Psychoneuroendocrinology (2005) 30, 225242

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 bottomup (effects of glucocorticoids on cognitive
function), and topdown (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 hypothalamicpituitaryadrenal (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).

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 610 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),

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 6774% 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.

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
individuals life (Landfield et al., 1978,1981).
Considering the importance of this issue, we
examined a large sample of aged (6087 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, 7080% of
patients with Cushings 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 causeeffect relationship between cumulative exposure to high levels of GCs, memory
impairments and hippocampal atrophy has also
been observed in humans. Indeed, patients suffering
from Cushings 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 individuals 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
(OKeefe 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.

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

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

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 primates 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 doseresponse
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 (OCarroll 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

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,

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 childs cortisol levels (Lupien et al., 2000).
Interestingly, it has been hypothesized that the
childs 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

Glucocorticoids and cognition across the human lifespan

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

237

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

6
8
10
12
14
16

Low SES

High SES

Positive

Negative

Positive

Negative

0.16
0.05
0.42*
K0.42*
0.26
K0.07

0.11
K0.19
0.05
0.03
0.40*
K0.25

26
25
35
20
27
24

K0.11
0.21
0.01
0.19
0.21
K0.13

0.05
K0.24
0.03
K0.22
0.03
K0.04

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.

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

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 bottomup 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
topdown 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.

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. JP work is funded by a Young Investigator
Award from the Fonds de la recherche en sante
du
Que
bec (FRSQ).

Appendix A. Test of Emotional

Plausibility
For each of these sentences, tell me if it is POSSIBLE
or IMPOSSIBLE that the depicted animal possesses
the suggested character.

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