baseline) reflects more ‘possible’ answers, while a negative score (below baseline) reflects more ‘impossible’ answers. Preliminary analysis on the factor of attribute (positive versus negative) revealed the absence of any SES or Age differences with regard to the plausibility score of positive and negative attributes so data were collapsed across subsequent analysis. An Anova performed on the global (positiveC negative) plausibility scores revealed significant main effects of SES [F(1307)Z8.8; p!.003], and Age [F(1307)Z5.67; p!0.0001], as well as a significant interaction between these two factors [F(5307)Z2.4; p!0.02]. A posteriori comparison by Age group revealed significant SES differences on plausibility scores at age 6, 8, 10, 12, and 14 (all p!0.05), with no significant SES difference on plausibility score at age 16. A close look at Fig. 3 shows that high SES children always scored above the baseline on plausibility (everything being possible), while this was not the case for low SES children. All low SES children from elementary school (from 6 to 10 year old), scored lower on plausibility scores when compared to high SES children (things being more impossible for these low SES children when compared to high SES children of the same age groups). This tendency reversed at age 12 (time of school transition), where low SES children scored higher on plausibility scores, when compared to high SES children. At age 14, this tendency reversed again, with high SES children scoring higher on plausibility scores when compared to low SES children. Finally, no SES differences were observed for plausibility scores at age 16. These results are interesting because they show that children from low and high SES significantly differ in their subjective evaluation of possible and impossible events. This difference in incidental emotional processing is accompanied by significant SES differences in basal cortisol levels, at least for the younger population of children. In order to assess whether the basal cortisol levels obtained in each age group as a function of SES was related to plausibility score for positive and/or negative attributes, we correlated the basal cortisol levels of each child to their own plausibility score for negative and positive attributes. Table 1 presents the coefficients of correlation obtained for each age group as a function of SES. The significance of the obtained correlations has to be taken with caution since we did not use a Bonferroni correction to control for the number of correlations performed. However, we felt it was appropriate to present these data as they may interest some readers in the potential relationship existing between a child environment, and the development of attribution of plausibility as a function of SES and basal cortisol levels. The correlations performed between basal cortisol levels and plausibility scores for positive and negative attributes in children from low Table 1 Coefficients of correlation obtained between morning cortisol levels and plausibility scores for positive and negative attributes in children from 6 to 16 years of age, from low and high socioeconomic status. Attributes Low SES Positive 6 8 10 12 14 16 0.16 0.05 0.42* K0.42* 0.26 K0.07 Negative 0.11 K0.19 0.05 0.03 0.40* K0.25 N 26 25 35 20 27 24 High SES Positive K0.11 0.21 0.01 0.19 0.21 K0.13 Negative 0.05 K0.24 0.03 K0.22 0.03 K0.04 N 12 18 15 26 36 34 238 and high SES revealed the presence of significant associations between cortisol and plausibility scores in the low SES children only, and at age 10, 12, and 14. At age 10, children from low SES presented a significant positive correlation between basal cortisol levels and plausibility score for positive attribute (‘positive attributes are more possible’). However, this association reversed at age 12 (time of school transition), where basal cortisol levels were negatively correlated with positive attributes (‘positive attributes are less possible, or more impossible’). Interestingly, at age 14, basal cortisol levels in low SES presented a significant correlation with negative attributes (‘negative attributes are more possible’). No other coefficients of correlation reached significance levels. Altogether, these results show that although children from low and high SES do not differ on baseline cognitive performance, they tend to present a different pattern of plausibility attribution. For children from low SES, impossible statements were always more frequent than possible statements, while it was the reversed for children from high SES. Moreover, plausibility scores for positive and negative attributes were associated with basal cortisol levels only in the low SES children from 10 to 14 years of age. These results are revealing a peculiar pattern of incidental emotional processing in children from low and high SES. The projective test used for this study should be validated with populations of depressed children, and this is the reason why we include the test in the appendix of the paper for those readers interested in using it. Although the data presented here on the emotional plausibility test are preliminary, these raise the intriguing issue that early exposure to stressful environments (in this case, SES), may shape the nature of the information processed by children. Clearly, future studies assessing specifically the nature of emotional processing in children from various SES should help shed light on this intriguing possibility. S.J. Lupien et al. performance can be acutely modulated by pharmacological manipulations of GCs. This later result suggests that pharmacological treatment could eventually be developed in order to prevent GC-induced cognitive impairments in the aged human population. In young adults, we have shown that cognitive process sustained by the frontal lobes is also sensitive to acute elevations of GCs, and as in the aged humans, we have shown that memory performance can be acutely modulated by pharmacological manipulations of GCs. Finally, we showed that adrenergic and GC hormones have a differential impact on short- and long-term memory of emotional and neutral information. Altogether, these results shed some new lights on the nature of the memory changes induced by various circulating levels of GCs. In children, we have shown that SES is a potent predictor of basal levels of cortisol. Children aged from 6 to 10 years from low SES present higher basal cortisol then children from high SES. In a new set of data presented here, we also showed that children from low and high SES also differ in the ways they process positive and negative attributes. In children form low SES, impossible statements were always more frequent than possible statements, while it was the reverse for children from high SES. Moreover, plausibility scores for positive and negative attributes were associated with basal cortisol levels only in the low SES children from 10 to 14 years of age. These results suggest that the impact of the environment in which a child lives may modify the nature of the information that is processed on a daily basis. Altogether, the results of these studies showed that human cognitive processing from childhood to old age is very sensitive to acute and chronic increases of GCs. For the last 10 years, our lab has been assessing the bottom–up effects of GCs on human cognitive function, i.e. measuring the modulatory effects of GCs on cognitive performance. However, one has to remember that a stressor is stressful only if the individual interprets it as being stressful. This suggests that studying the top–down effects of cognitive processing on secretion of GCs could also lead to interesting discoveries. This, in fact, will be the goal of our studies for the next few years. 2. Conclusion In this paper, we have reviewed the studies performed by our laboratory on the impact of GCs on human cognitive function in populations of aged adults, young adults and children. In the older adults, we have shown that chronic exposure to elevated levels of GCs is related to both memory impairments and a smaller volume of the hippocampus. We also showed that in aged humans with moderate circulating levels of cortisol, memory Acknowledgements The research on aged and adult human populations summarized in this paper has been funded by Glucocorticoids and cognition across the human lifespan a grant from the Canadian Institutes of Health Research (CIHR grant No.#15000) to SJL. The research on children summarized in this paper has been funded by a grant from the John and Catherine MacArthur Foundation to SJL. SJL work is funded by an Investigator Award from the Canadian Institute of Aging. 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