CNS & Neurological Disorders - Drug Targets, 2006, 5, 531-546 531
1871-5273/06 $50. 00+. 00 © 2006 Bentham Science Publishers Ltd.
Stress, Depression and Hippocampal Apoptosis
Paul J. Lucassen*,1, Vivi M. Heine1,2, Marianne B. Muller3, Eline M. van der Beek4,5,
Victor M. Wiegant6, E. Ron De Kloet7, Marian Joels1, Eberhard Fuchs8,
Dick F. Swaab9 and Boldizsar Czeh8
1Centre for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The
2Present Address: Pediatric Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston MA 02115, USA
3Max Planck Institute for Psychiatry, Kraepelinstrasse, Munich, Germany
4Human and Animal Physiology Group, Department of Animal Science, Wageningen University, Haarweg 10, 6709 PJ
Wageningen, The Netherlands
5Numico Research, Department of Biomedical Research, Bosrandweg 20, P.O.box 7005, 6700 CA Wageningen, The
6Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Center,
P.O.box 85060, 3508 ABUtrecht, The Netherlands
7Division of Medical Pharmacology, LACDR, Leiden University Medical Center, Leiden, The Netherlands
8Clinical Neurobiology Laboratory, German Primate Center, 37077 Göttingen, Germany
9Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ, Amsterdam, The Netherlands
Abstract: In this review, we summarize and discuss recent studies on structural plasticity changes, particularly apoptosis,
in the mammalian hippocampus in relation to stress and depression.
Apoptosis continues to occur, yet with very low numbers, in the adult hippocampal dentate gyrus (DG) of various species.
Stress and steroid exposure modulate the rate of apoptosis in the DG. Contrary to earlier studies, the impact of chronic
stress on structural parameters of the hippocampus like cell number and volume, is rather modest, and requires prolonged
and severe stress exposure before only small reductions (< 10 %) become detectable.
This does not exclude other structural parameters, like synaptic terminal structure, or dendritic arborization from being
significantly altered in critical hippocampal subregions like the DG and/or CA3. Neither does it imply that the functional
implications of the changes after stress are also modest. Of interest, most of the structural plasticity changes appear tran-
sient and are generally reversible after appropiate recovery periods, or following cessation or blockade of the stress or cor-
The temporary slowing down of both apoptosis and adult proliferation, i.e. the DG turnover, after chronic stress will affect
the overall composition, average age and identity of DG cells, and will have considerable consequences for the connec-
tivity, input and properties of the hippocampal circuit and thus for memory function. Modulation of apoptosis and neuro-
genesis, by drugs interfering with stress components like MR and/or GR, and/or mediators of the cell death cascade, may
therefore provide important drug targets for the modulation of mood and memory.
on structural plasticity changes, particularly apoptosis, in the
mammalian hippocampus in relation to stress and depres-
sion. As stress effects on adult neurogenesis will be ad-
dressed already in a separate chapter in this issue, this topic
will be discussed only when in relation to apoptosis or when
of particular relevance for the model of stress involved.
This review aims to summarize and discuss recent studies
*Address correspondence to this author at the Institute for Neurobiology,
Swammerdam Institute for Life Sciences, University of Amsterdam, Am-
sterdam, The Netherlands; E-mail: firstname.lastname@example.org
society, stress represents an old, yet essential alarm system
for any individual organism. By definition, stress systems are
activated whenever a discrepancy occurs between an organ-
ism’s expectations and the reality it encounters, that gener-
ally involves a threat to the organism’s homeostasis .
Lack of information, loss of control, unpredictability or un-
certainty when faced with predator threat, or physical pertur-
bations of homeostasis, like food or water shortage, blood
loss, injury, or inflammation e.g., but also psychosocial de-
mands can all produce stress signals. These signals activate a
complex regulatory system in the body and brain, that is
comprised of various adaptive physiological and psychologi-
Ever present as it may be in e.g. the modern Western
532 CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 Lucassen et al.
bic-hypothalamo-pituitary-adrenal (HPA) system, a classic
neuroendocrine circuit in which limbic and hypothalamic
brain structures integrate emotional, cognitive, neuroendo-
crine, and autonomic inputs, that eventually determine the
magnitude and duration of behavioral, neural and hormonal
responses to stress. Together with other neuro-hormonal
components such as the sympathico-adrenomedullary sys-
tem, stress induced activation of the HPA system triggers the
production of corticotropin-releasing hormone (CRH) in
parvocellular neurons of the hypothalamic paraventricular
nucleus (PVN). This in turn induces adrenocorticotroph
hormone (ACTH) release from the pituitary, which causes
glucocorticoid (GC) release (cortisol in primates including
man and pigs, corticosterone in rodents) from the adrenal
cortex into the blood.
Glucocorticoid plasma levels are carefully kept within
physiological limits through GC-mediated feedback inhibi-
tion at specific steroid receptors in the pituitary and PVN.
Also the hippocampus, that at least in rat, contains high den-
sities of glucocorticoid (GR) and mineralocorticoid (MR)
receptors, is sensitive to GC action. Upon steroid binding to
MR or GR, the activated receptor translocates to the nucleus,
where gene transcription and electrophysiological properties
can be altered. Amongst other brain areas, the hippocampus
is furthermore thought to exert an (indirect) tonic inhibitory
control on HPA system activity, and is important in emo-
tional processing and in key aspects of learning and memory
In mammals, the stress response is mediated by the lim-
itself, prolonged and sustained hyperactivity of the HPA
system can result in maladaptation following e.g. alterations
in HPA setpoint or feedback, that can cause prolonged
(over)exposure of the brain and body to aberrant levels of
glucocorticoids and can induce pathological conditions. A
wide range of studies have addressed the consequences of
chronic stress and prolonged glucocorticoid exposure for
hippocampal structural integrity and function [3, 8-51]. In
rodents and man, GC excess is generally associated with
deleterious functional changes in e.g. hippocampal excitabil-
ity, longterm potentiation and learning [19, 23, 24, 29-31,
34, 35, 52-62]. The deleterious effects of glucocorticoids on
structural parameters, on the other hand, comprise initial,
and still reversible, atrophy of the dendritic tree of particu-
larly CA3, and to a lesser extent, also of CA1 neurons [36,
39, 59, 63-73], and reversible remodelling of synaptic termi-
nal structures [39, 66]. In later stages, the hippocampus as a
whole shrinks, and an increased vulnerability to metabolic
insults and even neuronal death of CA3 neurons have been
reported [74-85], that appears glutamate receptor mediated
[86, 87], and can extend into regions CA1 and CA4 if severe
Even though the stress response is considered harmless in
ated through the GR. However, chronic stress may also alter
the function of the mineralocorticoid receptor (MR) that is
implicated in tonic inhibitory control of the HPA axis, sup-
presses adrenalectomy-induced hippocampal apoptosis and
modulates neurogenesis [2, 88-91]. In view of its proposed
inhibitory role in HPA activity control [4, 5, 7, 92, 93], neu-
ronal loss as initially reported in stressed laboratory animals
and later also in primates, was expected to cause a disinhibi-
Effects of chronic stress are assumed to be largely medi-
tion of the HPA axis, leading to a positive feedforward cas-
cade of increasing glucocorticoid levels over time, that was
hypothesized to cause e.g. an age-related accumulation of
hippocampal damage. At the time, in disorders like Alz-
heimer’s disease and major depression, reductions in hippo-
campal volume were reported, that were paralleled by ele-
vated basal glucocorticoid plasma levels. As also other data
suggested similar correlations between hippocampal volume
changes, cognitive impairment and changes in HPA axis
activity, the ‘glucocorticoid cascade concept of stress and
hippocampal damage” was put forward [84, 85, 94-98] that
has been further rephrased and adapted in later papers [48,
region was initially expected to be mediated through an
apoptotic type of cell death [75-77, 80, 101, 105-110]. Of
note, also in the hippocampal dentate gyrus, apoptosis oc-
curs, even in control animals not subjected to stress, and no-
tably in close association with adult neurogenesis in this re-
gion [73, 107, 111-113]. Unlike CA3, where no adult neuro-
genesis is known to occur, both cell birth and cell death are
closely correlated in the dentate gyrus (DG), albeit with dif-
ferent time kinetics. Whereas neurogenesis can be monitored
over time after Bromo-deoxy-uridine (BrdU) incorporation
in dividing cells in S-phase, apoptosis is extremely rare in
tissue sections, at least in non-acute disorders, due to its
shortlasting presence, i.e. hours, during which the cell death
process is completed. For the rat brain e.g., steroid related
apoptosis was detectable for a maximum of 72 hours .
Hence, the chance of “trapping” ongoing apoptosis in thin
tissue sections obtained from a chronic brain disorder, is
very low [78, 114-116]. Yet, accumulating over time, the
contribution of (shifts in) apoptotic rate to structural hippo-
campal changes, e.g. after an altered balance between DG
apoptosis and neurogenesis after stress, can be considerable.
Stress induced neuronal loss in the hippocampal CA3
date on the effects of stress on apoptosis and cellular integ-
rity of the hippocampus in various animal models for stress,
and in major depression. These include psychosocial conflict
in the tree shrew, chronic unpredictable multiple stress in rat,
chronic restraint in the pig, and the human hippocampus of
major depressed and of steroid treated patients. The tree
shrew was further studied for additional modulation of apop-
tosis by antidepressant treatment.
The present review aims to provide a summary and up-
HPA CHANGES AND THE HUMAN HIPPOCAMPUS
IN MAJOR DEPRESSION
that hyperactivity and disturbance of HPA axis function are
implicated in the pathogenesis of depression [6, 22, 70, 71,
78, 117-129]. Although other factors are involved as well,
HPA feedback abnormalities occur frequently in patients
with depressive symptomatology and often resemble a subset
of the changes seen in chronically stressed animals. In hu-
mans, depressive disorders are a collection of symptoms, that
together constitute a recognizable clinical condition. Patients
suffering from major depression frequently show psychomo-
tor retardation, a phase shift in circadian activity patterns,
early morning awakenings, appetite disturbances, weight loss
and a loss of libido. Hyperactivity of the HPA system is
common and reflected by the high percentage of dexametha-
Numerous clinical and preclinical studies have shown
Stress, Depression and Hippocampal Apoptosis CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 533
sone non-suppressors in this population, hypertrophy of the
adrenals and pituitary, increased plasma levels of ACTH and
cortisol, and increases in CRH and vasopressin expression in
PVN neurons [38, 119, 121, 124, 125, 130-135]. Moreover,
significant decreases in hippocampal volume, as measured
by magnetic resonance imaging (MRI), occur frequently in
depressed patients [70, 136-142]. On basis of these data, one
would expect hippocampal damage in this condition as well.
exposure for the human hippocampus, hippocampal tissue
was studied of a well characterized series of major depressed
patients. From a large part of these patients, changes in the
HPA axis at the level of the hypothalamus had been demon-
strated previously [124, 125, 130], yet their adrenal status or
cortisol level was unknown. To address the impact of high
steroid levels per se, an additional group of non-depressed
individuals was included that had been treated with high
dosages of synthetic steroids, like prednisone or dexametha-
sone, for various reasons. Despite their important peripheral
effects on e.g. inflammation and the fact that they suppress
the endogenous HPA axis, these drugs are likely to reach the
To address the neuropathological correlates of cortisol
brain as well, where they may affect hippocampal structure
and function [24, 87, 113, 143-155], and were even reported
to inflict a rare condition like steroid-induced dementia [156-
As glucocorticoids may increase susceptibility to apopto-
sis through calcium- and reactive oxygen species pathways,
in situ end labeling (ISEL) was applied, that identifies frag-
mented DNA associated with both apoptotic and necrotic
cell death, processes that can be discriminated using mor-
phological criteria. Additional indices were markers for oxi-
dative damage and cellular stress, such as inducible heat
shock protein 70 (HSP70), that is strongly upregulated in
response to insults and cell death, and nuclear transcription
factor kappa B (NFkB), a GC-regulated transcription factor
implicated in protection against apoptosis or oxidative stress.
The results revealed that the hippocampus of major de-
pressed patients is structurally intact, as no indications for
massive cell loss were observed in either the depressed or the
steroid treated group. Even though all patients in the former
group were established to have suffered from severe depres-
sion for a prolonged period, no significant structural, synap-
Fig. (1). Structural integrity of the hippocampus in major depression.
Representative photomicrographs (Nissl staining) from the hippocampus of A and B) a depressed patient, (C and D) a steroid-treated patient
and (E and F) a control subject. B, D and F show the CA3 area of the same patients at higher magnification. No morphological evidence for
neuronal damage or major cell loss can be observed in either the depressed or the steroid-treated patient. Scale bars, 710 mm (A, C and E),
45 mm (B, D and F). From , with permission).
534 CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 Lucassen et al.
tic or neurodegenerative alterations could be detected using
Alz-50, GFAP, Nissl (Fig. 1A-F) or Bodian Silver stain, nor
with synaptophysin or B-50, markers for synaptic density
and plasticity in these patients. In 11 out of 15 depressed
patients as well as in 3 steroid-treated patients, very rare, but
convincing apoptosis was found only in the entorhinal cor-
tex, subiculum, dentate gyrus and CA4 (Fig. 2A,B). Except
for some of the steroid-treated patients, HSP70 staining was
generally absent, nor were indications for NFkB activation
found [159, 160].
Fig. (2). Apoptotic cells in the hippocampus of depressed patients.
A: Apoptotic cell (arrow) just below CA1 of a depressed patient
with apoptotic bodies clearly visible as well as a smaller appearance
than healthy neurons (triangle).
B: Clearly ISEL-positive, apoptotic cell (arrow points to the apop-
totic bodies) in the subiculum of a depressed patient (From ,
The detection of apoptosis in 11 out of 15 depressed pa-
tients, in 3 steroid treated and in 1 control subject, suggests
that apoptosis is involved in steroid-related changes also in
the human hippocampus. However, apoptosis was absent
from areas at risk for GC damage like CA3 and mostly found
in the dentate gyrus. In absence of major pyramidal loss or
any obvious, lasting, neuropathological alteration, and as
supported by other observations as well  the anatomical
consequences of GC overexposure for the structural viability
or the induction of neuropathology in the human hippocam-
pus appear modest. They also indicate that apoptotic cell
death probably only contributes to a minor extent to the vol-
ume changes in depression. However, it can not be excluded
that increases in apoptosis had occurred already in earlier
stages, e.g. at the onset of the disorder, or that the present
apoptosis reflects interneuron or glia death. Moreover, al-
most all patients studied here received antidepressant therapy
during their lives, and often continued until death. From
many antidepressant drugs, it is known they can profoundly
influence neurogenesis and apoptosis as well [162-176] (see
below). However, in these patients, a clear relation between
the type of antidepressant medication and either of the pre-
sent markers studied, could not be established.
information on the neuropathology of depression becomes
known [177-179], a detailed (stereological) analysis of hip-
pocampal cell number, preferably in a non-medicated patient
cohort with previously established volume changes [69, 71],
has not been performed yet. Hence, subtle structural changes
too small to be detected with the present techniques, may
have gone unnoticed. Either way, the prominent morpho-
logical changes in previous animal experiments, that were
already apparent at low power morphological examination of
conventionally stained sections, were clearly absent in the
present cases that had suffered from major depression for
prolonged periods of time. Although subtle changes at the
level of the dendritic tree arborization [63, 64, 67] may have
gone unnoticed, our results, and those of others , do not
support the notion that stress or (endogeneous) corticosteroid
overexposure actually causes major and permanent hippo-
campal damage or induce cell loss in the human hippocam-
Additionally, modern stereological methods for unbiased
neuronal counting have recently been applied to estimate
changes in cell number in the hippocampus of chronically
stressed tree shrews, stressed or GC exposed rats or chicka-
dees, and GC-treated primates [73, 87, 103, 180-184]. Inter-
estingly, all failed to find major reductions in neuron number
in the main hippocampal subareas, consistent with the pre-
sent observations in depression. Interestingly, studies in
which the effects of synthetic steroid treatment, i.e. dex-
amethasone, were investigated in rats appear to be an excep-
tion to this. Since dexamethasone poorly penetrates the
bloodbrain barrier, these effects may be different from expo-
sure to the endogeneous hormone [146, 185]. In rats, clear
increases were found in apoptosis in the striatum and in all
hippocampal regions, but not the septal nucleus, after acute
treatment , that appeared more severe in aged animals
. Despite the fact that no parallel changes on neuro-
genesis were reported, these effects could, interestingly, be
attenuated by oestradiol and antidepressant treatment [152,
186, 187]. Similar analyses of dexamethasone effects on the
human brain indicate at least clear feedback effects on CRH
and AVP expression in the hypothalamus [188, 189], while
the consequences of dexamethasone treatment for the integ-
rity of the human hippocampus await further study (Lucas-
sen PJ, Kuipers A, Bauer J, Boekhoorn K, Ravid R, Swaab
DF, De Kloet ER and Joels M. Dexamathasone induced
changes in cell death and proliferation in the adult human
hippocampus, FENS Forum 2002; Abstract# 088.17).
Finally, it is important to point out that although more
Stress, Depression and Hippocampal Apoptosis CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 535
campal or brain atrophy, memory deficits and cumulative
GC exposure during e.g. aging and depression, although also
exceptions have been reported [24, 59, 70, 71, 82, 137, 141,
142, 190-192]. However, such studies do not provide con-
clusive evidence for permanent changes, such as cell loss.
Hippocampal volume reductions during high steroid doses,
or in Cushing’s disease, were reversible after a decrease or
cessation of the steroid exposure. This further agrees with
the general clinical experience with depressive or Cushing
patients, where treatment with GR antagonists or surgery can
relieve depressive symptoms, normalize several of the HPA
alterations and even the hippocampal atrophy as recently
demonstrated [164, 191, 193-200]. Hence, reversible and
adaptive, rather than neurotoxic phenomena are expected in
this subarea. Furthermore, as CA3 in man constitutes only a
relatively small part of the hippocampus proper, it awaits
further study whether GC-induced volume changes in this
particular subarea contribute significantly to the atrophy of
the entire hippocampus, that is already detectable at the
In vivo MRI studies suggest a correlation between hippo-
tween hypercortisolemia and brain volume may be a reduc-
tion in water content or balance caused by high levels of
corticosteroids [201-203]; an effect also observed in the
clinic when patients are treated with corticosteroids to reduce
oedema. A remarkable discrepancy further exists between
the relatively intact neurological and psychiatric status of
most patients treated with steroids and their obvious ven-
tricular enlargements. These enlargements and the parallel
cerebral atrophy may normalize following cessation of corti-
costeroid administration. Also, it was suggested that signifi-
cant reductions in neuropil in major depression may contrib-
ute to the decreased hippocampal volume detected by neuro-
imaging . Such mechanisms involving nonstructural
alterations like changes in water balance, are consistent with
the observations that the hippocampal atrophy and the de-
pressive symptoms that occur after glucocorticoid over ex-
posure, are reversible and may normalize following a de-
crease or cessation of steroid administration [198-203, 205,
206] or e.g. after operation in Cushing’s disease [198, 200,
207-209] that, interestingly, in Cushing’s disease, has been
associated with functional improvements .
One possible explanation for the inverse correlation be-
only possess GRs, but are also sensitive to steroid action, and
can even undergo apoptosis, e.g. following exposure to oxi-
dative stress [168, 210-212]. Indeed, previous work in the
tree shrew points to a role for glia, at least at the endstage of
the stress period [168, 172, 213-217]. Interestingly, recent
stereological analysis of hippocampal subareas of rats sub-
jected to stress or GC treatment, failed to reveal any change
in neuron number, whereas volume reductions were found in
the neuron-sparse subareas of the hippocampus, that contain
mainly glia [73, 87]. Also in patients with major depression
and bipolar disorder, reduced glial cell densities have been
reported in restricted brain regions, or propose glia as a tar-
get for antidepressant drugs [211, 218].
Aside from the obvious differences listed above, primary
alterations in feedback regulation through e.g. changes in GR
or MR affinity, function or number could create a relative
insensitivity of hippocampal neurons to GC excess. Studies
Another possibility is that GCs affect glia cells, that not
on GR polymorphisms so far do not indicate that these have
a major role in brain, nor do alterations in feedback sensitiv-
ity occur after chronic corticosterone treatment e.g. in rat
[12, 219, 220]. Studies on GR polymorphisms in depression,
have been inconsistent and incomplete until now [2, 165,
221-224]. Furthermore, RNA studies have been performed in
some brain areas [221, 225-229], but localization and quanti-
fication of GR and MR protein levels in human brain awaits
further studies , particularly in the main HPA feedback
areas in depressed patients. So far, however, unpublished
observations indicate that GR protein levels in primate and
human hippocampus are rather low. In a very recent study,
stereological analysis revealed a significant reduction of neu-
ron number in the PVN of depressed patients extending ear-
lier data indicating that in depression structural changes ap-
parently also occur in non-hippocampal, important compo-
nents of the HPA system [231-233].
PSYCHOSOCIAL STRESS IN THE TREE SHREW
stress-related structural alterations, reliable / suitable animal
models are a prerequisite that should at least meet the criteria
of predictive, face and construct validity for mood disorders.
In order to find possible parallels and further validate the
changes observed in human depressed cases, psychological
stress was studied in the non-rodent, day-active tree shrew,
an established animal model for aspects of major depresion
with considerable clinical relevance [164, 168, 234-236].
Whereas studies on stress are often performed in rats, apply-
ing physical stressors like restraint, most stressors and stress-
related disorders in humans, such as depression, are rather
psychological in nature. A considerable number of the symp-
toms seen in depression are comparable to the stress re-
sponses observed in subordinate tree shrews. These animals
reveal prominent changes in behavior and stress response
depending on their social status.
In order to improve our knowledge on the mechanisms of
cording to standard procedures described earlier in detail
[236-239]. Briefly, one naive male is introduced into the
cage of a socially experienced male, which results in active
competition for control over the territory. After establish-
ment of a clear dominant/subordinate relationship, the two
animals are separated by a wire mesh barrier that is removed
every day for approximately 1 hour, thereby allowing physi-
cal contact between the two males during this time only.
Using this procedure, the subordinate animal is protected
from repeated attacks, but is constantly exposed to olfactory,
visual and acoustic cues from the dominant animal. Under
these conditions, subordinate animals produce high and non-
adapting cortisol levels and display characteristic subordina-
tion behavior as well as selective atrophy of the CA3 region
and the hippocampus.
Interestingly, these stress-induced changes can normalise
after treatment with some, but not all antidepressants [168,
234, 242, 243]. For instance, treatment of subordinate ani-
mals with the antidepressants clomipramine and fluvoxam-
ine, counteracted the behavioral and endocrine effects of
chronic psychosocial stress. Of note, the time course of re-
covery corresponded closely to that observed when treating
depressed patients. In contrast, treatment of subordinate
animals with the anxiolytic drug diazepam had no beneficial
The induction of psychosocial conflict is carried out ac-
536 CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 Lucassen et al.
effects, supporting the view that the stress-induced behavio-
ral and neuroendocrine responses in psychosocially stressed
tree shrews are depression related.
ity‘, also a ‘predictive validity‘ for depression which makes
it an interesting non-rodent model for research on the etiol-
ogy and pathophysiology of depressive disorders. Until re-
cently, little was known about the neuropathological conse-
quences of this stressor, or the involvement of apoptosis in
this model. When studying the adult tree shrew brain using
ISEL, clear apoptosis was found in the hippocampus and
related cortical areas. Twenty one days of psychosocial stress
caused prominent rises in cortisol and reductions in body
weight, reductions in CA3 surface area, and affected apopto-
sis in an unevenly and even opposite manner in discrete hip-
pocampal subregions and cortex. Although a significant de-
crease in apoptosis in the CA1 stratum radiatum and increase
in the DG hilus were found after stress, no significant in-
crease was found in the CA3 pyramidal cell layer, an area
predicted to be at risk and rather a trend was found even to-
wards a reduced apoptosis after stress .
In view of the trisynaptic hippocampal circuit, apoptosis
that was initially induced in CA3 shortly after stressor onset,
could, in theory, have contributed, through anterograde or
retrograde projections, to subsequent apoptosis in other
subregions at a later timepoint. The apoptosis in the CA1
stratum radiatum area could be an example of this. Con-
versely, the CA3 receives strong, direct projections from the
DG. Since the DG is a highly plastic brain area, where adult
neurogenesis and apoptosis occur together [107, 112], it
would have been interesting to establish whether stress has
preferentially increased death of the newborn, rather than of
the residing, adult granular or glia cells. However, this would
require phenotyping of the dying cells by e.g. double label-
ing, which is currently technically not possible on this mate-
rial. The ISEL technique does not allow identification of the
cell type that dies by apoptosis, due to possible formalin
fixation induced epitope masking [244, 245], and/or to the
fact that apoptotic cells in this last phase of their demise,
have lost their protein markers. Based on the criterium of
anatomical location, primarily glial cells or interneurons are
expected to be involved, as supported by other observations
as well [210, 211, 218, 246].
The tree shrew model has besides its obvious ‘face valid-
may have died already shortly after stressor onset, leaving
less cells available to engage in apoptosis at later time
points. This could have resulted in lowered apoptosis at the
end of stress exposure. Indeed, also in chronically stressed
rats (see below), apoptosis (Fig. 3) was found to be de-
creased  (see below). Interestingly, in an earlier stere-
ological study with an identical design, no reductions were
found in the total numbers of CA1 and CA3 neurons ,
which agrees with the present failure to find significant
changes in apoptosis in these pyramidal cell layers in the
stressed tree shrew. It also is consistent with the significant
reduction found in surface area of the CA3 radiatum, con-
firming previous studies that show retraction of the dendritic
tree in this area after stress, and suggests that alterations in
CA3 may indeed contribute to the volumetric reductions of
the hippocampus as a whole [64, 168, 181, 247, 248].
Furthermore, as indicated above, large numbers of cells
Fig. (3). Example of an apoptotic cell in the subgranular zone
(SGZ) of the tree shrew hippocampus.
tively mild reductions in hippocampal volume, i.e. around 10
%, already shortly after stress, but prior to cognitive distur-
bances [55, 164, 236, 237, 248, 249]. This is consistent with
the 7.6 % reduction in total hippocampal volume found mor-
phometrically after prolonged psychosocial stress exposure
in the tree shrew [168, 236, 248, 249]. Admittedly, the initial
concept that chronic stress inexorably causes hippocampal
ageing and cell loss [48, 77, 80, 84, 95, 101-103, 190, 250,
251], is not necessarily in contrast with the results in tree
shrew, as the designs were clearly different. Yet, even
though the nature of the psychosocial stress differed consid-
erably from the physical stressors applied before, its duration
and resulting cortisol levels were similar.
Recent MRI studies in tree shrew have indicated rela-
campal volume and overall structure, i.e. hippocampal cell
numbers in the tree shrew are relatively mild while marked
changes were observed in the dendritic morphology of CA3
neurons . They are, importantly, subregion specific.
Also, differential changes in apoptosis were induced in dif-
ferent subfields of the adult tree shrew hippocampus and
entorhinal cortex. As no loss in the principal CA and DG
neuronal layers was previously found, it was concluded that
despite robust and long-lasting cortisol increases, the stress-
related change in apoptosis must reflect other parameters,
like interneuron or glial cell death that contribute to the hip-
pocampal changes in this experimental model [164, 168,
172, 210, 218, 243, 252].
In conclusion, effects of psychosocial stress on hippo-
PSYCHOSOCIAL STRESS IN THE TREE SHREW:
EFFECTS OF ANTIDEPRESSANT TREATMENT
for several decades, their underlying mechanisms of action
are still poorly understood. Earlier hypotheses have focused
Despite the fact that antidepressant drugs have been used
Stress, Depression and Hippocampal Apoptosis CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 537
on altered transmitter availability in the synaptic cleft, and
assumed antidepressants to act by readjusting the aberrant
intrasynaptic concentrations of serotonin and/or norepineph-
rine. Recent clinical and preclinical studies now suggest that
major depressive disorders may also involve impairments of
structural plasticity and cellular resilience [160, 165, 171, 253,
254]. If stress-induced changes in dentate granule cell turn-
over are indeed an important factor in the hippocampal vol-
ume reductions found in these disorders, antidepressants may
act by restoring altered rates of cell birth or death. Consistent
with this hypothesis, many different antidepressant treat-
ments including lithium and electroconvulsive therapy were
shown to stimulate dentate cytogenesis [165, 166, 168, 171,
172, 174, 253, 255-257] or exert neurotrophic/protective eff-
ects, by e.g. modulating factors involved in cell survival and
growth, such as CREB, BDNF and bcl-2 a.o. [78, 258, 259].
Previously, it was found that the antidepressant tianeptine
[216, 217, 260-262] normalized both stress-induced hippo-
campal volume reductions as well as the suppressed rate of
cytogenesis in stressed animals . An overview on the
actions of tianeptine is given in a recent review . Al-
though most studies investigated the effects of antidepres-
sants on cell viability in naive, unchallenged animals, these
drugs are mainly effective within the context of a clinical
condition—for example, a stress history—, and after chronic
application. Therefore, possible protective effects of chronic
antidepressant treatment was studied in the tree shrew model
. Animals were subjected to a seven-day period of psy-
chosocial stress before the onset of daily administration of
tianeptine (Servier, Courbevoie, France, 50 mg/kg per day),
and stress continued throughout the 28-day treatment period.
had a region-specific effect [168, 172, 239]; stress increased
apoptosis in the temporal cortex, while it reduced it in the
Ammon’s Horn (Fig. 4). No significant effect was observed
in the dentate gyrus. Interestingly, tianeptine treatment sig-
nificantly reduced apoptosis in the dentate gyrus, both in
control and stressed animals, but had no effect in the Am-
The results show that both stress and tianeptine treatment
Fig. (4). Effects of chronic psychosocial stress and concomitant tianeptine treatment on apoptosis in the temporal cortex (A), Cornu Am-
monis (B), dentate granule cell layer (C), and subgranular zone (D) of the tree shrew. (A) In the temporal cortex, chronic stress resulted in a
significantly increased occurrence of apoptotic cells, whereas anti-depressant treatment had a significant antiapoptotic effect in both control
and stressed animals. (B) In the Ammons Horn, the frequency of apoptosis was significantly suppressed after 5 weeks of psychosocial stress.
(C, D) In both the granule cell layer and the subgranular zone of the dentate gyrus, drug treatment significantly decreased the incidence of
apoptosis (a 2-way ANOVA revealed significant main effect of drug treatment, and the results of the Newman-Keuls post hoc analysis are: *
p < 0.05, versus Control. ## p < 0.01, ### p < 0.001, versus Stress). From , with permission).
538 CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 Lucassen et al.
mon’s Horn. Similar antiapoptotic changes were observed in
the associated temporal cortex, indicating that the effect of
tianeptine was not restricted to the hippocampus alone. To
address the type of cell that dies, parallel Fluoro-Jade (FJ)
staining for neurodegeneration on adjacent sections indicated
that the apoptosis detected with ISEL, at this stage after
stress, most likely represents non-neuronal cells .
effects , tianeptine exerts an antiapoptotic effect both in
hippocampal subfields as well as the temporal cortex [168,
172] (Fig. 4). These data agree with recent studies on rats
where hippocampal apoptosis after dexamethasone treatment
was also reduced by antidepressant treatment [152, 186]. In
general, the results are consistent with current theories that
ascribe enhanced general cell survival to antidepressant ac-
tion [163, 166, 168, 171, 173, 174, 253, 255, 265, 266].
Collectively, this shows that in addition to the cytogenic
CHRONIC UNPREDICTABLE MULTIPLE STRESS
EFFECTS ON THE RAT HIPPOCAMPUS
dent model, we turned to the rat. Stress induced volume and
functional changes in the rat hippocampus are generally at-
tributed to synaptic, axonal or dendritic tree changes, al-
though also exceptions have been reported. In addition, indi-
rect adaptation through modulation of DG structural plastic-
ity has been proposed [63, 65, 72, 87, 181, 182, 267-270].
Regarding the latter option, acute stress was known to sup-
press neurogenesis, but relatively little was known on how
chronic stress affects the turnover, i.e. proliferation and
apoptosis, of the rat dentate gyrus.
To address whether stress affects apoptosis also in a ro-
following 21 days of exposure to multiple unpredictable
stressors [63, 112, 271-275] that consisted of a mixture of
different psychosocial as well as physical stressors twice
daily, including cold immobilization, forced swim, cro-
wding and isolation. This paradigm not only reduces the risk
of adaptation, but also better mimics the variability of stres-
sors encountered in daily life, especially when compared to
chronic restraint. As described earlier, this paradigm is fur-
thermore associated with the classic parameters of chronic
stress exposure such as increased adrenal weight, reduced
thymus weight, reduced body weight gain, basal corticoster-
one hypersecretion and reduction in CA3 volume. Another
question we addressed was whether the structural DG
changes after stress are lasting, or rather reversible over time,
which is why an additional group was included that was al-
lowed to recover for 3 more weeks after the stress exposure.
Effects of acute stress and recovery were studied as well
Structural plasticity changes were studied in the rat DG
apoptosis in the rat hippocampus (Fig. 5). Acute stress
caused a significant increase in apoptosis in the hilus (h),
subgranular zone (SGZ), granular cell layer (GCL) and con-
sequently also over the whole DG in rats examined 24 h
later. These effects were already absent again when the rats
were allowed to recover for one more day. After chronic
exposure to stress, a rather heterogeneous picture of cell
death appeared with lower numbers of dying cells occurring
in the SGZ, and increased numbers in the GCL, but overall
less cell death in the DG compared to controls. This reduc-
tion in cell death rate was still present after a one-day recov-
Exposure to unpredictable stress differentially affected
ery but had normalized after 3 weeks. Overall, apoptosis thus
decreased in the whole dentate gyrus after chronic stress (h +
SGZ + GCL), but normalized after 3 additional weeks of
recovery (Fig. 5).
Fig. (5). Apoptotic changes in the DG of the rat hippocampus after
chronic, multiple unpredictable stress exposure (From , with
In view of the intimate association with cell death in the
DG, stress induced changes in cytogenesis are interesting in
this model as well; both acute as well as chronic stress de-
creased new cell proliferation in the rat DG. The reduced
proliferation rate found after acute stress had already com-
pletely normalized after one day of recovery, whereas after
chronic stress, the suppression of proliferation had partially
normalized after a subsequent stress free period of 3 weeks.
Of interest, in a related model of chronic stress, i.e. restraint,
others found 6 weeks to be required for full recovery from
stress induced structural changes [112, 276]. In the chronic
unpredictable paradigm furthermore, migration and the per-
centage of newborn neurons generated, was not affected by 3
weeks of chronic stress. Others, in a different model, have
recently shown also changes in newborn cell survival to de-
pend on the corticoid environment during this survival pe-
Together, this suggests that the acute stress effects on
apoptosis in different hippocampal subregions are short last-
ing; chronic stress however, has longer-lasting effects on the
main structural-dynamic hippocampal parameters, but most
are almost normalized after 3 weeks (Fig. 5). Since apoptosis
was increased and cytogenesis decreased after acute stress, a
rapid and short-lasting reduction in DG turnover probably
takes place, or, alternatively, increased cell death is paral-
leled by a reduction in new cell birth. This latter possibility
is consistent with the close association of the two processes
in the adult DG  and with observations showing that
around 50 percent of the newborn cells die between 1 and 2
weeks [278, 279] after their generation. Also in adult tree
shrews, apoptosis was decreased after 3 weeks of psychoso-
cial stress in the hilar region of the dentate gyrus [239, 244],
suggesting this effect is not limited to rats alone.
in apoptotic changes. In view of the trisynaptic hippocampal
Several explanations can be given for the heterogeneity
Stress, Depression and Hippocampal Apoptosis CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 539
circuit, initial apoptosis induced in e.g. CA3, could have
contributed to apoptosis in other sub-regions at later time-
points. However, no such increases in apoptosis were found
in CA3 in the acute stress group. After chronic stress, there
is clearly less apoptosis in the SGZ, which could be ex-
plained by a decreased presence of young proliferating cells
due to preferential death of this population in response to
corticosterone exposure. Even though it remains to be
proven whether stress preferentially increases death of new-
born, rather than residing, adult granular cells, or possibly
even glia or interneurons, differential susceptibility to cell
death may also depend on the age of individual cells, or on
the extent and type of their already established connections
and synaptic input. In view of this heterogenous nature of the
DG, it is most likely that distinct types of cells in the GCL
react differently to acute and chronic stress, a phenomenon
also seen after adrenalectomy or NMDA receptor blockade
[107, 113, 278, 280].
structural plasticity are rather modest and adaptive for the rat
DG, rather than neurotoxic for the CA3, a result that is in full
agreement with the human data obtained in patients with
longterm depression or treatment with corticosteroids. The
temporary suppression in turnover following chronic stress,
predicts that the age composition of the DG population, their
connectivity and the resulting circuit properties, are quite
different from control situations. Indeed, clear changes in
various physiological parameters were found, a.o., in a paral-
lel series of electrophysiological and molecular studies on
the same model [3, 12, 14, 16-19, 54, 281].
Clearly, the effects of chronic unpredictable stress on
exist already prior to the onset of clinical symptoms in de-
pression [2, 120, 126-128, 282, 283], it is worth mentioning
that the clinical symptoms of patients with psychotic depres-
sion quickly ameliorated upon treatment with a high dose of
a GR antagonist [193, 194, 284, 285]. As suggested by the
normalization of the corticosterone-induced suppression of
neurogenesis after already a short treatment with the GR
antagonist RU486 . It will be of interest to address
whether GR antagonist treatment can also reverse the struc-
tural and physiological changes induced in the chronic un-
predictable stress model as well.
As chronic stress and abnormalities in HPA axis activity
MR that is implicated in tonic inhibitory control of the HPA
axis. MR activation is known to suppress adrenalectomy-
induced apoptosis and is involved in (maintenance of) neu-
ronal viability and implicated in neurogenesis [2, 88, 185,
286-288]. Moreover, MR activation modulates hippocampal
calcium currents and serotonin responses [286, 289, 290] and
its expression is altered after stress or antidepressant treat-
ment and in brain regions in depression [2, 88, 90, 91, 226,
Similarly, an interesting candidate in this respect is the
STRESS EFFECTS ON APOPTOSIS IN NON-RODE-
NT SPECIES: THE PORCINE HIPPOCAMPUS
laemia for the rodent and tree shrew DG are well described,
relatively little is known about other mammals. To address
whether the effects in rodents are comparable to other spe-
cies, we choose to study the porcine hippocampus, as these
social and intelligent animals not only share many features
Although the consequences of stress and hypercortiso-
with humans with regard to their brain (e.g. larger brain size
than rodents, a more mature stage of brain development at
the moment of birth), they are, like humans, also very sensi-
tive to stress. Recently, corticosteroid receptors have been
identified in the porcine hippocampus [150, 294-299]. Fur-
thermore, in husbandry practice, breeding pigs are often in-
dividually housed in narrow boxes, tethered with a short
chain around the neck to the floor. As this prevents them
from interactions with other animals or explorative behav-
iour, tethered housing in fact resembles a chronic restraint
stress condition [300-305], which is supported by the charac-
teristic alterations in behaviour, autonomic and endocrine
regulation, documented previously. Tethered housed pigs
develop behavioural stereotypies, increased sympathetic re-
activity, increased adrenocortical steroidogenic capacity and
sensitivity to ACTH, chronic hypercortisolaemia and a flat-
tened diurnal cortisol rhythm [300, 306-310]; all conditions
that were shown to affect hippocampal viability in rat.
affected structurally by chronic stress, we studied structural
parameters of the porcine DG after 5 months of tethered
housing and investigated the possible relation between saliva
cortisol measured antemortem and neuronal number or vol-
ume of the DG in the individual animal. Also neuropa-
thological correlates of this chronic stressor were examined
in this species, or whether a relation would be present be-
tween cortisol and apoptosis. Conventional Nissl, ethylgreen,
H&E, silver staining and Alz-50 immuno-cytochemistry
were used to visualize early degenerative or neuropathologi-
In order to address whether the porcine hippocampus was
DG volume and neuron number in individual animals in both
hemispheres. Notably, basal cortisol was negatively corre-
lated with volume and neuron number of the left, but not
right DG (Fig. 6). Although obvious neuropathology was
completely absent, apoptosis was present in DG and alveus
and less so in CA areas. The stereologically estimated num-
bers of apoptotic cells in the DG were negatively correlated
with cortisol, but this was not found for other hippocampal
subregions  (Fig. 7).
Stereological analysis revealed high correlations between
zation in the relationship between DG structure, apoptosis
and basal cortisol after stress in pigs. Even though five
months of chronic stress failed to induce any lasting neuro-
pathology, the accumulation of changes in apoptosis over
time could have contributed to the structural alterations ob-
served in the DG although this obviously also depends on
putative parallel changes in neurogenesis. Clearly, the in-
verse correlation, i.e. higher numbers of apoptosis with
lower levels of cortisol, agrees with similar correlations in
e.g. the adrenalectomy model of DG apoptosis in rat [312-
314]. Further studies should reveal whether stress has been
instrumental in this or whether such differences were present
from early life onwards. Recent studies in rodents at least
indicate that early life stress can permanently affect cell birth
and death rates. These effects can last throughout adult life
of the offspring in rodents, often in parallel to alterations in
hippocampal functioning [315-322], but also affect e.g. adult
DG size in a sex specific manner . A lateralization after
stress is furthermore consistent with reports on lateralized
hippocampal volume changes in stress-related human disor-
These data indicate for the first time a profound laterali-
540 CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 Lucassen et al.
ders [69, 71, 137, 139, 141, 142, 190, 324, 325] suggesting
that these effects are not limited to this species alone.
hippocampus. Even though its occurrence in tissue sections
is low due to its rapid time kinetics, apoptosis is clearly
modulated by stress and steroids in several conditions and
models. Rather than inducing apoptosis in CA areas, stress
and steroid exposure appear mainly to interfere with the rate
of ongoing apoptosis in the DG area. Since chronic stress
induces parallel decreases in adult proliferation in the DG,
stress in fact influences the turnover rate of DG cells, which,
in turn, may affect its main projection area, the CA3 region
and, together, could induce functional alterations.
Apoptosis continues to occur in the adult mammalian
impact of chronic stress on the main structural parameters of
the main hippocampal areas like cell number, appears rather
modest, and may require more prolonged and severe expo-
sure before only small reductions (< 10 %) will become de-
tectable [112, 276]. Even though these overall anatomical
changes are small, this does not exclude that still other pa-
rameters, e.g in critical hippocampal subregions like the DG
and/or CA3, are significantly altered, such as synaptic termi-
Contrary to the conclusion from previous studies, the
nal structure, or dendritic arborization [39, 63, 64, 67], nor
do they imply that the functional implications of such
changes are also modest. Clearly, the temporary slowing
down of structural DG turnover by chronic stress changes
the overall composition, average age and identity of DG
cells, which is likely to have considerable consequences for
the connectivity and properties of the circuit and hence for
hippocampal function .
Regarding the discrepancy between hippocampal volume
reductions in the absence of clear reductions in neuron num-
ber, it is important to realize that most of the structural plas-
ticity changes are transient and generally reversible after
appropiate recovery periods or following cessation of the
stress or corticosteroid exposure.
network properties and the proposed correlations with learn-
ing and memory performance [315, 317, 326-330], modula-
tion not only of neurogenesis, but also of hippocampal apop-
tosis, either through pharmaceutical or environmental means,
may thus have important consequences for the composition
and function of the DG and the hippocampus as a whole. A
possible candidate in this respect is the MR that is implicated
in tonic inhibitory control of the HPA axis and involved in
neuronal viability and neurogenesis [2, 88, 185, 286, 331].
In view of their established contributions to hippocampal
Fig. (6). Correlation of averaged, basal (prefeeding) salivary cortisol levels with total volume (A,C) and neuron number (B,D) in the left
(A,B) and right (C,D) dentate gyrus (DG) of the porcine hippocampus. Cortisol concentrations were negatively correlated in a highly signifi-
cant way with total neuron number (r = -0.72, P =0.006) and volume (r = -0.61, P= 0.047) of the left hippocampal lobe. No such correlation
was found between cortisol and these structural parameters in the right DG (P > 0.05) (From , with permission).
Stress, Depression and Hippocampal Apoptosis CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 5 541
Moreover, MR activation modulates hippocampal physio-
logical properties [286, 289, 290] and its expression is al-
tered after stress, antidepressant treatment and in depression
[2, 88, 90, 91, 226, 228, 291-293]. Also blockade of the GR
seems, at least in clinical studies, a promising tool to effec-
tively treat psychotic forms of depression normalize or neu-
rogenesis after stress [2, 22, 193, 194, 332]. The changes in
apoptosis after stress summarized here, suggest that modula-
tion of hippocampal structural plasticity by drugs interfering
with MR and/or GR action , and/or with mediators of
the cell death cascade, may provide important drug targets
for the modulation of mood and memory.
ACTH = Adrenocorticotroph hormone
= Brain derived neurotrophic factor
CA = Cornu ammonis
= Cyclic AMP response element binding protein
= Corticotropin-releasing hormone
DG = Dentate gyrus
GFAP = Glial fibrillary acidic protein
= Glucocorticoid receptor
= Granular cell layer
H&E = Haematoxylin eosin
NMDA = N-methyl-D-aspartate
PVN = Paraventricular nucleus
SGZ = Subgranular zone
= Heat shock protein 70
= In situ end labeling
= Mineralocorticoid receptor
= Magnetic resonance imaging
= Nuclear transcription factor kappa B
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