Behavioural Brain Research 127 (2001) 137– 158

www.elsevier.com/locate/bbr

Stress, memory, and the hippocampus: can’t live with it, can’t live
without it
Sonia J. Lupien a,b,*, Martin Lepage a
a
Research Center, Douglas Hospital Research Center, Department of Psychiatry, McGill Uni6ersity, Verdun, Quebec, Canada H4H 1R3
b
Laboratory of Human Psychoneuroendocrine Research, Douglas Hospital Research Center, Montreal Geriatric Institute, 6875 Bld. Lasalle,
Verdun, Quebec, Canada H4H 1R3
Received 30 April 2001; received in revised form 19 June 2001; accepted 25 July 2001

Abstract

Since the 1968s discovery of receptors for stress hormones (corticosteroids) in the rodent hippocampus, a tremendous amount
of data has been gathered on the specific and somewhat isolated role of the hippocampus in stress reactivity. The hippocampal
sensitivity to stress has also been extended in order to explain the negative impact of stress and related stress hormones on animal
and human cognitive function. As a consequence, a majority of studies now uses the stress– hippocampus link as a working
hypothesis in setting up experimental protocols. However, in the last decade, new data were gathered showing that stress impacts
on many cortical and subcortical brain structures other than the hippocampus. The goal of this paper is to summarize the four
major arguments previously used in order to confirm the stress– hippocampus link, and to describe new data showing the
implication of other brain regions for each of these previously used arguments. The conclusion of this analysis will be that
scientists should gain from extending the impact of stress hormones to other brain regions, since hormonal functions on the brain
are best explained by their modulatory role on various brain structures, rather than by their unique impact on one particular brain
region. © 2001 Elsevier Science B.V. All rights reserved.

Keywords: Glucocorticoids; Hippocampus; Memory; Brain imaging; Human; Receptors

1. Introduction and cognitive deficits, named ‘steroid psychosis’ [25].

For many years, endocrinologists and neuroscientists
thought that hormones, which are biological products
secreted by peripheral glands, did not access the brain
and acted mainly at the level of the peripheral nervous
system. However, in the early 1960s, the discovery of
neuropeptides as substances having not only classical
endocrine effects, but also affected brain and behavior,
significantly extended our view of hormones and
opened the door to new possibilities of hormonal ac-
tions on the brain (for a complete historical back-
ground, see [38]). The idea of a central action of
hormones was supported by previous studies showing
that long-term therapy with anti-inflammatory drugs
(which are synthetic hormones) led to significant mental
* Corresponding author. Tel.: + 1-514-761-6131x3359; fax: +1-
514-888-4064.
E-mail address: lupson@douglas.mcgill.ca (S.J. Lupien).
The presence of a mental disorder induced by exposure
to high levels of a hormone strongly suggested that
these substances could, in some way, access the brain
and impact on affect and behavior.
The search for brain receptors able to recognize
peripheral hormones was then opened. In 1968, it cul-
minated with Bruce McEwen’s seminal Nature paper
([120]; see also [63]) showing that the rodent brain was
indeed able to recognize hormones, particularly corti-
costeroids, which are hormones involved in the en-
docrine response to stress. The story then took a very
important detour when McEwen and collaborators re-
ported that the brain region showing the highest density
of receptors for corticosteroids was the hippocampus, a
brain region significantly involved in learning and
memory [183]. As pointed out by de Kloet [38] in a
recent review of the historical background of stress and
the hippocampus, ‘‘[…] the important stress hormone
retained in the hippocampus, an area with a critical

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138 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
Fig. 1. Schematic representation of the HPA axis. Following the
perception of a stressor, the hypothalamus releases CRF, which
activates the pituitary and leads to secretion of ACTH. The levels of
ACTH are detected by the adrenal cortex which then secretes corti-
costeroids. Corticosteroids will enter the blood circulation and act
peripherally and centrally. At the level of the brain, both the frontal
lobes and the hippocampus contain corticosteroid receptors, although
the hippocampus contains both MRs and GRs, while frontal lobes
contains mostly GRs. Both cortical structures inhibit HPA axis.
Along with inhibitory actions of the frontal and hippocampal region,
circulating corticosteroids will act at the level of the hypothalamus to
inhibit further secretion of CRF, and at the level of the pituitary to
inhibit the secretion of ACTH. Circulating levels of ACTH also act at
the level of the hypothalamus to inhibit secretion of CRF. The
consequence of these negative feedback loops will be a significant
decrease of circulating levels of corticosteroids after the end of the
stressor.
function in cognition and affect. That could not be a
coincidence!’’.
At this point, the stress– hippocampus link was born
and it has been kept alive for the last three decades by
a variety of research findings confirming the significant
impact of stress hormones on hippocampal structure
and/or function, and on animal and human learning
and memory (for reviews, see [106,124– 126]). In gen-
eral, four major arguments are used in order to confirm
the stress– hippocampus link. The first one relates to
the presence of glucocorticoid receptor (GR) in the
animal and human hippocampus. The second one con-
cerns the fact that high levels of stress hormones are
associated with significant impairments in declarative
memory function, a type of memory thought to be
dependent upon adequate hippocampal function. The
third one relates to the fact that chronic exposure to
high levels of stress hormones is associated with atro-
phy of the hippocampus, and the fourth one concerns
that fact that stress (and its related stress hormones)
can impair neurogenesis in the hippocampus.
This is thus a very exciting time for the field of
psychoneuroendocrinology, which measures the impact
of hormones on animal and brain function. Most stud-
ies performed today uses the stress–hippocampus link
as the first premise in the establishment of a working
hypothesis regarding the impact of stress and related
stress hormones on animal and human behavior. Al-
though this is surely a positive aspect of the research
performed to this day, this fact can, however, have for
consequence to bias the study design in such a way that
only one brain region (i.e. the hippocampus) will be
studied at the detriment of other brain regions that
could also be involved in corticosteroid actions. Indeed,
new data obtained within the last decade confirmed
that corticosteroids impact on various brain regions
and cognitive functions in both animal and human
populations. By concentrating the totality of our efforts
on the stress– hippocampus link, we as scientists might
miss a great opportunity to explain the real actions of
stress hormones on the brain.
As with most scientific data, one needs solid argu-
ments in order to prove or disprove a point. The main
goal of this review will thus be to use each of the four
arguments for the stress–hippocampus link and report
new data showing the involvement of regions other
than the hippocampus for each of these arguments. The
ultimate goal here will be to convince the reader that,
contrary to many researchers working in the field of
psychoneuroendocrinology, stress hormones may not
necessarily have a preference for the hippocampus.
2. Stress mediators
Stress is often cited as the cause of many psychologi-
cal and physical problems. Many of us have experi-
enced stress at one point or another of our life, and
noted that stress can have important effects on our
memory. One can have forgotten an important meeting
or anniversary due to work overload, or else, one can
have a vivid recollection of a car accident or any other
stressful experience. Because of their impact on our
lives, we have a tendency to pay more attention to the
negative effects of stress on our memory, and to forget
that under certain conditions, stress can also have a
positive impact on physical and mental health (for a
review, see [127]). In general, the stimuli that induce a
stress response involve novelty and unpredictability, a
lack of sense of control and threats to the sense of self
[118].
The subjective experience that individuals describe as
‘stress’ does not always predict increased activity of the
hormonal systems that are linked to stress, namely, the
sympathetic nervous system and the hypothalamo–pi-
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
tuitary–adrenal (HPA) axis (see Fig. 1). The HPA axis,
along with the sympathoadrenal system governs
metabolic responses to the slings and arrows of every-
day life, as well as to the beleaguering demands that
prevail under conditions of chronic, severe stress. In
response to a stress, hypothalamic neurons release cor-
ticotropin-releasing factors (CRF) and this triggers sub-
sequent secretion and release of ACTH from the
pituitary. In response to ACTH stimulation, corticos-
teroids are secreted and released from the adrenal
glands. The responsivity of the HPA axis to stress is, in
part, determined by the ability of corticosteroids to
regulate ACTH and CRF release. Circulating corticos-
teroids feedback onto the pituitary and hypothalamus
to inhibit the secretion of CRF and ACTH. In addition
to pituitary and hypothalamic sites, there is now con-
siderable evidence for the importance of the limbic
system, particularly the hippocampus, as well as corti-
cal areas, particularly the prefrontal cortex, in the
regulation of HPA activity. This regulation is possible
through an inhibitory role of these regions on HPA
activity [54,55].
In most studies, the physiological assessment of stress
in animal and human populations involved measure-
ments of corticosteroids (cortisol in humans, and corti-
costerone in animals), and ACTH levels in blood or
cortisol in saliva or urine. Activity of the sympathetic
nervous system is generally assessed by measures of
catecholamines or monitoring of heart rate and blood
pressure. When one is measuring reactive hormonal
actions in response to stress, it is important to consider
the time of day of this assessment, given the fact that
cortisol follows a circadian rhythm. In humans, under
basal conditions, cortisol secretion exhibits a 24-h circa-
dian profile in which cortisol concentrations exhibit a
morning maximum, declining levels during the late
morning and afternoon, a nocturnal period of low
concentrations, and an abrupt elevation after the first
few hours of sleep [208].
3. Arguments for a stress – hippocampus link
3.1. Glucocorticoid receptors in the hippocampus
Today, there is abundant evidence for the importance
of the hippocampus in feedback regulation of HPA
function [82,123,169]. Following the discovery of corti-
costeroid receptors in the hippocampus of the rat in
1968 [120], a plethora of studies characterized the role
of the hippocampus in HPA feedback regulation. In
general, these studies have shown that lesions to the
hippocampus result in elevated corticosterone levels
under basal and post-stress conditions [57,170,218],
whereas corticosteroid implants into the hippocampus
normalize ACTH levels in adrenalectomized rats [14].
139
Hippocampectomized animals show reduced suppres-
sion of HPA activity following exogenous corticos-
teroid administration [55]. Finally, hippocampectomy
results in increased CRH mRNA levels in the parvocel-
lular region of the PVN (a region which contains
neurons whose axons terminate in the median emi-
nence; [80]), and increased portal concentrations of
ACTH secretagogues [172].
However, one cannot appreciate the entire array of
functions of corticosteroids in the brain without know-
ing more about the historical background surrounding
the discovery of corticosteroid receptors in the rodent
hippocampus. Here, history shows us that the majority
of physiological and behavioral effects previously at-
tributed to the impact of corticosteroids on the
hippocampus might be actually sustained by a receptor
type that is poorly distributed in the rodent hippocam-
pus and even less present in the primate and human
brain.
3.1.1. One hippocampus, one receptor type
Before the mid-60s, the endocrine knowledge sur-
rounding the HPA axis unanimously predicted that the
hypothalamus should be the major site of the central
action of corticosteroids, so that receptors for this
hormone were expected to be solely localized in the
CRF producing cells of the hypothalamus (for a com-
plete review, see [38]). However, in their important
Nature paper published in 1968 [120], McEwen and
collaborators described the retention of corticos-
terone— a naturally occurring corticosteroids in the
rodent brain— in the adrenalectomized rat brain. The
rats were first adrenalectomized in order to deplete the
rat’s system of any endogenous circulating corticos-
teroids, and then corticosterone was injected and reten-
tion of this naturally occurring corticosteroid was
assessed. Using this method, McEwen and collabora-
tors [120] showed that corticosterone was highly re-
tained by the hippocampus, an area critically involved
in learning and memory [183]. In a second set of
experiments, McEwen and collaborators [122] com-
pared the brain regional distribution of cell nuclear
corticosteroids of adrenalectomized rats with corticos-
terone replacement, with that of intact rats with normal
levels of the circulating hormones and tested either at
08:30 h, or 15 min after ether stress. The results re-
vealed a pattern of distribution of cell nuclear corticos-
teroids in intact rats of both groups very similar to that
seen in adrenalectomized rats with corticosterone re-
placement. In both cases, the highest concentrations of
corticosteroid receptors were observed in the
hippocampus.
In 1974, de Kloet and collaborators [35], assuming
that a synthetic corticosteroid called dexamethasone
would be even better retained by the hippocampus than
the naturally occurring corticosterone, duplicated
140 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
McEwen’s study using dexamethasone and found out
that this assumption was in fact incorrect. Indeed,
dexamethasone was very poorly retained by the
hippocampus of the rodent brain, and this, irrespective
of the route of administration (peripheral vs. intracere-
broventricular), suggesting that this compound does
not readily access the brain. Later, these authors in
collaboration with Bruce McEwen, showed that the
small amounts of dexamethasone that penetrated the
brain was retained in a regional pattern that was dis-
tinctively different from corticosterone [35,121]. More-
over, another steroid (cortisol) that is not a natural
corticosteroid in the rat (although it is in humans) was
very poorly retained in the rodent brain [121]. On the
contrary, corticosterone as well as aldosterone (another
naturally occurring corticosteroid in the rodent) were
highly retained by the rodent hippocampus and sur-
rounding limbic structures.
The different modes of action of dexamethasone and
corticosterone on the rodent brain gave indications that
these two compounds might bind to different types of
corticosteroid receptors. This idea was confirmed 6
years later by Veldhuis and collaborators [210].
3.1.2. One hippocampus, two receptor types
The discovery that two types of corticosteroid recep-
tors were present in the rodent brain was made possible
by the development of potent selective corticosteroid
agonists and antagonists by Roussel-Uclaf (France) in
the early 1980s. Using these new selective compounds,
Veldhuis et al. [210] observed the presence of mineralo-
corticoid (MR) and glucocorticoid receptors in the
rodent hippocampus. In 1985, Reul and De Kloet [158]
showed that the tracer amounts of corticosterone that
were previously retained so abundantly by the rodent
hippocampus were actually bound to MRs, and not to
GRs. In fact, these authors showed that affinity of
hippocampal GRs for corticosterone in the rat brain
was actually too low for any signal to be detected.
In summary, before 1985, the majority of corticos-
teroid effects in the hippocampus were entirely ascribed
to GRs, while after 1985, the field had to re-establish its
focus on both MRs and GRs in order to explain the
impact of stress hormones on the rodent brain.
3.1.3. Distribution and affinity of MRs and GRs:
ethological considerations
The story of MR/GR distribution in the brain con-
tinued with the report by Sutanto et al. [198] showing
that the retention of corticosteroids in the hippocampus
depended on the species studied. In the rat, which is a
corticosterone secreting animal, naturally occurring
corticosterone will be highly distributed in the
hippocampus (by binding to MRs and GRs), while
other synthetic corticosteroids will not bind with high
affinity to hippocampal MRs. However, in the hamster,
which is a cortisol secreting species just as humans,
hippocampal MRs will display a higher affinity for
cortisol, when compared with corticosterone, although
the same compound (cortisol) will very poorly penetrate
the rodent brain [199]. In the rodent brain, MRs are
more heterogeneously expressed than GRs, with highest
levels of expression in the hippocampus and surround-
ing limbic system, and certain brainstem motor nuclei.
GRs are widely expressed in most brain regions and are
detected, among other brain regions, in the hippocam-
pus, the paraventricular nucleus and other hypothala-
mic nuclei, the limbic system, the cerebral cortex, and
most brainstem monoaminergic nuclei (for a review, see
[158]).
Whereas the anatomic distribution of rat hippocam-
pal MRs and GRs has been extensively described, very
little is known about MRs and GRs distribution in the
primate brain. However, in the mid-1980s, the cDNAs
for human MRs and GRs was cloned, and it has been
shown that each corticosteroid receptor exists in two
isoforms [4,51,81,224], allowing for their structural and
functional characterization [1,165]. Recent studies map-
ping both MRs and GRs distribution in the primate
brain strongly suggest that extrapolation from rat brain
to primate brain may be misleading when discussing the
impact of MRs and/or GRs on the hippocampus.
Indeed, a recent study performed by Sanchez and
collaborators [167] 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, cere-
bellum, hypothalamic paraventricular nucleus and pre-
frontal cortices. When studying the distribution of MRs
in the macaque’s brain, Sanchez et al. [167] reported
that MR mRNA was abundantly observed within the
dentate gyrus and Cornu Ammonis of the hippocam-
pus. Although previous studies have reported the pres-
ence of GRs in the hippocampus of humans
[102,183–185,201,216], and non-human primates [85],
these results were obtained by means of in situ hy-
bridization. However, two recent abstracts summarizing
studies using immunohistochemistry report that the
primate’s hippocampus is not the major site of GR
expression [99,150]. Although these results are interest-
ing in line with previous data obtained by in situ
hybridization, immunohistochemistry only reveals the
presence of the GR proteins at the time of the experi-
ment. It is thus possible that GR protein expression
may change following a stressor. Also, it is important
to note that immunohistochemistry is at best a semi-
quantitative method and absolute densities of GR re-
ceptors cannot be estimated with this technique.
Indirect results obtained from human populations also
suggest that GR expression might not be as important
as previously thought in the human hippocampus. For
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
example, the down-regulation of hippocampal GRs
that should be observed in patients showing chronic
hypercortisolemia is not reported [185], and an up-regu-
lation of GRs is actually reported in Alzheimer’s pa-
tients with high corticosteroid levels [216].
3.1.4. Corticosteroid receptors in the
hippocampus— conclusion
The results summarized above with regard to the
search of corticosteroid receptors in the brain of vari-
ous species show that although such receptors have
been originally found in the rodent hippocampus, the
characterization of the different distribution and
affinity of two corticosteroid receptor types involves a
more complex network of corticosteroid actions on the
brain. First, when studying the impact of stress hor-
mones on the brain, one has to consider the type of
corticosteroid receptors that might be involved, in line
with its preferential distribution and affinity in the
brain. Second, when studying the effects of corticos-
teroids on the brain, one has to take into account the
important species differences reported for the distribu-
tion of corticosteroid receptors in the brain. In this
sense, extrapolation of rodent data to human popula-
tions might be misleading.
More importantly, the observation that MRs are
widely distributed in the rodent, primate, and human
brain while GRs are weakly distributed in the primate
and human brain has another serious implication for
the stress–hippocampus link theory. Indeed, as will be
summarized in the next section, most of the negative
effects of stress (and related corticosteroids) on animal
and human cognitive function have been related to GR
actions. The relative absence of such receptor type in
the hippocampus either suggests that the negative ef-
fects of stress on cognitive function are related to
hippocampal MRs, or that these negative effects are
related to the isolated and/or combined actions of MRs
and GRs on various brain regions. These two issues
will now be discussed.
3.2. Corticosteroid effects on cognition
Since the seminal work performed by Scoville and
Milner [183] with amnesic patients having undergone a
bilateral ablation of the hippocampus, it has been
known that this structure serves a critical role in mem-
ory formation. Given the presence of corticosteroid
receptors in the rodent and human hippocampus, it has
been suggested that the corticosteroid modulation of
hippocampal activity may underlie some aspects of the
acute and/or chronic effects of corticosteroids observed
in animal learning and memory processes. The effects
of adrenal steroids on animal cognition and its neural
substrate have been studied using, for the most part,
three types of models that tap into hippocampal func-
141
tion. The first approach is to examine the neuroen-
docrine modulation of a physiological model of
neuronal excitability that is relevant to memory.
Hippocampal long-term potentiation (LTP) describes a
long-lasting enhancement in synaptic efficacy that oc-
curs in response to high-frequency electrical stimulation
[110,205]. LTP shares many characteristics in common
with memory, the most important being its rapid induc-
tion and its long duration. The second approach is
through the measure of associative learning, as defined
by various aspects of conditioning behaviors. The third
approach is through the study of spatial memory
[84,149].
In contrast, the effects of corticosteroids on human
cognition have been studied using, for the most part,
measures of declarative and non-declarative memory.
The logic for the inclusion of this amnesic dissociation
is due to the fact that studies report that the hippocam-
pus is essential for declarative memory, while it is not
essential for non-declarative memory [191]. 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 (priming). Thus, this somewhat
specialized role of the hippocampus serves as the basis
for specific hypotheses regarding the relationship be-
tween increased cortisol secretion and impaired cogni-
tive function in humans.
3.2.1. Animal studies
A number of studies have reported that the induction
of LTP in the hippocampus is blocked by the adminis-
tration of corticosterone [47,56]. The role of corticos-
teroids in hippocampal LTP have further been
confirmed by studies showing that the acute administra-
tion of corticosteroids in the dentate gyrus of the
hippocampus produces LTP [56,152]. In 1991, Bennett
and collaborators [8] reported the existence of a nega-
tive correlation between the magnitude of LTP in the
CA1 population spike in the hippocampus and the level
of circulating corticosteroids, thus suggesting a dose-de-
pendent relationship between corticosteroids and their
detrimental effects on LTP. One year later, Diamond
and collaborators [42] reported the presence of an
inverted-U shape relationship between the level of cir-
culating corticosteroids, and LTP. They described a
positive correlation between corticosterone and primed
burst potentiation (PBP; which is a low threshold form
of LTP; [8]) at low levels of corticosteroids and a
negative correlation between corticosterone and PBP at
high levels of corticosteroids. These results provided a
strong support for the hypothesis that corticosteroids
exert a concentration-dependent biphasic influence on
LTP.
142 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
Direct effects of corticosteroids on associative learn-
ing paradigms have also been described and the major-
ity of them revealed modulatory effects of
corticosteroids on animal cognition. For example, acute
administration of either corticosterone or dexam-
ethasone accelerates the rate of extinction of a shock
avoidance response [10,11,70,162]. Similarly to studies
performed on LTP, it has been shown that the effects of
corticosteroids on animal cognition follow an inverted-
U shape relationship [93]. In 1976, Kovacs and collabo-
rators [93] reported that low doses of corticosterone
facilitate extinction of an avoidance response, while
high doses of corticosterone delay the rate of extinction
of the conditioned response. Finally, biphasic modula-
tory effects of corticosteroids were also reported using
spatial memory paradigms (see [105]). Altogether, these
results (obtained mainly in the rodent population)
confirmed the important role of the hippocampus
in explaining corticosteroid-induced cognitive impair-
ments.
3.2.2. Human studies
In humans, the effects of corticosteroids on cognitive
function have been measured using mainly cognitive
tasks assessing declarative memory, which is a type of
memory thought to be sustained by the hippocampus.
In general, declarative memory function can be assessed
using tasks involving a conscious recollection of previ-
ously 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 corticosteroids on cognitive
function report impaired declarative memory function
after acute and/or chronic administration of synthetic
corticosteroids (for a complete review, see [105]). Inter-
estingly, the first study performed on the acute effects
of corticosteroids on human memory process was a
dose – response study. In 1986, Beckwith and collabora-
tors [7] showed that the effects of hydrocortisone on
human memory performance depend upon the dose
administered. Only the highest doses of hydrocortisone
(40 mg) enhanced recall when subjects were presented
with more lists of words. In 1993, Fehm-Wolfsdorf and
collaborators [53] reported that hydrocortisone admin-
istration in the morning (at the time of cortisol peak)
impaired declarative memory function, while it had no
effect on cognitive performance when administered at
night. In 1996, Kirschbaum and collaborators [89]
showed that the oral administration of 10 mg of hydro-
cortisone leads to a significant decrease in memory
performance as tested 60 min after hydrocortisone in-
take. The results showed that subjects who received
hydrocortisone treatment presented an impaired perfor-
mance in the declarative memory task but not in the
non-declarative memory task, thus suggesting that cor-
tisol interacts with hippocampal neurons to induce
cognitive deficits.
Besides acute actions, delayed effects of corticos-
teroids were reported in memory studies on human
subjects. In 1990, Wolkowitz and collaborators
[219,220] observed impaired memory performance in
normal adults following 5 days administration of high
doses of prednisone (80 mg p.o. daily), but normal
memory performance in another group of subjects fol-
lowing a more acute administration of 1 mg of dexam-
ethasone. In 1994, Newcomer and collaborators [143],
using a 4 days administration procedure with 0.5, 1, 1,
1 mg per day of dexamethasone in normal controls,
reported impaired declarative memory performance (ac-
quisition and recall) on the fourth day of treatment
only. No immediate or delayed effects of dexam-
ethasone were observed on non-declarative memory,
and selective attention performance. These results were
in accordance with a hippocampal involvement in corti-
costeroid-related cognitive deficits and argued against a
non-specific effect of the steroid on attention and
arousal. The same year, our lab reported that 4-year
exposure to high endogenous levels of cortisol in elderly
humans led to significant declarative memory impair-
ments, without impairing non-declarative memory func-
tion [104].
In summary, the majority of studies performed in
human populations tend to confirm the rodent litera-
ture reporting negative effects of corticosteroids on
hippocampal-dependent forms of memory. Altogether,
the rodent and human data strengthened the view that
stress hormones have a specific and isolated impact on
the hippocampus.
3.2.3. Problem c 1: memory does not equal
hippocampus in humans
Even if both animal and human studies have confi-
rmed the important impact of corticosteroid hormones
on cognitive function, there are still many flaws to the
conclusions that have been reached to this point. First,
one has to consider the fact that tasks that are etholog-
ically relevant to animals might not be as relevant in
human individuals (for a complete review, see [200]).
Indeed, although hippocampal-dependent tasks in ro-
dents have been confirmed using lesion studies, one has
to keep in mind the important phylogenetic differences
between development of the rodent and human brain.
Subcortical structures tend to have a more important
role to play in cognitive function in lower species such
as the rodent, while in primate and human populations,
development of cortical areas leads to a stronger in-
volvement of these regions in cognitive function. Also,
studies have shown that the more neuroethologically
relevant the spatial tasks are to the particular animal
(here, the rat), the more the hippocampus can be shown
to be prominent and to play an important role in these
tasks [200]. Given this later fact, it is thus possible that
a conclusion reached in the rodent population with
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
regard to the impact of corticosteroid on hippocampal-
dependent memory task might not be confirmed in
human individuals, when submitted to so-called ‘declar-
ative memory tasks’.
The second point relates directly to the measure of
memory function in both animals and humans. In all
species, memory lends itself to study through its re-
trieval, whether it is evaluated by the behavior of a rat
in a swimming pool, or by a verbal report in a human
subject. As summarized by William James in 1890 [83],
‘‘the only proof of there being retention is that recall
actually takes place’’. In many psychoneuroendocrine
studies performed in rodents and humans, a deficit in
recall is often related to a hippocampal-dependent form
of memory impairment. By doing so, researchers con-
sider memory as a single entity that is mainly localized
in the hippocampus. However, new studies performed
in human populations and using in vivo imaging of
brain function (functional neuroimaging technology)
under various memory tasks now consistently report
that memory is not a single entity. The success of the
functional neuroimaging approach is partly imputable
to the extensive use of concepts borrowed from the
cognitive psychology of human memory. Because re-
searchers have examined memory not as a single entity,
but instead as involving multiple and separable cogni-
tive processes such as encoding and retrieval just to
name a few, this has favored the observation of consis-
tent patterns of activation. A direct consequence is that
we now know that when a person encodes or retrieve
from memory a specific information, in addition to the
hippocampus, several brain regions exhibit increased
activity and the location of such increases is often
dependent on the memory process examined. In order
to extend our understanding of the impact of corticos-
teroids on human cognitive function, we will describe
recent human data obtained in brain imaging studies
which specify the role of the hippocampus and other
brain structures during memory encoding and retrieval.
This is not intended as an exhaustive review of the
literature as several have been published recently (see
[30,96,180]).
3.2.3.1. Memory encoding
Item encoding. Several PET and fMRI studies have
reported activations in or near the hippocampal region
during the encoding of information in memory. Mem-
ory encoding is a process that can be further divided
into different subprocesses, some of which have also
been linked to hippocampal activity. One of the first
role ascribed to the hippocampus had to do with ‘item’
encoding. For example, PET and fMRI studies have
shown that the hippocampus and adjacent cortex par-
ticipate in encoding of information about faces but not
about its retrieval [73]. The hippocampal region also
encodes meaningful actions [34] relative to meaningless
143
ones. Other studies have reported hippocampal region
activity during the encoding of visual objects [160,217],
visual patterns [217], and deeply processed words [207].
No6elty encoding. In a similar vein, other early func-
tional neuroimaging studies of memory suggested a role
of the hippocampal region during novelty encoding/as-
sessment [72,199]. This hypothesis states that a funda-
mental component of memory encoding is
discriminating whether stimuli are novel or familiar,
with the increased likelihood of novel stimuli to be
further encoded. Several researchers have examined the
involvement of the hippocampal formation during nov-
elty assessment. For example, Tulving and collabora-
tors [202,203] showed greater hippocampal activity
during a recognition task in which subjects had to
decide whether a presented item was ‘new’ (never pre-
sented before) as opposed to ‘old’ (previously studied
item). Similarly, Stern et al. [197] observed greater
hippocampal activation when subjects encoded new
pictures than when they encoded a single picture re-
peatedly. Dolan and Fletcher [44] found greater
hippocampal activations when both members of cate-
gory-exemplar word pairs were new than when either
the category or exemplar or both had been previously
presented to subjects. Kopelman et al. [92] also ob-
served greater hippocampal and parahippocampal acti-
vation, among other regions, during encoding of novel
words when compared with encoding of familiar words
and similar findings were observed using visual scenes
[131]. Finally, Martin et al. [117] found greater right
hippocampal activation when a task was being per-
formed for the first time (novel) than when it was being
performed for the second time (familiar), even though
the stimuli differed between the first and second trial of
the task. This possible involvement of the hippocampus
in detection of novelty is to be put in relation with
previous data showing that novelty is a potent inducer
of stress reactivity in both animals and humans [118].
Associati6e encoding. Other functional neuroimaging
studies have specifically investigated the neural corre-
lates of associative encoding of verbal [77,87,98,139,
159,161,207], and non-verbal stimuli [76,138]. For in-
stance, Henke et al. [76,77] contrasted neural activity
induced by an associative semantic encoding task to
that of a single-item encoding task for similar materials
and reported greater anterior hippocampal region activ-
ity during the former. These studies have collectively
identified brain regions that appear to make a signifi-
cant contribution to processes involved in association
formation. A common observation across these differ-
ent studies is the activation of the hippocampal region
during associative encoding [30]. Evidence in animal
neuroscience also suggests a significant role of the
hippocampal region in associative or relational process-
ing [29,48].
144 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
Successful encoding. Two recent fMRI studies
[18,212] have presented evidence for a role of
hippocampal region in successful memory encoding.
These two studies examined neural activity during a
memory encoding task consisting of the visual presenta-
tion of words [212] or pictures of landscapes [18].
Following the encoding task, subjects were adminis-
tered a memory recognition test composed of items
previously studied of never studied before. Based on the
behavioral performance during this recognition task, an
analysis of the fMRI data examined the differential
activity for encoding items that were subsequently suc-
cessfully recognized versus those items that were subse-
quently forgotten. This analysis identified brain regions
where neural activity was greater during ‘successful’
encoding. Both studies reported greater activity for
successfully encoded items relative to forgotten items in
the parahippocampal region. In addition, in the Wag-
ner et al., study which examined verbal material, this
difference was observed in the left hippocampal region
(parahippocampal gyrus) whereas in the Brewer et al.
[18] study which examined figural information, this
difference was observed in the hippocampal region
(parahippocampal gyrus) bilaterally.
While functional neuroimaging techniques can
provide information about the contribution of particu-
lar brain region such as the hippocampus to a specific
memory process, it can also provide valuable informa-
tion concerning changes in neural activity in all areas of
the brain. Perhaps we can understand better the role of
the hippocampal region during a specific memory task/
process if we are to examine systematically what ‘hap-
pens’ elsewhere in the brain. McIntosh [128,129] has
termed such an approach ‘neural context’ which simply
put, suggests that a given brain region may be engaged
in a specific process depending on activity in other
brain regions. In other words, a mental set is not
localizable to a given brain region but is instead repre-
sented in the activity of networks of brain regions.
Therefore, it is conceivable that a brain structure such
as the hippocampus may contribute to different mem-
ory processes depending on the synchronous activity in
other brain regions.
As we have seen earlier, functional neuroimaging
studies that have examined associative encoding or
relational processing have produced some of the most
exciting and reliable results in brain imaging research of
memory to date. From these PET and fMRI studies,
one common finding is the observation of hippocampal
activation in an experimental condition involving asso-
ciative encoding compared with a baseline condition.
This has been taken as a strong evidence for a role of
this brain region in relational processing [30].
In a recent PET study, Lepage and collaborators [98]
examined associative encoding and retrieval for verbal
material. In this study, three associative encoding con-
ditions differing in the number of words (0, 1, or 2)
semantically related to a third word representing the
name of a semantic category were examined. For exam-
ple, the category could be ‘FRUITS’ and the exemplars
‘BANANA’ and ‘ORANGE’ A recall task consisting in
the presentation of the category names (e.g. ‘FRUITS’)
as cues for retrieving the other two members of the
triads followed each encoding condition. A multivariate
analysis (partial least squares) of the PET data iden-
tified task-related patterns of activity distinguishing the
three associative encoding conditions from the three
cued-recall conditions. During associative encoding, rel-
ative activation was observed in the anterior hippocam-
pal region bilaterally, in the inferotemporal gyrus
bilaterally, left prefrontal cortex and in the fusiform
gyrus bilaterally.
The observation of hippocampal activation was cer-
tainly consistent with existing data but these authors
were interested to know whether brain regions other
than the hippocampus would exhibit the same consis-
tent and reliable activation during associative encoding
across the three conditions. They used these regions just
described as a starting point to review the functional
neuroimaging literature on association encoding. They
found eight other functional neuroimaging studies of
associative encoding [76,77,87,138,139,159,161,207].
Activation in four of these regions has been consistently
reported in previous studies of associative encoding
using PET, fMRI, and SPECT. These included the
hippocampal region, but also the left fusiform gyrus,
the left prefrontal cortex and the inferior temporal
gyrus bilaterally. These studies have compared neural
activity during an associative encoding task to all kinds
of control tasks and have used different kinds of mate-
rials including words, faces, houses, landscapes and line
drawings of objects.
The general picture that emerges is that hippocampal
region and left fusiform gyrus activations constitute the
most robust findings, observed in eight out of nine
studies including our PET study. Left inferior prefron-
tal cortex and inferior temporal cortex have been re-
ported in seven out of nine studies. The consistent
observation of increased activation in these four regions
is taken as strong evidence of their participation in
associative encoding. This finding suggests that in addi-
tion to the hippocampal region, other brain regions
make a unique contribution to the formation of associ-
ation in memory. Perhaps these different regions play a
different role in associative encoding. Studies that ma-
nipulate specific aspect or processes involved in associa-
tive encoding, such as the ease of association formation
or inter-modal associations will surely provide interest-
ing data on this problem.
3.2.3.2. Memory retrie6al. While many studies have
proposed a role for the hippocampus during the encod-
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
ing of information in memory, several other experi-
ments have produced data suggestive of a role of this
region during memory retrieval. As with encoding stud-
ies, the first wave of functional neuroimaging studies of
memory retrieval did not systematically manipulate spe-
cific processes. Instead, neural activity observed during
an episodic (declarative) memory retrieval task was
contrasted to that of a task not involving the retrieval
of information from memory but otherwise, similar in
terms of perceptual processing and response generation.
For instance, Squire et al. [192] contrasted a stem cued
recall task (a declarative retrieval task) to a stem com-
pletion task (a non-declarative retrieval task), and ob-
served greater hippocampal activity in the former.
Rugg et al. [164] reported greater left hippocampus
activation during the retrieval of deeply encoded words
relative to the retrieval of shallowly encoded words.
Kapur et al. [86] observed greater hippocampal activity
during the recognition of previously studied faces com-
pared with a resting condition, whereas Schacter et al.
[179] reported similar hippocampal activation during
the recognition of drawings of three-dimensional
objects.
These reports of hippocampal activation during
memory retrieval are certainly interesting, but they say
little about the underlying processes subserved by the
hippocampus during recall and recognition tasks.
Schacter et al. [178] compared two memory recall con-
ditions, one in which recall performance was high and a
second one in which performance was low. Greater
hippocampal activity was observed during the high
performance condition relative to the low performance
one. This finding is particularly interesting since both
conditions involve retrieval attempts but one condition
is more ‘successful’ than the other one. These findings
prompted Schacter and colleagues to suggest that the
hippocampal region is involved in the actual conscious
recollection of previously studied events but not in the
effort to do so. Another PET study based on this
experimental design yielded similar results [75] whereas
other studies that have looked at different levels of
performance between cued-recall tasks have failed to
reproduce these findings [163].
A recent fMRI study also suggests a role for the
hippocampal region in the subjective (conscious) experi-
ence associated with the act of retrieving information
from memory [49]. In this fMRI study, subjects indi-
cated during a recognition task whether for each item
previously categorized as ‘old’, there was a feeling of
recollection (remember judgments) or a feeling of famil-
iarity (know judgments). Relative to new items and
‘know’ judgments, ‘remember’ judgments led to a sig-
nificant increase in activity in the hippocampal region
among other regions. Similarly, Henson et al. [78] using
an even-related fMRI design observed greater posterior
hippocampal region activation during the recognition
145
of previously studied words associated with a ‘remem-
ber’ judgment relative to the presentation of new (never
studied before) words.
Although hippocampal activations have been re-
ported during memory retrieval, brain pattern of activ-
ity during recognition is quite different from that
observed during memory encoding [20,41,145,166,204].
In a recent paper using a meta-analysis of various
studies measuring brain activation during memory re-
trieval, Lepage et al., 2000 [97] have provided evidence
for the involvement of frontal lobes in memory re-
trieval. In order to do so, these authors combined data
from four previous PET studies [45,86,146,147] whose
designs included the requisite conditions. The purpose
was to get robust and stable results since the analysis
would be done on data from 53 subjects, something
that one rarely sees in functional neuroimaging studies.
The findings pointed to six specific cortical regions at
which recognition testing of old items exhibited as
much differential activation as did testing of new items
compared with the control condition. One of these sites
was in the anterior cingulate. The other five were all in
prefrontal cortex, and included two homotopic sites
situated bilaterally and symmetrically, one in anterior
prefrontal cortex (BA 10), the other near the opercular
region (BA 47/45). The fifth one was a right dorsal
prefrontal site near BA 8/9. These activations were
stronger and had a greater spatial extent in the right
hemisphere. From these results, it was concluded that
these six retrieval mode sites are involved in the estab-
lishment and maintenance of a brain state that sub-
serves the cognitive set of episodic memory retrieval
mode. It is interesting to note that such retrieval mode
activity was observed only in the frontal lobes and not
in posterior brain regions.
Moreover, other functional neuroimaging studies
have shown that under certain conditions, old and new
items can lead to differential activation with left pre-
frontal regions exhibiting greater activity for old (famil-
iar) items [72,91]. We refer to such findings as
item-related activity because they are attributable to the
nature of the item while the task requirements are kept
constant. In addition, other item-related retrieval pro-
cesses have been proposed and include post-retrieval
processing [163], monitoring [79], and retrieval effort
[178]. A recent study by McDermott et al. [119] has
reported fMRI data in which activity for old items were
associated with greater activity in anterior prefrontal
and right frontal opercular region.
Taken together, these studies make it increasingly
clear that recognition memory relies heavily on prefron-
tal cortex, especially in the right hemisphere. It has
been hypothesized that the hippocampal region is re-
lated to conscious recollection during recognition mem-
ory [49]. Since prefrontal cortex seems also involved in
memory retrieval, with greater activity in several re-
146 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
gions greater for remembered items than for new items
that cannot induce remembering, it seems difficult to
disentangle the contribution of prefrontal and
hippocampal regions to such retrieval process. At the
same time, these results suggest that memory retrieval
involves several brain regions, some of which appears
to make a task-related contribution and others an
item-related contribution to memory retrieval. There-
fore, if a region of prefrontal cortex is from an hemody-
namic point of view ‘behaving’ in the same way as a
region of the hippocampal region then it cannot be
ruled out that they are contributing to the same
process.
In summary, recent contributions from brain imaging
studies revealed that although the human hippocampus
is certainly involved in some facets of memory encoding
and retrieval, it is certainly not the only brain region
involved in these processes. Multiple cortical and sub-
cortical regions show increased activity during memory
encoding and retrieval tasks and these findings are not
limited to humans. For instance, a recent functional
brain imaging study using 2-deoxyglucose autoradiog-
raphy in mice has reported increased activity in multi-
ple neocortical areas, notably in the frontal cortex,
during a spatial memory retrieval task [13]. In conse-
quence, taking recall performance as the sole measure
of ‘hippocampal-dependent memory function’ in hu-
man populations when measuring the impact of corti-
costeroids might lead to significant errors in
interpretation of cognitive results. Such discrepancies
have been reported in human studies in which exoge-
nous or endogenous increases in corticosteroids has
been shown to impair either encoding [89,106,142,144]
or retrieval [39]. Knowing the important involvement of
the frontal lobes in retrieval of information (see previ-
ous section), one can ask whether the corticosteroid-in-
duced memory retrieval impairments observed in
human populations could in fact be better explained by
the impact of corticosteroid receptors activation on the
frontal lobes. The next section describing the differen-
tial effects of MRs and GRs activation on animal and
human cognitive function will shed light on this
question.
3.2.4. Problem c 2: differential in6ol6ement of MRs
and GRs in corticosteroid-induced memory changes
As we have summarized above, even if the majority
of human psychoneuroendocrine studies reported corti-
costeroid-induced declarative memory impairments, re-
cent brain imaging studies now show that one cannot
interpret a deficit in declarative recall performance as
being solely related to hippocampal function since (a)
the hippocampus has been shown to be involved in
memory encoding and (b) other brain regions actively
participate in both memory encoding and retrieval,
sometimes to a larger extent than the hippocampus per
see.
The second problem that emerges with regard to
interpretations of corticosteroid-induced declarative
memory impairments relates to the differential distribu-
tion and affinity of MRs and GRs within the rodent
and human brain. Although both receptor types have
been implicated in mediating corticosteroid feedback
effects (see [158]), there are two major differences be-
tween MRs and GRs that have to be taken into ac-
count when discussing the effects of corticosteroids on
human cognition. First, MRs bind corticosteroids with
an affinity that is about six to ten times higher than
that of GRs. This differential affinity results in a strik-
ing difference in occupation of the two receptor types
under different conditions and time of day. Low, basal
corticosteroids levels observed during non-stressed peri-
ods or PM phase in humans serve to activate largely
MRs, whereas the elevated corticosteroids levels char-
acteristic of periods of stress or AM phase in humans
activate both MRs and GRs [158]. The second major
difference between these two receptor types is related to
their distribution throughout the brain. MRs are
present exclusively in the limbic system, with a prefer-
ential distribution in the hippocampus, parahippocam-
pal gyrus, entorhinal and insular cortices. On the
contrary, GRs are present in both subcortical (paraven-
tricular nucleus and other hypothalamic nuclei, the
hippocampus and parahippocampal gyrus) and cortical
structures, with a preferential distribution in the pre-
frontal cortex [43,120,123,130,176,177]. Because of the
high affinity of hippocampal MRs for corticosteroids,
these receptors are thought to mainly control low basal
circadian levels of circulating corticosteroids, and to
enhance adrenocortical secretion following stress (tonic
influence; [158]). In contrast, the low affinity GRs ter-
minate high stress-induced levels of corticosteroids (dy-
namic influence; [158]).
To this day, the only consistent finding that has
emerged from the literature concerned with the acute
impact of corticosteroids on animal and human cogni-
tive function is that an inverted-U shape relationship
exists between the dose of corticosteroids acutely ad-
ministered, and its impact on cognitive performance
(for a review, see [105]). There have been two explana-
tions for the existence of this inverted-U shape func-
tion. The first one relates to the exclusive activation of
GRs [31,153], while the second one relates to a balance
of MR/GR activation [37].
3.2.4.1. In6erted-U shape function and GR acti6ation.
This hypothesis of corticosteroid actions is mainly
based on human studies measuring the effects of supra-
physiological increases (stress and/or exogenous admin-
istration) of corticosteroids on cognitive function. In
the majority of these studies, corticosteroids
[39,58,143,144,182] and stress [89,106] have been shown
to impair cognitive function, although this has not been
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
confirmed in other studies [193,209]. In most of these
studies, the implicit assumption made about the impact
of corticosteroids on human memory is that saturation
of GRs, by acute elevations of corticosteroids, impairs
hippocampal-dependent forms of memory.
Although this is certainly a very interesting hypothe-
sis that has been validated using various protocols,
there are still two main problems with the hypothesis as
it is stated now. The first one relates to the differential
distribution of MRs and GRs in the primate and
human brain, as opposed to the rodent brain. The
second relates to the type of neuroendocrine protocols
used in animal versus human studies, and the different
conclusions that are reached using these different
protocols.
In primates and humans, as opposed to rodent, GRs
have a preferential distribution in cortical areas, partic-
ularly in the prefrontal cortex [167,176], while the
hippocampus contains high levels of MRs, with low
levels of GRs. Today, there is evidence for a high
density of corticosteroid receptors in the prefrontal
cortex of both the rat [123,130], and human [177].
Binding studies in rats reveal a high retention of 3H-
CORT in the cortex, particularly in the medial prefron-
tal regions [43]. Further studies in rats [5,55,137], and
humans [141,189] show that the prefrontal cortex is a
significant target for the negative-feedback actions of
circulating corticosteroids [55,137], which suggests that
this area could play a significant role in the acute effects
of corticosteroids on cognitive function.
Thus, if one attributes the negative impact of corti-
costeroids on human memory as being related to acti-
vation of GRs, then one has to take into account this
preferential distribution of GRs in the prefrontal cortex
and postulate that in humans, cognitive function prefer-
entially sustained by prefrontal regions should be more
sensitive to acute increases of corticosteroids, when
compared with cognitive function preferentially sus-
tained by the hippocampus.
In primates and humans, prefrontal cortex has been
shown to be a key structure (without being the sole
region involved) in working memory (WM) function
[64,65,151,154] while the hippocampus is a key struc-
ture (again, without being the sole region involved) for
declarative memory function [183,191]. As we have
previously discussed, declarative memory refers to the
conscious and voluntary recollection of previously
learned information, while WM serves to store and
manipulate information within a short period of time
until it is transferred into long-term memory.
Two recent studies performed in humans report that
WM is more sensitive than declarative memory to acute
and short-term (10 days) increases in corticosteroids.
Young and collaborators [223] administered 20 mg
hydrocortisone for 10 days to young normal male
volunteers and measured various cognitive functions in
147
a randomized, placebo control, crossover, within-sub-
ject design. They showed that this regimen of hydro-
cortisone led to deficits in cognitive function sensitive to
frontal lobe dysfunction, while it did not impact on
cognitive function sensitive to hippocampal damage.
Similar results were obtained by our group [108] using
an acute dose–response neuroendocrine protocol. By
administering three different doses of hydrocortisone or
placebo in the morning (AM Phase; saturation of MRs,
partial occupancy of GRs), we were able to measure the
curve function relating GRs occupancy and cognitive
performance in humans. In our study, 40 young sub-
jects were infused for 100 min with either hydrocorti-
sone or placebo and memory function was tested
during the infusion period. The results revealed that
performance on the WM task decreased significantly
whereas performance on the declarative memory task
remained the same following an acute elevation of
corticosteroids. Curve fit estimations revealed the exis-
tence of a significant quadratic function (U-shape
curve) between performance on the WM task and
changes in cortisol levels after hydrocortisone infusion.
The results of these two studies suggest that in young
individuals, WM is more sensitive than declarative
memory to an acute elevation of corticosteroids. They
also suggested that this effect is significantly related to
GRs occupancy/sensitivity within the prefrontal cortex.
The presence of a GR-induced cognitive impairment
for prefrontal but not hippocampal function might at
first sight seem puzzling since the hippocampus also
contains GRs. However, animal studies have shown
that the presence of MRs in the hippocampus acts by
creating a physiological balance of both types of recep-
tors for their action on the HPA axis (called the ‘binary
hormone response system’ by Evans and Arriza [52]
and the ‘MR/GR balance hypothesis’ by Oitz et al.
[148] and reviewed by De Kloet et al. [37]). This sug-
gests that the presence of MRs within a structure acts
by decreasing GR responsivity to corticosteroids be-
cause of the tonic influence of MRs on the HPA axis
[148]. This suggestion implies that the absence of the
tonic influence of MRs (e.g. in prefrontal regions)
would increase GRs sensitivity and lead to increased
sensitivity of prefrontal regions to acute changes in
corticosteroids levels, when compared with the
hippocampus.
3.2.4.2. In6erted-U shape function and MR/GR balance.
Although the majority of studies performed in human
populations still report negative effects of corticos-
teroids on cognitive function (for a complete review, see
[105]), various studies performed in rodents report a
positive impact of corticosteroids on learning and mem-
ory [12,36,132,133,135,211]. One possible reason for
such a discrepancy between rodent and human studies
was recently discussed by De Kloet and collaborators
148 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
[37] as being related to the fact that every human study
performed to this day has measured the impact of
supra-physiological increases of corticosteroids on
learning and memory, while rodent studies have used
hormone replacement protocols.
In a hormone-replacement protocol, the behavior
resulting from the absence of the hormone of interest is
first measured, and then, baseline hormonal levels are
restored to normal values and the same behavior is
measured once again. It is postulated that if the hor-
mone of interest has a real impact on the behavior
tested, then this behavior should be restored to normal
value after hormonal replacement (see [19]). In studies
of the impact of corticosteroids on cognitive function,
the reason why hormone replacement protocols might
permit to assess the positive impact of corticosteroids
on cognitive function relates directly to the differential
involvement of MRs and GRs in corticosteroid-induced
cognitive changes.
Remember that given their differential affinity for
corticosteroids, MRs will always have to be totally
saturated (100% activated) before GRs can start to be
activated. During periods of stress or high levels of
corticosteroids, both MRs and GRs will be saturated.
Many studies performed in rodents have shown that the
ratio of MR/GR occupation is the major determinant
of the direction of GR-induced cognitive changes (for a
review, see [37]). For example, LTP has been reported
to be at optimal level when corticosteroids levels are
middly elevated, i.e. when the ratio of MR/GR occupa-
tion is high (i.e. MRs are saturated (100%) while GRs
are only partially occupied (50%). In contrast, signifi-
cant decreases in LTP are observed after adrenalec-
tomy, when the ratio of MR/GR is very low (absence
of MRs or GRs occupancy). The same negative impact
of corticosteroids on LTP is reported after exogenous
administration of supra-physiological doses of synthetic
corticosteroids, which saturate both MRs and GRs,
leading again to a low MR/GR ratio. It has thus been
suggested that the negative view of corticosteroids ac-
tions on human cognitive function can be partly ex-
plained by limitations in previous human experimental
designs, which did not allow to differentially manipu-
late MR and GR levels, as can be done in rodent
hormone replacement protocols.
In order to test this suggestion, we have performed a
hormone replacement study in a population of young
normal controls [109]. In this protocol, we used a
within-subject double-blind experimental protocol in
which we first induced a chemical lowering of corticos-
teroids levels by administration of metyrapone, a po-
tent inhibitor of corticosteroids synthesis, and then
restored baseline circulating corticosteroid levels with
subsequent infusion of hydrocortisone. Memory perfor-
mance of participants under each of these conditions
was compared with that measured on a placebo day.
The results showed that, when compared with placebo,
the pharmacological decrease of circulating levels of
corticosteroids induced by metyrapone significantly im-
paired delayed memory performance. Most impor-
tantly, we showed that this impairment was completely
restored after hydrocortisone replacement. These results
are the first obtained in a human population showing
that corticosteroids can modulate memory function. We
have suggested that this modulation can happen
through a differential activation of MRs and GRs.
Indeed, during the metyrapone condition, both MRs
and GRs were unoccupied, resulting in a low MR/GR
ratio and impaired memory performance. On the con-
trary, during the hydrocortisone replacement condition,
cortisol levels were restored to the levels typical of those
measured in the AM phase, i.e. leading to a saturation
of MRs, with partial occupancy of GRs. This differen-
tial occupation thus led to an increased MR/GR ratio,
and a restoration of baseline cognitive performance. In
addition to confirming the positive impact of corticos-
teroids in human cognitive function, these results pro-
vided preliminary evidence that a threshold for
corticosteroid-induced cognitive impairments might ex-
ist, and might be related to the balance in MR/GR
occupancy.
As one can see from the above discussion of the
differential impact of MRs and GRs on cognitive func-
tion, it is difficult at this point of research to disentan-
gle the impact of MR/GR balance versus GR
saturation on human cognitive function. However, it is
becoming clear from this set of data that the actions of
corticosteroids on the brain are less specific and isolated
to the hippocampus than was previously thought. Hor-
mones such as corticosteroids are usually thought to be
modulators of behaviors, rather than inducers of partic-
ular sets of behaviors. Also, hormonal changes occur in
response to environmental challenges, and such envi-
ronmental challenges have to be interpreted as such by
the brain in order to induce hormonal variations. Thus,
although corticosteroids might modulate cognitive
function, cognitive processing can in turn modulate
corticosteroid secretion and enter a closed-loop system
of modulatory actions. In this sense, the static unidirec-
tional view of corticosteroid actions on the brain
should be re-analyzed if one wishes to understand the
multiple subtleties of the relationship between stress,
memory and the brain. The impact of stress hormones
on hippocampal atrophy and/or neurogenesis might
help shed light on these complex relationships.
3.3. Corticosteroids and atrophy of the hippocampus
The third argument that has been consistently used in
order to confirm the stress–hippocampus link is that
chronic exposure to high levels of corticosteroids leads
to hippocampal atrophy in both animals [94,95], and
humans [101,107,194].
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
In the rat and monkey, chronic hypercortisolemia
and/or stress has been shown to increase hippocampal
neuronal vulnerability to subsequent insults, and in
some case, neuronal loss has been reported
[3,24,32,94,95,136,168,171,206], although not in all ex-
perimental paradigms [6,9]. Interestingly, in the rat, less
severe forms of chronic stress paradigms have been
shown to produce a different pattern of hippocampal
morphological changes reflected in neuronal dendritic
atrophy. This type of atrophy is characterized by an
atrophy of CA3 pyramidal neurons and includes a less
complex branching pattern and decreased total length
of apical dendrites. It appears generally after 21 days of
corticosterone treatment of 6 h/day of restraint stress
[62,111–113,140,214,215,221]. Interestingly, neurons
exhibiting dendritic atrophy are not necessarily commit-
ted to stress-induced neuronal death [167], which could
explain recent results showing that chronic stress- and/
or corticosterone-induced hippocampal atrophy in the
rat is reversible [114]. However, given that no other
brain regions have been studied in relation to chronic
exposure to stress or high levels of corticosteroids, it is
difficult at this point to ascertain that the impact of
corticosteroids on brain atrophy is specific to the
hippocampus.
Due to obvious ethical reasons, most of the human
studies that assess the impact of hypercortisolemia on
hippocampal atrophy are correlational, although some
of them have prospectively measured the impact of
treatment on hippocampal volume [195]. In general,
four types of pathologies associated with changes in
circulating levels of corticosteroids have been studied,
namely Cushing’s disease [194,195], depression
[17,103,157,187], post-traumatic stress disorder [15–
17,71,196,213], and unhealthy aging [33,107].
Patients with Cushing’s syndrome represent a power-
ful model in which to assess the association of hyper-
cortisolemia and hippocampal atrophy in humans since
these patients experience high levels of endogenous
cortisol for periods of months or years. Using magnetic
resonance imaging (MRI) of the brain, Starkman et al.
[194] showed that Cushing’s patients have decreased
hippocampal volume when compared with controls. In
the same study, hippocampal volume was negatively
correlated with plasma cortisol concentrations, and
positively correlated with scores on verbal learning and
recall tasks. More recently, the same group [195] re-
ported that therapeutic decrease in cortisol levels in
Cushing’s patients increased by 10% the hippocampal
formation of treated patients, revealing some forms of
reversibility of hippocampal atrophy in human
populations.
A similar atrophy of the hippocampus has been
reported in depressed patients by Sheline and collabora-
tors [187], and more recently by Bremner and collabo-
rators [17]. However, and in contrast with studies
149
performed in Cushing’s patients, the hippocampal atro-
phy reported to occur in depressed populations was
observed in the absence of increased hypercortisolemia
[187], or absence of cortisol measurement [17] in patient
populations. In this context, it is particularly difficult to
associate the observed hippocampal atrophy to the
presence of hypercortisolemia in the patient population.
Also, depressive disorder has been related to frontal
lobe dysfunction, a suggestion confirmed by neu-
roimaging studies showing a 7% reduction of the total
volume of the frontal lobe in major depressive disorder
[28], and a substantial 39–48% decreases in the subgen-
ual prefrontal gray matter in patients with major de-
pressive disorder and bipolar depression [46]. The
frontal lobe atrophy associated with depression has
recently been confirmed by morphometric studies of
human postmortem brain tissues [157], and a new study
by Lucassen and collaborators [103] report that
hippocampal apoptosis in major depression is a minor
event and is absent from areas at risk for corticosteroid
exposure in human postmortem brain tissue. In conclu-
sion, even if some form of hippocampal atrophy has
been reported in depressive disorders, this atrophy is
not isolated to the hippocampal formation, and has not
been significantly correlated with increased secretion of
corticosteroids.
However, the combined implication of frontal and
hippocampal pathologies in depressed population is an
interesting finding, in line with previously summarized
data revealing the presence of MRs and GRs in both
frontal and hippocampal human structures. The differ-
ential involvement of MRs and GRs in the acute versus
chronic effect of corticosteroids on the brain could
explain recent results obtained by Sheline and collabo-
rators [188] showing that depression duration but not
age predicts hippocampal volume in depressed women.
Given the possible protective effects of MR/GR bal-
ance in the hippocampus, one could suggest that
hippocampal dysfunction and/or atrophy could appear
after multiple exposure to high levels of corticosteroids
(tonic protection from MRs), while frontal dysfunction
and/or atrophy should appear more rapidly (no tonic
protection from MRs) in response to stress-induced
corticosteroid increase. Such a pattern could explain the
impact of depression duration on hippocampal volume
in depressed populations [187]. However, it is clear that
only a longitudinal follow-up of depressed patients
could confirm such a suggestion.
The same frontal/hippocampal rationale could also
apply to patients with post-traumatic stress disorder, in
whom atrophy of the hippocampus has been reported
[15–17,71,196,213]. Again, there is discrepancy in this
finding given data showing that PTSD patients present
hypocortisolemia, instead of hypercortisolemia (for a
review, see [222]), and other reports showing prefrontal
system dysfunction in PTSD populations [90]. Given
150 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
these results, it is difficult at this point to relate
hippocampal atrophy to basal cortisol levels in PTSD
populations, or relate hippocampal atrophy to prefron-
tal cognitive impairments. However, in most PTSD
populations studied at this point, trauma occurred
many years before the actual measurement of
hippocampal volume, so that it might be possible that
similarly to depressed patients, duration of stress-in-
duced symptoms is the important factor explaining
development of hippocampal atrophy in this
population.
Finally, using a 4-year longitudinal study performed
with elderly humans, we previously showed that ap-
proximately 30% of this aged cohort presents a signifi-
cant endogenous increase of cortisol levels with years
that is related to a 14% atrophy of the hippocampus
when compared with elderlies with normal secretion of
cortisol over the 4-year period [107]. Interestingly, we
also reported that this group of aged humans presented
memory impairments [104] as well as reported more
frequent feelings of stress, fatigue and depression when
compared with the other elderly individuals [107]. Al-
though in this study, the atrophy was shown to be
specific to the hippocampus when compared with other
temporal lobe structures, there was no MRI measure-
ments performed on frontal lobe regions, thus prevent-
ing any definite conclusion as to the specificity of
corticosteroid-induced effects on the aged human brain.
A retrospective analysis of these brain images is actu-
ally being performed by our group in order to assess
whether long-term exposure to high levels of corticos-
teroids had any significant impact on frontal regions in
this elderly population.
Altogether, these data tend to support the idea that
chronic exposure to high levels of corticosteroids induce
an atrophy of the hippocampus. However, most studies
performed in humans are somewhat weakened by un-
controlled factors that could explain the observed
hippocampal atrophy. Also, one has to come to the
conclusion that a unidirectional point of view of nega-
tive corticosteroid actions on the hippocampus is usu-
ally taken by scientists in the field. However, the
observation that some of the reported hippocampal
atrophy is reversible would tend to suggest that high
corticosteroid levels could be a consequence rather than
a cause of hippocampal atrophy. Indeed, comparative
studies of different species show that hippocampal vol-
ume is increased in mammalian and avian species that
depend critically on spatial memory for survival. Exam-
ples of such critical memory skills involve home-range
navigation, migration, brood parasitism, and memory-
based cache recovery in birds that hide food [200].
This association between performance on spatial
tasks and hippocampal size could be explained in terms
of the impact of environmental demands on hippocam-
pal volume, rather than the converse. For example,
Clayton and collaborators [26,27] reported that the
hippocampus of titmice and chickadees increases in
volume in association with the experience of storing
and recovering food cache. This result shows that in
animals, there can be an experience-dependent
hippocampal growth that occurs at a relatively late
stage in development. Similar results of experience-
based hippocampal volume were recently reported by
Maguire and collaborators [116] in humans. These au-
thors tested the hypothesis that the ability of taxi cab
drivers to navigate correlates with hippocampal vol-
ume. They showed that compared with age-matched
controls, the taxi drivers had larger posterior
hippocampi. Although these results surely do not
confirm that the experience of driving a taxi cab in the
complex streets of London has a significant effect on
hippocampal volume, they nonetheless raise the intrigu-
ing possibility of hippocampal plasticity in response to
environmental demands.
This later hypothesis is to be put into perspective
with the previously summarized data of hippocampal
atrophy in PTSD, depressed, and unhealthy elderlies. In
each of these states, stress has been shown to be a
significant factor in inducing or perpetuating the nega-
tive symptoms. It is known that the HPA axis is a
system, which monitors and responds to the environ-
ment throughout life. Given the combined implication
of stress and the HPA axis in these various disorders
related to hippocampal atrophy, it could be suggested
that stress will act by decreasing the capacity of the
individual to respond to environmental demands. Given
the relationship observed between environmental de-
mands and hippocampal volume, one could thus postu-
late that the hippocampal atrophy observed in these
populations is the results of a stress-induced decrease in
response to environmental demands, which then leads
to atrophy of the hippocampus. Although this is surely
a hypothesis that will need confirmation before being
seriously proposed, it nonetheless shows that the
stress–hippocampal atrophy link can be studied using
other important variables.
3.4. Corticosteroids and hippocampal neurogenesis
Although for a long time it was thought that the
brain of adult mammals do not generate new nerve
cells, more recent evidence showed that neurons are
born in the adult mammalian brain [2]. Interestingly, in
the adult brain, the generation of new neurons (called
neurogenesis) occurs in only two regions. The first
regions is the subventricular zone in the wall of the
lateral ventricle where new interneurons are generated
for the olfactory bulb, and the second region is the
subgranular zone of the dentate gyrus of the hippocam-
pus, which gives rise to the granule cells. Moreover,
recent evidence show that adult neurogenesis in the
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
dentate gyrus of the hippocampus is a feature of all
mammalian species, occurring in rats, mice, tree shrews,
marmosets, macaques, and humans [23,50,67– 69,88].
Although the functional significance of hippocampal
neurogenesis has been questioned in the past, a new
study published in the March 2001 issue of Nature
reported that neurogenesis in the adult is involved in
the formation of trace memories, suggesting that the
new neurons actually contribute to the function of the
adult brain [190].
Corticosteroid effects on hippocampal neurogenesis
have been extensively studied and it has been shown
that throughout post-natal life, corticosteroid exert sup-
pressive effects on cell proliferation in the dentate gyrus
[165,176]. Interestingly, the stress hyporesponsive pe-
riod observed shortly after birth in the rat coincides
with a period of maximal granule cell production in the
dentate gyrus [181], which suggests an inhibitory action
of corticosteroids on post-natal cell proliferation.
Similar detrimental effects of corticosteroids on adult
hippocampal neurogenesis have been reported. Treat-
ment of adult rats with corticosterone decreases the
proliferation of granule cell precursors [21], while re-
moval of adrenal steroids stimulates the proliferation of
granule cell precursors during adulthood [22]. Given the
suppressive actions of corticosteroids on hippocampal
neurogenesis, acute stressful experiences (which activate
secretion of corticosteroids) have been suggested to
inhibit cell proliferation in adulthood, a hypothesis that
has been demonstrated. An acute stressful experience
decreases the number of adult-generated neurons in the
dentate gyrus in various species, including the rat
[61,74,186], tree shrew [67], and marmoset [68]. In a
similar vein, repeated stress also produces prolonged
suppression of cell proliferation in the dentate gyrus of
the adult tree shrew [59,60]. Although it has not been
demonstrated, stress induced decrease in dentate gyrus
cell proliferation could also contribute, in line with
atrophy of the pyramidal cells of the hippocampus, to
changes in hippocampal volume observed after chronic
exposure to high levels of corticosteroids (see previous
section).
Interestingly, it has been shown that experience can
also induce cell proliferation in the dentate gyrus.
Gould and collaborators [69] reported that training on
a task that requires the hippocampal formation results
in an increase in the number of adult-generated granule
cells. Importantly, these authors showed that in un-
trained adult laboratory animals, the majority of gener-
ated cells degenerate within 2 weeks of production,
while training on hippocampal tasks rescued a signifi-
cant proportion of these cells [69]. In line with experi-
ments showing experience-dependent hippocampal
volume changes, studies performed in adult neurogene-
sis show that learning can enhance the number of
granule neurons. If this is the case, any change in the
151
learning experience (due to social isolation, disease,
depression, aging etc.) could lead to significant changes
in hippocampal neurogenesis and contribute to both
the memory impairments and hippocampal atrophy
reported to occur with chronic exposure to high levels
of corticosteroids.
The mere presence of neurogenesis in the hippocam-
pal regions (along with neurogenesis in the olfactory
bulb), and the important effects of stress hormones on
hippocampal neurogenesis have been taken as good
evidence that stress has a specific impact on the
hippocampus. However, a recent study reported the
induction of neurogenesis in the neocortex of adult
mice [115]. These authors destroyed a subset of pyrami-
dal neurons that project from the neocortex to the
thalamus, a technique that resulted in the slow death by
apoptosis of the targeted cells only, without affecting
the surrounding cortical tissue. Although the number of
new cells formed in the 2 weeks after the lesion was
similar in control and experimental mice, about 1–2%
of the newly formed cells in the damaged neocortex
expressed neuronal markers in the experimental mice
only. Interestingly, the new neuronal cells occurred only
in the cortical layer undergoing degeneration, and some
of these cells had the morphological characteristics of
pyramidal neurons. Although the neurogenic response
observed by these authors was very limited, it nonethe-
less raises the possibility of neurogenesis elsewhere in
the brain. Given the presence of MRs and/or GRs in
the cortex of primates and humans, it is clear that
further developments in this field of research will help
extend our understanding of the impact of stress and
related stress hormones on brain neurogenesis.
4. Conclusion
In this review of the literature, we summarized the
four arguments for a stress–hippocampus link used in
animal and human psychoneuroendocrine research, and
reported new evidence showing that this link, although
it surely exists, might not be the only one relating stress
to the brain. Indeed, two types of corticosteroid recep-
tors are distributed differentially in the rodent and
primate brain, which could explain some discrepancies
in results obtained with both types of populations.
Also, what is called ‘learning and memory’ and concep-
tualized as a single entity in some studies is actually a
composite of various cognitive processing components
that are also distributed in different regions of the
brain, including the hippocampus but also cortical ar-
eas such as the frontal and prefrontal cortices. Third,
although chronic exposure to high levels of corticos-
teroids certainly contribute to atrophy of the
hippocampus and inhibition of dentate gyrus cell prolif-
eration, these two processes are also very sensitive to
152 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
environmental demands, which can themselves be
modified by stress.
All these evidences point to a modulatory role of
corticosteroids on the rodent and human brain and the
necessity to integrate various levels of analysis in our
search for corticosteroid actions on the brain. Three
new levels of analysis should be seriously considered by
scientists interested in studying the impact of corticos-
teroids on human cognitive function. The first one
relates to a methodological refinement of our neuroen-
docrine protocols and to a tighter control of time of
cognitive measurements. It has been known for a while
that baseline cognitive function is not the same in the
AM versus PM phase in humans [53]. In 1996, Fehm-
Worlsdorf and collaborators [53] postulated that this
natural diurnal variation of cognitive function could be
related to circadian variations in cortisol levels. In their
study, they measured the effect of an oral administra-
tion of 50 mg of hydrocortisone on a free recall task in
young normal controls in the morning, when endoge-
nous cortisol levels are at their peak, and at night, when
they are at their lowest concentration. The results re-
vealed that hydrocortisone administration suppressed
the increased cognitive performance in the morning,
while it had no effect on cognitive performance when
administered at night. We recently extended this result
in young normal controls in which we showed that
administration of 35 mg hydrocortisone in the evening
(PM phase) significantly increased cognitive efficiency
when compared with placebo treated subjects [109].
Altogether, these results show that because of the dif-
ferential involvement of MRs and GRs on the magni-
tude and/or direction of corticosteroid-induced
cognitive changes, time of testing of endogenous or
exogenous increases of corticosteroids can be a crucial
factor in determining both the magnitude and direction
of cognitive changes induced by corticosteroids.
The second level of analysis that should be taken into
account concerns the type of population studied when
assessing the effects of corticosteroids on human cogni-
tive function. Knowledge of the differential impact of
MRs and GRs on cognitive function might help disen-
tangle some of the effects of hypo- versus hypercorti-
solemia on cognitive function. Given that absence of
MR and GR activation (induced by surgical or chemi-
cal adrenalectomy) can induce cognitive impairments as
important as saturation of MRs and GRs (for a review,
see [37,105]), one has to take into account the fact that
cognitive impairments in hypocortisolemic populations
such as PTSD or burn-out patients might have a differ-
ent cause than those observed in hypercortisolemic
populations such as Cushing or depressed patients.
Also, and based on the MR/GR balance theory, one
should postulate that endogenous or exogenous admin-
istration of corticosteroids should have a different im-
pact on these populations, based on their baseline levels
of cortisol before treatment.
Finally, our analysis of new human brain imaging
data shows that memory function cannot be envisioned
as a single entity process and each component of learn-
ing and memory (encoding, consolidation, retrieval)
involves the combined activation of various brain re-
gions. Although corticosteroid effects have been re-
ported for encoding [89,143,144], consolidation
[105,106], and retrieval [39], one has to take into ac-
count recent studies [142] of old concepts
[40,66,100,134,156,173–175] revealing the phenomenon
of ‘reconsolidation’ and showing that reactivated mem-
ory are more sensitive to various amnestic treatments
than newly acquired memories (for a recent review, see
[174]). In summary, these studies show that treatments
that are ineffective at impairing memory when adminis-
tered right before recall can in fact do so if memory for
the event is reactivated just before treatment. These
results show that memories exist in an active state
during which they are labile and susceptible to disrup-
tion by amnestic agents, and in an inactive state during
which they are resistant to amnestic treatments.
Interestingly, a new study by Przybyslawski and col-
laborators [155] showed that although systemic injec-
tions of propanolol (a b-adrenergic antagonist) are
ineffective in inducing memory impairments when given
right before retrieval, the same treatment induces sig-
nificant memory impairments when administered right
after reactivation by a simple retention test applied 48 h
after training. The demonstration of the vulnerability of
memory when it is in an active state reinforces the idea
that memories, reorganized as a function of new experi-
ences, undergo a reconsolidation process that can be
modulated by various treatments and can be sustained
by various brain regions at different times of the mem-
ory formation.
In line with these new and exciting data, it is becom-
ing clear that a conception of stress, memory and the
entire brain will emerge in which the effects of stress on
memory will be assessed using a theoretical framework
taking into account the fact that the brain is not a
spectator but rather an active participant in its response
to the environment, and particularly environmental
stress.
Acknowledgements
S.J. Lupien research summarized in this paper was
funded by a Scientist Research Award from Fonds de
la recherche en santé du Québec (FRSQ), by an operat-
ing grant from Canadian Institute of Health Research
(CIHR), and by a Research Scholar Award from EJLB
Foundation. The Douglas Hospital Longitudinal Study
of Normal and Pathological Aging is funded by a grant
from the Alzheimer Society of Canada. Part of M.
Lepage research summarized in this paper was sup-
 S.J. Lupien, M. Lepage / Beha6ioural Brain Research 127 (2001) 137–158
ported by a foundation of Anne and Max Tanenbaum
in support of research in cognitive neuroscience.
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