Journal of Neuroendocrinology, 1994, Vol.

6, 341-345

Prenatal Stress Increases the Hypothalamo-Pituitary-Adrenal Axis

Response in Young and Adult Rats

Chantal Henry, Moharned Kabbaj, Herve Simon, Michel Le Moal and Stefania Maccari
Psychobiologie des Cornportements Adaptatifs, lnstitut National de la Sante et de la Recherche Medicale U. 259,
Universite de Bordeaux II, Domaine de Carreire-Rue Camille St Saens, 33077 Bordeaux Cedex, France.

Key words: hyporesponsive period, hippocampus, plasma corticosterone, type I and type II corticosteroid receptors.

Abstract
Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is
still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility
the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional proper'ties of the
hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days
of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats-at 3 and 21 days after exposure to novelty. At 90
days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was
observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of
prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the
hypothalamo-pituitary-adrenal axis in the offspring.

The development of the central nervous system and of behavior
is determined by genetic factors and by the postnatal environment,
but also by the maternal environment during gestation (1).
Clinical studies have shown a highly significant correlation
between infant morbidity and maternal stress (2-4). However,
these studies present methodological and interpretative difficulties.
Thompson (S), conducted the first experiment to explore the
manipulation of the prenatal environment in animals. Further
animal studies have shown behavioral abnormalities in the off-
spring of stressed dams, lasting until adulthood (6-7). Stress
during pregnancy induces alterations in early motor development
(S), increases emotionality in adulthood and disrupts the normal
course of sexual differentiation (8-1 1 ). We have recently shown
that prenatally-stressed animals exhibit a higher locomotion
response to novelty and a higher level of amphetamine self-
administration (12).
It has also been found that prenatal stress reduces dopamine
turnover rates in the left corpora striata (13-14) and induces
changes in brain 5 hydroxytryptamine especially in the hypothal-
amus at 60 days of age (15). The activity of the hypothalamo-
pituitary-adrenal (HPA) axis may also play a critical role in the
behavioral modifications observed in prenatally-stressed rats
since, in the adult, the HPA axis is central for the control of the
homeostatic disturbances induced by stress ( 16) and the hyperac-
tivity of the HPA axis has already been associated with behavioral
disorders (17-19). It has been shown that a maternal corticos-
terone manipulation modifies the development of this axis (20).
Thus, the development of the HPA axis of the fetus could be
influenced by in-utero exposure to abnormal levels of maternal
glucocorticoids during stress which are able to cross the placental
and blood-brain barriers (21) and could result in long Iasting
perturbations in the offspring. However, literature data show that
a prenatal stress is able to increase HPA axis reactivity in the
early stage of life (15, 22) but it is not clear if this manipulation
modifies glucocorticoid feedback in the adult and, if so, by which
mechanism (23, 24). Hippocampal type I and type 11 corticos-
teroid receptors regulate at least in part the negative feedback of
the HPA axis in adult animals (25, 26). Long-lasting alterations
in these receptors are responsible for impaired stress responses,
and aged rats which have less corticosteroid receptors in the
hippocampus have a delayed stress-response (27).
Given this evidence, we investigated the influence of restraint
stress, during the third- week of pregnancy, on the development
of the HPA axis and corticosteroid receptors of the offspring.
Thus, we have measured basal and stress corticosterone levels in
3, 21, and 90 day-old male rats and hippocampal type I and
type I1 corticosteroid receptors at the same age.
Results
Data concerning circulating corticosterone levels in 3, 21, 90 day-
old rats under basal conditions, at the end of a 30 min exposure
to novelty and, for the adult subjects, also after 120 min of
exposure to novelty, are shown in Figure 1.

Correspondence 20: D r Stefania Maccari, INSERM U259-Universitt de Bordeaux 11, Rue Camille St Saens, 33077 Bordeaux Cedex, France.
342 Prenatal stress increases HPA axis response

3D 21 D ** 90 D

2.5 -- *
25 25
T
- 20
E 20
0
z -
p 2.0
Q)
C 15 15
E
c
v)
0
.-
5 1.5- 10 10
V

5 5

l.1
I
- 0 a I I I I 0 I I I I I
0 10 20 30 0 10 20 30 0 30 60 90 120
lime (min)

FIG.1. Study of corticosterone secretion after exposure to novelty in 3- 21- and 90-day-old rats. Basal levels (T 0) of corticosterone were not affected
by prenatal stress in 3-, 21- and 90-day-old male rats. Conversely, 3 and 21 day-old offsprings of stressed mothers exhibited a significant rise in
corticosterone after exposure to stress (T 30), whereas control 3 day-old pups remained unresponsive. At 90 days of age the prenatally-stressed animals
showed no difference 30 min after stress (T 30) however, after 120 min (T 120), corticosterone levels remained elevated in prenatally-stressed rats with
respect to controls. Eight to 5 animals were used for each group. *=P<O.O5; * * = P t 0 .0 1 . 0 Control; 0 Prenatal Stress.

At 3 days of age prenatal stress modified stress-induced corticos-
terone secretion (ANOVA Prenatal Stress x stress novelty inter-
action F( 1.28) = 3.84; P ~ 0 . 0 5 ) No
. difference was observed in
the basal corticosterone levels of the two groups, however, the
corticosterone levels in response to stress (T30) were higher for
the prenatally-stressed group ( F ( 1.14)= 5.342; P < 0.05).
Furthermore, control rats at 3 days of age displayed no response
to novelty-stress ( F ( 1.14) =0.246; P = 0.6277), whereas at the
same age prenatally-stressed rats were able to respond to stress
(F(1.14)= 15.323; P<O.OOl).
At 21 days of age both groups of animals were able to respond
to novelty (ANOVA novelty stress effect F ( 1.28) = 67.94,
P <0.0001). However, prenatally-stressed animals showed a
higher corticosterone secretion (ANOVA Prenatal Stress effect
F( 1.28) = 7.97; P < 0.01 ). Thus, prenatally-stressed animals
showed a higher response to stress (T30) than controls (ANOVA
F(1.14)= 12.39; P<O.Ol).
At 90 days of age, prenatal stress also increased plasma
corticosterone secretion (ANOVA Prenatal Stress effect F ( 1.9) =
8.531; P=O.O17) and this effect depended on the time of exposure
to stress (ANOVA Prenatal Stress x Time interaction F(2.18) =
5.041; P=0.018). Thus, the prenatally-stressed rats showed a
higher corticosterone secretion only after 120 min of novelty
exposure ( F ( 1.9)= 12.087; P=0.007).
These changes in corticosterone responsiveness to novelty were
concomitant to a decrease in cytosolic corticosterone receptors in
the hippocampus of prenatally-stressed offspring at different
ages (Fig. 2).
At 3 days of age type I and type I1 corticosteroid receptors did
not differ between the two groups. At 21 days the number of the
two types of receptors was significantly lower in prenatally-
stressed rats (ANOVA Prenatal Stress effect F ( 1.28)= 13.614;
P=O.OOl). Thus, type I receptors were reduced of 31% and
type I1 of 18%. The same results were found at 90 days of age.
Type I and type I1 receptors were reduced by prenatal stress
(ANOVA Prenatal Stress effect F(1.12)=6.35; P=0.02). Type I
receptors were reduced by 70% and type I1 by 30%.
The affinities of both receptors for these compounds remained
unaffected (Table 1) .
Discussion
The data indicate that maternal stress during pregnancy has
short- and long-term effecfs on HPA axis reactivity of the
offspring. In 3 and 21 day-old male rats, the rise in plasma
corticosterone in response to stress was significantly higher in
prenatally-stressed pups. Furthermore, control 3 day-old rats
showed no response to novelty-stress. h control adult rats
corticosterone levels declined at 120 min, whereas prenatally-
stressed subjects still displayed elevated levels after the same
delay. Prenatal stress decreased type I and type I1 corticosterone
receptors in the hippocampus at 21 and 90 days of age, whereas
the same group studied at 3 days after birth did not display any
change in receptor number. No change in receptor affinity was
encountered in animals examined at 21 and 90 days of age. This
study shows that both basal and stress corticosterone levels
increase during development. Type I1 hippocampal glucocorticoid
receptor density appeared to be greater than type I density at
 Prenatal stress increases HPA axis response 343
125 TABLE 1. Affinity Values of Type I and Type I1 Hippocampal
Corticosteroid Receptors in 21- and 90-Day-Old Rats.
21 Days 90 Days
100

I
~~~ ~

Kd type I Kd type I1 Kd type I Kd type I1

Control 1.39k0.24 1.51k0.15 2.1350.28 1.42k0.22

Prenatal stress 1.15 k0.21 1.13k0.13 1.63k0.23 1.47 k0.35
75

I
The apparent affinities (Kd) of both receptors did not change in pre-
natally-stressed rats with age. The kd is expressed innM. The values
indicate the mean +SEM.
50

** corticosterone secretion after exposure to various stresses (3 1-34),

T

25 as we found in control 3 day-old rats. This hyporesponsive period

-.-
C
was recently discussed, and Walker et al. (35) reported that under
particularity severe forms of stress 1 and 5 day-old pups are able
al
c
to respond. These pups show an increase in corticosterone levels
g o
r
with a peak 10 min after the exposure to stress. However, in the
0 D 90 D mentioned study, the pregnant mothers were obtained on day 18
E"
2- of gestation, we could thus hypothesize that the attenuation of
E
'C 250
the SHRP in the pups could have been due to this maternal stress
(36). In fact, in our experiment we show that 3 day-old animals
X
born by mothers stressed during days 14 to 21 of pregnancy
;
rn - respond to the stress procedure. Furthermore, the prenatally-
200 stressed 3 day-old rats had the same density of hippocampal
corticosteroid receptors than controls, so the changes in corticos-
terone secretion appear earlier than the changes in corticosteroid
receptors. This disappearance of the SHRP could account for
150 * the decrease in hippocampal glucocorticoid receptor densities

I
T observed in prenatally-stressed 21 and 90 day-old rats. In fact,
rats treated with glucocorticoids during the first week of life have
100
permanently reduced brain weights and DNA contents (37, 38)
and the effects are most profound in those brain regions where
there is extensive postnatal mitosis, such as the hippocampus (39).
Our study shows that maternal stress alters in the long run the

L
50
0 3
3D
Type It
FIG.2. Hippocampal type I and type I1 corticosteroid receptor numbers
in 3-, 21- and 90-day-old male rats. The maximal binding capacity (BmaX)
of type I receptors is indicated in the top of the figure. The B,,, of type I1
receptors in indicated in the bottom of the figure. Type I and type I1
corticosterone receptor numbers were no different at 3 days of age, but
were significantly lower in prenatally-stressed animals compared to con-
trols at 21 and 90 days. At 21 days, type I was -31% and type I1 - 18%.
At 90 days of age type I was -70% and type I1 -30%. For the study
at 3 and 21 days of age the number of animals was 14-16 for group;
for the study at 90 days of age 7 rats for group were used. *=P<0.05;
**=P<O.Ol; ***=P<O.OOl. 0 Control; Prenatal stress.
every age and type I and type I1 receptors reached the adult's
density at 21 days. These observations are in agreement with
previous works (28, 29).
One of the salient points in our observation actually lies in the
plasticity of the stress hyporesponsive response period (SHRP)
proposed by Schapiro (30), which is mainly based on the lack of
reactivity of the HPA axis in response to stress and decreases the
number of type I and II corticosterone receptors in the hippocam-
pus of adult rats. The efficacy of the negative-feedback is deter-
mined by the ability of glucocorticoids to inhibit subsequent
ACTH release and is mediated by corticosteroid receptors. In
addition to target sites such as the pituitary and the hypothalamus,
it seems, as previously mentioned, that hippocampal receptors
play a role in terminating the HPA response to stress (25). The
decrease of hippocampal type I and type I1 corticosteroid recep-
tors observed in prenatally-stressed rats could be responsible, at
least in part, for the liigher and longer corticosterone secretion.
The major interest of this model lies in the demonstration of
long lasting modifications in the central nervous system induced
by environmental modifications that have occurred in early life,
but the mechanisms remain unclear. Maternal corticosterone,
secreted during the stress, could play a decisive role in this
phenomenon. In fact, this hormone crosses the placental and
hematoencephalic barriers (21) and can thus interact with the
central nervous system of the developing fetus. Furthermore, we
know that in adult animals high levels of corticosterone, obtained
by stressing the subjects or by repeated corticosterone injections,
causes a decrease of glucocorticoid receptors (40-42).
In conclusion, it would be interesting to link these short and
long-term changes on HPA axis activity induced by prenatal
344 Prenatal stress increases HPA axis response
stress with behavioral impairment observed in these animals ( 12,
23, 43). Interestingly, higher corticosterone secretion has been
related t o various psychiatric conditions such as depression (18)
and t o impaired performance in memory tasks (44). Furthermore,
the increase in vulnerability to addictive drugs m a y depend on
changes in t h e activity o f the H P A axis (19).
Materials and Methods
Animals and housing conditions
Virgin female Wistar rats (Iffa-Credo, Lyon) were obtained at 15 weeks
of age. Sexually experienced male Wistar rats were used for mating.
Animals were supplied with ad libitum food and water and maintained
on a constant light/dark cycle (light on from 06.00-20.00), with constant
temperature (23 "C).
Breeding
Breeding was carried out in our laboratory in order to avoid the stress
due to shipping of pregnant females (36). For reproduction, 1 male was
housed with 4 females overnight during a whole estrous cycle. Vaginal
smear was examined every morning for the presence of sperm (indicating
day 1 of pregnancy). Pregnant rats were then individually housed in
plastic breeding cages, and divided into 2 groups: stress (n= 10) and
controls (n = 10).
Prenutal stress procedure
Stress began on day 14 and ended on day 21 of pregnancy (11). The
stress sessions consisted of introducing females in Plexiglas holders
(20 x 6 x 8 cm) exposed to bright light for 45 min. Animals were submitted
to three daily stress sessions starting at 09.00, 12.00 and 17.00. Control
animals were left undisturbed in their home cages. The litters used for
both groups contained between 8 and 14 pups. Litters with different
numbers of pups were eliminated. Offspring were weaned 21 days after
birth and housed in isosexual groups of 3 animals until 90 days of age.
A maximum of 2 male pups was taken from each litter.
Corticosterone secretion in the male offsprings
Three day-old and 21 day-old pups before weaning
In order to determine baseline secretion, blood was collected from 8 pups
per group in an adjacent room immediately after removal from the litter.
For determination of stress secretion, 2 pups of a same litter were
separated from their mother and placed for 30 min in a clean cage. The
blood was collected immediately at the end of this stress period. All tests
were performed in the morning between 09.00 and 11.00. Trunk blood
was collected in heparinized tubes. Tubes were centrifuged at 4 "C for
20 min at 3000 rpm. Plasma was aliquoted and stored at -20 "C until
assay.
Ninety day-old rats
At this age both groups (n=5-6 per group) were implanted with
intracardiac catheters. Animals were anaesthetized with chloral hydrate
(3.50 mg/kg, i.p.), and a catheter (Silastic, Sigma Medical, Nanterre) was
inserted into the right auricle through the external jugular vein, passed
under the skin, and exited in the mid scapular region. After 6 days of
recovery, the rats were tested for their response to novelty. The animals
were placed in the room of the test the day before the stress session. The
morning after, the animals were placed for 120 min in the novel environ-
ment, which consisted of a circular corridor (10 cm wide and 70 cm in
diameter). Corticosterone was assayed in three blood samples (500 pl
each) collected immediately before the exposure to novelty and at 30 and
120 min. Samples were collected through the catheter.
Plasma corticosterone was measured by radiocompetitive binding after
extraction with dichloromethane (45). Corticosteroid-binding globulin
was obtained from pregnant women, and dextran-coated charcoal was
used to remove the unbound steroid. The sensitivity of the assay was
0.4 ng per tube, and the inter-and intra-assay variations were, respectively,
7% and 3.8% at a mean value of 1.2 ng per tube and 9.8% and 5% at a
mean value of 5 ng per tube.
Type I and type I1 corticosteroidreceptors in male offspring
Three day-oldpups ( n = I4--15per group)
Each hippocampus was homogenized in 700 ml of ice-cold TEGDM
buffer and individual maximal binding was determinated with tritiated
corticosterone (3H-B) and tritiated RU 28362 at a concentration of
20 nM. Non-specific binding (NSB) for the 3H-B binding was determined
in the presence of a 500-fold excess of unlabeled corticosterone, and for
3H-RU 28362, was assessed in the presence of a 500-fold excess of
unlabeled RU 28362. Binding equilibrium was reached after 22 h at 4 "C.
Twenty-one day-old rats ( n = 14-16per group) and 90 day-old rats (n = 7
per group)
In order to eliminate endogenous corticosterone, type 1 and type I1
corticosteroid receptors were determined using an exchange assay as
previously shown (46).
One hippocampus per animal was used. The tissue was homogenized
in 2 ml of ice-cold TEGDM buffer for the 90 day-old rats, whereas for
the 21 day-old rats 1.7 ml were used (30 mM Tris, pH adjusted to 7.4
with HC1 6N, 1 mM EDTA, 10 mM sodium molybdate, 1 mM dithio-
threitol and 10% glycerol). The tissue was centrifuged (105,OOOg, 15 min
in a Beckman TL 100 ultracentrifuge) at 2 "C. Endogenous, unbound
steroids were removed from the soluble fraction by passing the sam-
ples through LH-20 columns equilibrated with TEGM buffer (10 mM
Tris, 2 m M EDTA, 10mM sodium molybdate and 2.3 mM
p-mercaptoethanol). For the type I receptor assay, aliquots of cytosol
(140 pl) were incubated with tritiated corticosterone (specific' activity
88 Ci/mmol, New England Nuclear, Paris) over a concentration range of
0.625-20nM (6 points for each Scatchard plot), and with a 100-fold
excess of unlabeled'RU 28362. Unlabeled RU 28362 was used to displace
'H-B from type I1 receptors (47). Type I1 receptor binding was evaluated
directly using pure glucocorticoid 3H-RU 28362 (specific activity
74.3 Ci/mmol, Dositek) over a concentration range of 1.25-40 nM (6
points for each Scatchard plot). This has been shown to be sufficient for
maximal exchange, and binding remains stable over this period (48, 49).
Bound and unbound 3H-B or 3H-RU 28362 were separated on Sephadex
LH-20 columns equilibrated with TEDGM buffer at 2 "C, using 60 pl of
the incubates and eluding with 940 pl of TEDGM buffer. A milliliter of
elute containing the bound form was added to 3 mi of scintillation fluid
(Aqua Luma Plus, Lumac, Paris), and radioactivity was counted. Protein
concentration was determined according to Lowry et al. (SO) using
albumin as standard. The apparent maximum binding capacity (Bmax)
of 3H-B or 3H-RU 28362 and dissociation constants (Kd) for both
receptor types were evaluated from Scatchard plots (51).
Statistical analysis
Analysis of variance (ANOVA) for repeated measures was employed for
type I and type I1 corticosteroid receptors and plasma corticosterone
levels in 90 day-old rats. For the analysis of plasma corticosterone levels
at 3 and 21 days of age, time of sampling was introduced as between
factor. The Crunch statistical package (Crunch Software, Oakland CA,
USA) was used throughout. A logarithmic transformation was applied
to normalize the distribution. Results are expressed as the mean & SEM.
Acknowledgements
This study was supported by Institut National de la Sante et de la
Recherche Medicale (INSERM), University de Bordeaux 11, Fondation
pour le Recherche Medicale and Conseil Rtgional d'Aquitaine. We thank
Roussel-UCLAF for providing RU 28362.
Accepted 24 February 1994
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