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Volume 16, Number 10,
Issue of May 15, 1996
pp. 3534-3540
Copyright ©1996 Society for Neuroscience
Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of
Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews
Ana María Magariños1,
Bruce S. McEwen1,
Gabriele Flügge2, and
Eberhard Fuchs2
1 The Rockefeller University, New York, New York
10021, and 2 German Primate Center, 37077 Göttingen, Germany
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
We have shown previously that repeated laboratory restraint stress
or daily corticosterone administration affects the structure of CA3
hippocampal neurons in rats. In the present study, we investigated the
effect of repeated daily psychosocial stress on the structure of
hippocampal CA3 pyramidal neurons in male tree shrews (Tupaia
belangeri). Male tree shrews develop social hierarchies in which
subordinates show characteristic changes in physiological and
behavioral parameters when confronted with a dominant. In the present
experiments, subordinate animals lost body weight soon after
starting the daily social conflict, and urinary excretion of cortisol
was elevated throughout the experiment as compared with the control
period. Golgi-impregnated brain tissue from subordinates exposed to 28 d (1 hr/d) of social confrontations was compared with that from
control nonstressed animals. The apical dendrites of the CA3
pyramidal cells from subordinates had a decreased number of branch
points and total dendritic length as compared with controls. No
differences were observed in apical dendritic spine density or in the
basal dendritic tree morphology. The stress-induced CA3 apical
dendritic atrophy in subordinates was prevented by administering daily
oral doses of the antiepileptic drug phenytoin (Dilantin, Sigma, St.
Louis, MO) (200 mg/kg), which interferes with excitatory amino acid
(EAA) action. These results suggest that the naturalistic stressor
psychosocial stress induces specific structural changes in
hippocampal neurons of subordinate male tree shrews. These changes,
like those in the rat after glucocorticoid treatment or restraint
stress, probably are mediated by activation of the
hypothalamo-pituitary-adrenal-axis acting in concert with endogenous
EAAs from mossy fiber input.
Key words:
Golgi impregnation;
hippocampus;
Tupaia;
pyramidal neuron;
excitatory amino acids;
phenytoin;
glucocorticoids
INTRODUCTION
Repeated restraint stress or a combination of
daily stressors in rats induce atrophy of hippocampal CA3 pyramidal
neurons (Watanabe et al., 1992c ; Magariños and McEwen, 1995a).
This atrophy is mimicked by daily treatment with corticosterone
(Woolley et al., 1990), indicating that elevated circulating adrenal
steroids secreted during stress may be involved in triggering the
morphological alterations. Indeed, the pharmacological blockade of the
corticosterone stress response prevented the hippocampal atrophy
(Magariños and McEwen, 1995b). However, glucocorticoids have been
shown to act synergistically with excitatory amino acids (EAAs)
(Krugers et al., 1993; Lowy et al., 1993), and mossy fibers originating
from granular neurons of the dentate gyrus provide a strong input of
EAAs into the hippocampal CA3 region (Clairbone et al., 1986). Thus,
daily treatment of rats with phenytoin, an antiepileptic agent that
interferes with EAA release and action, blocked both corticosterone-
and stress-induced CA3 pyramidal neurons atrophy (Watanabe et al.,
1992a). The pharmacological blockade of central NMDA receptors also
prevented the hippocampal atrophy (Magariños and McEwen, 1995b).
Taken together, these results suggest a synergy between glucocorticoids
and EAAs in stress-induced atrophy of CA3 pyramidal neurons.
Most preclinical studies relating stress and hippocampal morphology
derived from studies in rodents. Only a limited number of
investigations examined the influence of stress or long-term
glucocorticoid treatment on hippocampal neurons in other species (Uno
et al., 1994). To better understand the effects of stressful
psychological situations in a nonrodent mammalian species, we used the
psychosocial stress paradigm in male tree shrews (Tupaia
belangeri). This species is regarded phylogenetically as an
intermediate between insectivores and primates (Martin, 1990) and
proved to be a suitable model to study the neuro-behavioral
consequences of the naturalistic psychosocial stressor (Flügge et
al., 1992; Jöhren et al., 1994; Flügge, 1995; Fuchs et al.,
1995). Adult male tree shrews display an intense territoriality that
can be used to establish a naturally occurring challenge situation
under experimental control in the laboratory. Coexistence of two males
in one cage leads to a stable dominant-subordinate relationship, with
subordinates showing distinct stress-induced behavioral and
physiological alterations from the moment of subjugation onward.
Subordinates withdraw from the field of vision of the dominant, become
hypoactive, alter their sleeping pattern (Aue, 1989), and show
increased adrenal hormone levels and decreased gonadal activity
(Fischer et al., 1985; Fuchs et al., 1993). The characteristic
reduction of body weight in subordinates is related to a diminished
food and water intake and to an elevated metabolism (Aue, 1989;
Jöhren et al., 1991). After chronic psychosocial stress, central
 2-adrenoceptors are affected in areas involved
primarily in the regulation of autonomic functions (Flügge et
al., 1992), and hippocampal glucocorticoid receptors are downregulated
while corticotropin-releasing hormone receptors are up- or
downregulated in a region-specific manner (Fuchs and Flügge,
1995). Using this well-characterized tree shrew stress paradigm, we
investigated the impact of psychosocial stress, as well as cotreatment
with the antiepileptic phenytoin, on the morphology of
Golgi-impregnated hippocampal CA3 pyramidal neurons in subordinate tree
shrews as compared with control nonstressed animals. Dominant animals
were only used to induce psychosocial stress in subordinates. All
animals were tested for daily urinary cortisol excretion and body
weight.
MATERIALS AND METHODS
The experiments were conducted with adult male tree shrews
(Tupaia belangeri) from the breeding colony at the German
Primate Center (Göttingen, Germany). All animal experimentation
was conducted in accordance with the National Institutes of Health
Guide for the Care and Use of Laboratory Animals and were approved by
the Government of Lower Saxony, Germany. The animals were housed
individually on a regular dark/light cycle with artificial illumination
from 8 A.M. to 8 P.M. in air-conditioned rooms (for details, see Fuchs
and Schumacher, 1990).
Experimental procedures. During a 10 d control period, the
body weights of five subordinate, five dominant, and five control male
tree shrews were recorded, and the basal activity of the
pituitary-adrenocortical-axis was determined by measuring cortisol in
the morning urine, which was collected after a light massage of the
hypogastrium daily between 7:45 A.M. and 8.00 A.M. The time between
initially perturbing the animals and the collection of urine was always
less than 2 min.
The experimental induction of psychosocial conflict was carried out as
follows. After the control period, the opaque partition between the
neighboring cages of two males unknown to one another was removed. This
resulted in an active competition for control over the enlarged
territory. After establishment of a stable dominant-subordinate
relationship, the two males were separated by a transparent wire mesh.
Under these conditions, the subordinate animal reduced its sphere of
action in the cage and avoided situations that could evoke attacks from
the dominant animal. This period of psychosocial conflict lasted for 28 d. During this time, the wire mesh was removed every day for 1 hr
between 9.00 A.M. and 11.00 A.M. Urine samples were collected every
morning between 7:45 A.M. and 8.00 A.M., and the animals were weighed
as described above. The time between initially perturbing the animals
and the collection of urine, again, was less than 2 min, and there were
no differences in time in relation to social position. Control animals
lived in separate quarters elsewhere in the animal facility. From these
animals, morning urine samples were collected and body weight was
recorded daily as described for the experimental animals.
Pharmacological treatment. In a second experiment,
subordinate animals (n = 6) were administered a daily oral
dose of phenytoin (Sigma, St. Louis, MO) each morning (200 mg/kg,
diluted in water). For this purpose, each animal was grabbed gently,
and a bulb-headed probe was inserted into its mouth, slid over the
tongue, and then slipped carefully down the esophagus. With this
procedure, the dose was swallowed completely and the stress caused to
the animals was minimized, because control tree shrews (n = 5) that received water in the same way that phenytoin was given to
subordinates showed no stress-induced urinary cortisol excretion. The
rest of the psychosocial confrontation experiment was conducted as
described above. Several dosages of phenytoin, ranging from 5 to 200 mg/kg, were tried in pilot experiments and the 200 mg/kg dose was
selected, because it yielded average plasma levels of 20 µg of
phenytoin per ml. This titer is within the concentration range
described in the literature to be effective as a neuroprotectant (Yaari
et al., 1986; Taft et al., 1989). Phenytoin levels were measured in
plasma samples withdrawn 3 hr after its administration using an
Automated Direct Reading of Fluorescence Polarization Immunoassay
(Abbot Diagnostics) (Jolley, 1981).
Golgi impregnation and analysis. At the end of the
confrontation period, subordinate and control animals were killed
between 8:00 A.M. and 9:00 A.M., and care was taken to exclude
nonspecific stress effects. They were anesthetized deeply with a
Ketamine/Xylazine mixture and perfused transcardially with 100 ml of a
commercial blood substitute (Onkovertin, Braun, Melsungen, Germany) for
3 min, followed by 150 ml of 4% paraformaldehyde in 0.1 M phosphate buffer. Brains were post-fixed
overnight in the perfusate at 4°C. Sections, 100 µm thick, were cut
with a vibratome into a bath of 3% potassium dichromate in distilled
water and then processed according to a modified version of the
single-section Golgi-impregnation procedure (Gabbot and Somogy, 1984).
Briefly, the brain sections were incubated overnight in 3% potassium
dichromate dissolved in distilled water, then rinsed in distilled water
and mounted on plain slides. A coverslip was glued over the sections at
the four corners. These slide assemblies were incubated overnight in
1.5% silver nitrate, in the dark. The following day, the slide
assemblies were dismantled and the tissue sections rinsed in distilled
water, dehydrated, and defatted with a graded series of ethanol,
followed by Histoclear (Americlear). Finally, the sections were mounted
on gelatin-coated slides and coverslipped with Permount (Fisher
Scientific, Orangeburg, NY). Slides containing brain sections were
coded before quantitative analysis; the code was not broken until the
analysis was complete. To be selected for analysis, Golgi-impregnated
neurons had to possess the following characteristics: (1) location
within the CA3 subregion of the hippocampus; (2) dark and consistent
impregnation throughout the extent of all of the dendrites; (3)
relative isolation from neighboring impregnated cells, which could
interfere with the analysis; and (4) somata located in the middle third
section to minimize the number of truncated branches. For each brain,
six to eight pyramidal cells from area CA3 were selected. Because three
subtypes of CA3 neurons with different apical branching patterns can be
impregnated (Fitch et al., 1989), the same proportion of neuronal
subclasses was included for each brain. Each neuron selected was traced
at 400× magnification using a light microscope with a camera lucida
drawing tube attachment. From these drawings, the number of dendritic
branch (bifurcation) points within a 100 µm section of each dendritic
tree was determined for each neuron selected. In addition, the length
of the dendrites present in a 100 µm section was determined for each
dendritic tree using a Zeiss Interactive Digitizing Analysis System.
For each pyramidal cell, spine density analysis was performed at the
stratum lacunosum moleculare level of the CA3 field from the most
lateral tertiary dendrite on the apical tree. Camera lucida tracings
(1250 ×) were obtained from selective dendritic segments that remained
in the plane of focus and had a length between 30 and 70 µm. All
visible spines along the selected dendritic segment were measured from
the camera lucida drawings with the Zeiss Interactive Digitizing
System, and spine density values were expressed as number of spines/10
µm dendrite. Six CA3 pyramidal cells from each animal were chosen for
the study. For each neuron, six dendritic branches were analyzed. For
each variable (branch points, length, and spine density) and for each
subject, mean ± SEM was determined, and the resulting values were
analyzed statistically as indicated below.
Analysis of urine samples. Urinary cortisol was measured by
a scintillation proximity radioimmunoassay (Udenfriend et al., 1985)
using anti-rabbit cortisol antiserum (Paesel-Lorei, Frankfurt,
Germany), anti-rabbit IGG-coated fluomicrospheres (scintillation
proximity assay anti-rabbit reagent type I) (Amersham, Braunschweig,
Germany), and [3H]cortisol (Amersham) as
tracer. To correct for physiological dilutions, the resulting
concentrations were related to creatinine concentrations, which were
determined with a Beckman Creatinine Analyzer 2.
Statistical analysis. Number of branch points, total
dendritic length, and spine density averages for each subject were
analyzed with Student's t test. Body weight and cortisol
data analysis were assessed by the Kruskal-Wallis one-way ANOVA,
followed by the Mann-Whitney U test. A probability level of
p < 0.05 was used to determine statistical significance.
RESULTS
Psychosocial stress effect on CA3 pyramidal neuron structure
After 28 d of daily social conflict, subordinate animals showed a
significant decrease in the number of apical branch points
(p < 0.01) and total apical dendritic length (p < 0.05) in hippocampal CA3 pyramidal neurons as compared with controls
(Fig. 1). All neuronal subtypes showed atrophy of their
apical trees, but no detectable changes were observed in the morphology
of the basal dendritic trees of the same neurons, regardless of the
subclass considered. Figure 2 depicts representative
camera lucida drawings of CA3 neurons for control and subordinate tree
shrews. We also analyzed the apical dendritic spine density of CA3
neurons, and no differences were apparent between control and
subordinate animals after 28 d of psychological stress (21.0 ± 1.5 and
21.5 ± 1.8 spines/10 µm, respectively). The social confrontation did
not affect either the dendritic arborizations of the principal neurons
in areas CA1 and CA2 or the dentate gyrus (data not shown).
Fig. 1.
Effect of 28 d of psychosocial stress on dendritic
morphology of CA3 pyramidal neurons is shown for apical and basal
dendrites. Note that psychosocial stress reduces the number of apical
branch points in subordinates (SUB) as compared with
controls (CON). Bars represent the mean ± SEM;
double asterisk indicates p < 0.01, and
asterisk indicates p < 0.05 as compared with
controls (Student's t test).
[View Larger Version of this Image (39K GIF file)]
Fig. 2.
Camera lucida drawings of representative
Golgi-impregnated CA3 pyramidal neurons from control (not subjected to
stress) and subordinate tree shrews (after 28 d of psychosocial
stress). Notice the decreased branching pattern in the subordinate
apical dendritic tree as compared with the control.
[View Larger Version of this Image (33K GIF file)]
Psychosocial stress and phenytoin treatment effect on CA3 pyramidal
neuron structure
Because of our previous data showing that phenytoin blocks both
stress- and corticosterone-induced atrophy of CA3 dendrites in rats
(Watanabe et al., 1992a), we used phenytoin in tree shrews in an
attempt to block psychosocial stress-induced atrophy. Administration of
a 200 mg/kg oral dose of phenytoin for 28 d prevented the psychosocial
stress-induced apical atrophy of CA3 hippocampal neurons in subordinate
tree shrews. Figure 3 shows that control animals had a
similar number of branch points and total dendritic length compared
with subordinate animals treated with phenytoin. It is important to
note that the different values for control groups in Figures 1 and 3
are attributable to the fact that different proportions of pyramidal
neuron subtypes were impregnated in the two experiments. Whereas the
basal trees show a similar degree of arborization complexity,
regardless of the neuronal subtype considered, the apical trees vary
according to the subclass examined. In the first experiment, each
subject contributed with 20% of long-shaft neurons, 45% of
short-shaft neurons, and 35% of two main-shaft neurons to the final
average. In the second experiment, the Golgi staining favored a larger
number of long-shaft neurons, and each brain contributed with 38% of
long-shaft neurons, 50% of short shaft neurons, and 12% of two
main-shaft neurons to the final average. In other words, in the second
experiment, a larger proportion of neurons with poorer apical dendritic
trees (long-shaft neurons) and a smaller proportion of neurons with
richer apical arborizations (two main-shaft neurons) are reflected in
the lower final averages (Fig. 2).
Fig. 3.
Daily oral administration of phenytoin
(DIL, 200 mg/kg) to subordinate animals (SUB)
during the 28 d stress period prevented the occurrence of the CA3
apical dendritic atrophy. Control animals (CON) showed a
number of apical dendritic branch points similar to that for
subordinates treated with phenytoin. No statistical differences were
found in apical dendritic length as well. Bars represent the
mean ± SEM.
[View Larger Version of this Image (35K GIF file)]
Urinary parameters and body weight
In subordinate animals, the hypothalamo-pituitary-adrenal
(HPA)-axis became chronically activated as indicated by the elevation
of urinary cortisol throughout the confrontation period (days 10-38)
(Fig. 4) (p < 0.01, Kruskal-Wallis one-way
ANOVA, followed by the Mann-Whitney U test). The intensity
of psychosocial stress in subordinates also was indicated by a
significant reduction of their body weight from the initiation of
social conflict onward (Fig. 4) (p < 0.01, Kruskal-Wallis
one-way ANOVA, followed by the Mann-Whitney U-test).
Phenytoin treatment did not affect the stress-induced urinary cortisol
of subordinates (Fig. 5). However, body weight reduction
in phenytoin-treated subordinates during the psychosocial stress period
was less pronounced than in pharmacologically untreated subordinates
(Figs. 4, 5). Control animals (kept in a separate room and not
subjected to stress) showed no stimulation of HPA-axis activity, and
their body weights remained constant during the entire experimental
period (Figs. 4, 5). In the first social confrontation, dominant
animals experienced a transient body weight loss at the beginning of
the psychosocial conflict period, and cortisol urinary excretion
remained within control levels except for days 34-36, when they were
slightly increased (Fig. 4). When confronted with phenytoin-treated
subordinates, dominant animals did not lose weight, but their cortisol
urinary excretion increased slightly during the conflict period,
although not as prominently as in subordinates (Fig. 5).
Fig. 4.
Effect of psychosocial stress on cortisol in
morning urine and relative body weight during a control period
(CO) and a subsequent period of psychosocial stress
(PSS). Control animals were handled like subordinates and
dominants, but were not subjected to psychosocial stress. Data are
given as percentage of mean values during the control period (mean ± SEM).
[View Larger Version of this Image (30K GIF file)]
Fig. 5.
Effect of phenytoin treatment on morning urine
cortisol levels and body weight during a control period (CO)
and a subsequent period of psychosocial stress (PSS).
Control animals were handled and treated with phenytoin as
subordinates, but were not subjected to psychosocial stress. Data are
given as percentage of mean values during the control period (mean ± SEM).
[View Larger Version of this Image (30K GIF file)]
DISCUSSION
Subordination through psychosocial encounters is an effective
stressor, and clear bio-behavioral indices differentiate subordinate
from dominant tree shrews (Aue, 1989). In line with these data, the
present study revealed several distinctive physiological
characteristics of subordinate animals, namely, a rapid and consistent
weight loss and an increased and nonhabituated urinary cortisol
excretion that is indicative of a prolonged activation of the
HPA-axis.
After daily psychosocial confrontation, we observed a stress-induced
apical dendritic atrophy of hippocampal CA3 pyramidal cells in the
subordinate tree shrews as compared with nonchallenged control animals.
All CA3 neuron subtypes of subordinates showed both a lower number of
apical dendritic branch points and a smaller apical dendritic length
after 28 d of psychosocial stress as compared with controls. Thus,
pyramidal neurons from subordinate animals appear to retract their
dendrites, a change that might have an impact on the total number of
dendritic synapses. However, the spine density of CA3 apical dendrites
of subordinate tree shrews was not altered after the confrontation
period. Because we did not measure the total number of apical dendritic
spines, additional studies should elucidate whether psychosocial stress
affects the total number of pre- and postsynaptic elements.
Psychosocial stress also is known to cause other morphological
alterations within the hippocampus of tree shrews: light microscopic
analysis of Nissl-stained hippocampal sections revealed an increased
staining intensity of the nucleoplasm in CA1 and CA3 pyramidal neurons
of subordinate tree shrews (Fuchs et al., 1995). Considering the
present results, the modified appearance of the nucleus may reflect
altered genomic activity that could underlie the atrophic changes in
the dendrites.
In contrast to subordinates, dominant male tree shrews revealed only a
transient increase in cortisol excretion during the late phase of the
confrontation period in the first experiment. Transient increases in
cortisol excretion can be attributed to sometimes uncontrollable
stimuli (e.g., noise in the animal facility). In the second experiment,
the increase of urinary cortisol levels in dominants may result from
the fact that the data were calculated as percentage of the control
period and, in this particular experiment, control levels were somewhat
lower than usual. Although the alterations in dominant urinary cortisol
levels are minimal in comparison to the changes observed in
subordinates, it cannot be excluded that dominants also experienced
some stress during the social confrontation, despite the fact that no
noticeable behavioral and physiological alterations were described
before (Aue, 1989; Jöhren et al., 1991; Fuchs et al., 1993).
However, future studies will be needed to establish the possible degree
of stress-induced hippocampal changes in the dominants. For the present
study, we focused on those tree shrews that obviously were undergoing
pronounced and chronic stressful experiences as indicated by the
changes in physiological parameters as well as by the characteristic
subordination behavior.
As in the rat and other mammalian species, including human beings, the
hippocampus of tree shrews contains high levels of receptors for
adrenocorticoids as shown by in vivo autoradiography
(Flügge et al., 1988). A recent in situ hybridization
study demonstrated that the density of mRNA encoding the glucocorticoid
receptor was decreased in the hippocampal formation of subordinate tree
shrews (Jöhren et al., 1994). Glucocorticoids have a permissive
role and act synergistically with EAAs in producing neuronal death in
cell culture and in vivo (Sapolsky, 1992). The major
excitatory input to the CA3 pyramidal cells is the mossy fiber
projection from the granule neurons from the dentate gyrus (Clairbone
et al., 1986). In addition, the possibility of an excitatory input from
commissural or associational afferents has to be considered (Bayer,
1985). Furthermore, electrical stimulation of the perforant path leads
to granule neuron seizure activity, which, in turn, induces CA3
dendritic damage and neuronal loss (Sloviter, 1993). Such damage is
potentiated by glucocorticoids and appears to involve endogenous
glucocorticoid and EAA receptor-dependent processes (Sapolsky, 1992).
Moreover, a significant increase of extracellular hippocampal glutamate
concentration was reported after acute restraint stress (Moghaddam,
1993), and, in another experiment using microdialysis probes implanted
into the hippocampus, adrenalectomy suppressed the stress-induced
release of glutamate completely (Lowy et al., 1993). Thus, it is
possible that glutamate release is an important component of
stress-induced processes leading to atrophy of CA3 neurons. Finally, as
noted above, phenytoin, an antiepileptic drug that inhibits EAA release
and blocks its activation of T-type calcium channels, prevented both
the corticosterone- and the stress-induced atrophy of hippocampal CA3c
apical dendrites in rats (Watanabe et al., 1992a). And, indeed, as
shown in the present study, whereas glucocorticoid levels are clearly
elevated in subordinate tree shrews and are likely to contribute to the
atrophy in the hippocampus as they do in the rat (Magariños and
McEwen, 1995b), daily treatment of subordinate tree shrews with
phenytoin prevented the psychosocial stress-induced dendritic atrophy.
Although phenytoin's mechanisms of action appear to be complex and to
involve many components (De Lorenzo, 1989), the present results imply
that EAAs may be involved, an inference that is supported by the fact
that NMDA receptor blockade prevented stress-induced atrophy of apical
dendrites of CA3 neurons in the rat hippocampus (Magariños and
McEwen, 1995b).
Besides adrenal steroids and EAAs, potentially important connections
exist between EAAs and serotonin (5-HT). As discussed above, EAAs have
the ability to promote dendritic atrophy by mechanisms involving NMDA
receptors (Magariños and McEwen, 1995b). Serotonin inhibits
neurite outgrowth and synaptogenesis (Haydon et al., 1985) and has been
reported to facilitate neuronal responses to EAAs (Nedergaard et al.,
1987). Hippocampal serotonin concentrations are increased during
psychosocial conflict in rats (Blanchard et al., 1993) and also are
increased in the brains of subordinate tree shrews, as indicated by a
downregulation of 5-HT1A receptors (Flügge,
1995). Thus, a pharmacological agent that reduces serotonin levels
during stress might prevent stress-induced atrophy of hippocampal CA3
dendrites. Indeed, tianeptine, an atypical tricyclic antidepressant
that facilitates serotonin uptake, blocked the corticosterone- and
stress-induced dendritic atrophy in rats (Watanabe et al., 1992b).
Future experiments will address the possible involvement of 5-HT in the
morphological effects of psychosocial stress in the tree shrew.
In view of the role of the hippocampus in spatial information
processing and episodic learning and memory (Squire, 1983; Eichenbaum
and Otto, 1992), the functional significance and the behavioral
consequences of the stress-induced atrophy are beginning to receive
increasing attention (McEwen and Sapolsky, 1995). One question is
whether this atrophy is the beginning of irreversible hippocampal
damage or a protection mechanism to prevent neuronal loss. It is
interesting to note that in rats, the stress-induced atrophy is a
reversible phenomenon within 10 to 20 d after the termination of daily
stress (A. M. Magariños and B. McEwen, unpublished observations).
Thus, it is possible that by reducing the number of contacts with the
excitatory inputs from the mossy fibers and other synaptic inputs, the
apical dendritic atrophy might protect CA3 pyramidal neurons from
destruction. Likewise, the reduction of glucocorticoid receptor mRNA
levels in tree shrew hippocampus by psychosocial stress (Jöhren
et al., 1994) might downregulate one of the principal mechanisms by
which neuronal destruction is produced.
Yet, protective or not, the dendritic atrophy found in the tree shrew
and the rat may contribute to cognitive impairment as has been
demonstrated in rats after 21 d of daily restraint stress (Luine et
al., 1993). This impairment was reversible and could be blocked by
phenytoin and tianeptine, the same agents that blocked stress-induced
atrophy of CA3 pyramidal neurons (Luine et al., 1993). In primates,
prenatal dexamethasone treatment of Rhesus monkeys resulted in later
life in a significantly elevated cortisol level and an ~30%
reduction of hippocampal size and volume (Uno et al., 1994). Because
the hippocampus is highly vulnerable to various challenges such as
ischemia, epilepsy, and aging (Sapolsky, 1992; McEwen et al., 1993),
additional studies should find out whether similar neuronal effects
also occur in the human brain. Initial evidence suggests that the
underlying cellular mechanisms in humans and experimental animals may
be comparable in that in Cushing's disease patients and normal elderly
subjects, reduced hippocampal volume is correlated with elevated plasma
cortisol levels and with deficits in delayed recall of word lists
(Starkman et al., 1992; Golumb et al., 1994; Convit et al., 1995).
Furthermore, reduced hippocampal volume was suggested to be a risk
factor for later dementia (Convit et al., 1995).
In conclusion, the present experiments establish that a
naturalistic psychosocial stressor in a nonrodent mammal, which is
situated phylogenetically between insectivores and primates, produces
morphological changes in the CA3 region of the hippocampal formation of
the mature brain, much as was demonstrated in the rat brain after 21 d
of chronic corticosterone treatment or repeated laboratory stresses
(Watanabe et al., 1992c; Magariños and McEwen, 1995a,b). The
present study also supports a crucial role of glucocorticoids and EAAs
(Magariños and McEwen, 1995b; Moghaddam, 1993) in triggering
dendritic atrophy and points out the need to investigate mechanisms in
primate and human brains by which cortisol elevation and persistent
stress may lead to hippocampal morphological changes and cognitive
impairment.
FOOTNOTES
Received Oct. 11, 1995; revised Feb. 29, 1996; accepted March 4, 1996.
This research was supported by National Institutes of Health Grant
MH41256 and The Health Foundation, New York, to B.Mc. We appreciate the
advice of Dr. Barry Smith, The Health Foundation, New York, regarding
phenytoin, and the help of Dr. Bruce Schneider (Vet Research) for
measuring phenytoin in the tree shrew plasma. We express our thanks to
Andreas Heutz for his excellent technical assistance.
Correspondence should be addressed to Dr. Ana María
Magariños, The Rockefeller University, 1230 York Avenue, New
York, NY 10021.
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