Вы находитесь на странице: 1из 11

Psychoneuroendocrinology (2013) 38, 1407—1417

Available online at www.sciencedirect.com

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n

Acute stress further decreases the effect of


ovariectomy on immobility behavior and
hippocampal cell survival in rats
Nelly M. Vega-Rivera a,b, Alonso Fernández-Guasti b,
Gerardo Ramı́rez-Rodrı́guez c, Erika Estrada-Camarena a,*

a
Laboratory of Neuropsychopharmacology, Division of Neurosciences, National Institute of Psychiatry, México, D.F., Mexico
b
Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), México, D.F., Mexico
c
Laboratory of Neurogenesis, Division of Clinical Research, National Institute of Psychiatry, México, D.F., Mexico

Received 1 March 2012; received in revised form 30 November 2012; accepted 11 December 2012

KEYWORDS Summary Most studies relating experimental depression and neurogenesis use mainly male
Acute stress; rodents subjected to models of chronic stress. The forced swimming test (FST) is a widely utilized
Forced swimming test; model of acute stress, but its effects on the neurogenic process in the hippocampus using females
Cell proliferation; in different endocrine conditions has not been explored. The aim of this study was to evaluate the
Cell survival; cell proliferation and early-, short- and long-lasting effects of forced swimming (FS) on adult
Neurogenesis hippocampal neurogenesis in rats in two endocrine conditions: proestrous and ovariectomized. To
determine cell proliferation we used the endogenous marker Ki67. Cell survival was established
with the thymidine analog, BrdU (75 mg/kg, 2/12, i.p.), which was administered before FS to
proestrous and ovariectomized rats. FS increased immobility and corticosterone levels in OVX but
not in rats in proestrus. In addition, FS did not affect cell proliferation but significantly decreased
the number of BrdU-labeled cells at 2 h only in OVX-rats, an effect that remained for 3 and 14 days
after FS. Data are discussed taking into consideration the relationship between gonadal and
adrenal hormones in adult hippocampal neurogenesis in adult females. Our data also support the
use of FS as a model for studying neurogenesis.
# 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Stress is considered a response for homeostasis preservation


and survival (Selye, 1976) that produces physiological
* Corresponding author at: Laboratorio de Neuropsicofarmacolo-
gı́a, Dirección de Neurociencias, Instituto Nacional de Psiquiatrı́a,
effects such as alterations in neurotransmitter function,
México, D.F., Mexico. Tel.: +52 55 41605053. synthesis and release of hormones, and conduct to develop
E-mail address: estrada@imp.edu.mx (E. Estrada-Camarena). coping behaviors (Morilak et al., 2005). Stress produces

0306-4530/$ — see front matter # 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.psyneuen.2012.12.008
1408 N.M. Vega-Rivera et al.

changes in the neuroplasticity of different brain structures synaptic processes, and decrease cell death in the dentate
such as the prefrontal cortex and the hippocampus where it gyrus of non-stressed adult female rats (Tanapat et al.,
reduces the number of glial cells, dendritic spines, arbor- 1999). In addition, the depressive-like effect produced by
izations and, importantly, new neuron formation (Gould a single exposure to the FST has been associated with DNA
et al., 1997; Gould and Tanapat, 1999; Campbell and Mac- damage in the hippocampus, an action that lasts for one
queen, 2004; Sapolsky, 2004). The neurogenic process con- week, suggesting an impaired neurogenic process (Consiglio
sists of several distinct phases progressing from cell et al., 2010). To establish whether cell proliferation in the
proliferation to final integration of newborn neurons (Kem- hippocampus is affected by a single exposure to forced swim
permann et al., 2004). Recently, based on the expression of (FS), we characterized the cell production with the antibody
different markers and the lapse between the injection of Ki67 on OVX and sham operated rats selected in proestrous.
thymidine analogs and sacrifice, the term neurogenesis has Also we analyzed the effects of a FS exposure on three
been redefined by distinguishing proliferation phases, survival times: 2 h, 3 and 14 days after the last BrdU admin-
immediate survival of newly generated cells, short- and istration (Kronenberg et al., 2003) on OVX rats and sham
long-term cell survival, and integration of new neurons into operated animals selected in proestrous. As aforemen-
the neuronal network (Thomas et al., 2007). One of the main tioned, based on the lapse between BrdU injection and
markers for cell proliferation is Ki67 which labels cells during sacrifice, the phases of early survival of newly generated
the phases M, G1, G2 and S of the cell cycle (Plümpe et al., cells, short- and long-term cell survival, and integration of
2006). new neurons into the neuronal network may be discerned
Stress is one of the most important factors underlying (Kronenberg et al., 2003; Llorens-Martin and Trejo, 2011).
affective disorders such as depression (Heim and Nemer- Thus, when the sacrifice takes place at around 2 h, 3 days, or
off, 1999; Nestler et al., 2002; Caspi et al., 2003; McEwen, 14 days after BrdU administration, early-, short-, and long-
2004; de Kloet et al., 2005). Several authors have term cell survival of newborn cells are implied (Kronenberg
described the neuronal and molecular effects of chronic et al., 2003). To establish the relation between changes in
stress (Sarter and Turchi, 2002). For example, it has been neurogenesis with immobility levels, independent group of
reported that chronic variable stress (CVS) induces signs of rats were retested for forced swimming at 3 and 14 days after
depression such as anhedonia and corticosterone hyperse- the first test. Previous data (Detke et al., 1997; Estrada-
cretion (Jayatissa et al., 2006) that underlie the morpho- Camarena et al., 2004, 2008) have shown that separating
logical changes in the hippocampus (Sheline et al., 1999), two FS sessions with these intervals does not affect the
as well as the reduction in new cell proliferation and increased immobility induced by the first session.
survival (Barha et al., 2011; Veena et al., 2009; Dagytė
et al., 2011). 2. Materials and methods
Models of acute stress have gained attention because
they induce long-term physiological and behavioral changes
2.1. Animals
(Belda et al., 2008a,b). For example, studies in male rats
have reported that a single exposure to a severe stressor,
Three-month old female Wistar rats (250—300 g) were used in
such as immobilization, social defeat, or predator odor
all experiments. Animals were housed in standard laboratory
causes long-term desensitization of the hypothalamic-pitui-
cages under 12-h light/12-h dark cycles (12-h light cycle
tary-adrenal axis (Armario et al., 2008; Belda et al., 2008b)
starting at 22:00 h) at a temperature of 23  1 8C and with
response and a reduction in the number of proliferating
access to food and water ad libitum. All experimental pro-
cells in the dentate gyrus of the hippocampus; an effect
cedures were performed in accordance with the Mexican
that persists at least one week after the stressant stimuli
official norm for animal care and handling (NOM-062-ZOO-
(Gould et al., 1997; Tanapat et al., 2001; Holmes and Galea,
1999) and approved by the Institutional Ethics Committee of
2002).
the National Institute of Psychiatry ‘‘Ramón de la Fuente
The forced swimming test (FST) is an animal model of
Muñiz’’ and CINVESTAV-IPN.
acute stress commonly used for the screening of antidepres-
One week after arrival, all rats were bilaterally OVX or sham-
sant drugs in rodents (Borsini, 1995); it is also considered
operated under anesthesia (2,2,2-tribromoethanol; adminis-
useful for the analysis of the neurobiological bases of depres-
tered by intraperitoneal injection, i.p.) as previously reported
sion (Duncan et al., 1985; Kirby et al., 1995; Kirby and Lucki,
(Estrada-Camarena et al., 2003). To evaluate the effect of OVX,
1997; Connor et al., 1999). In this paradigm, the animal faces
in the acute stress test, sham-operated control animals were
an inescapable stress that induces hopelessness, expressed
tested in proestrus, since in this phase there are elevated levels
as immobility, which has been interpreted as a depressive-
of estrogens and progestins accompanied by low levels
like behavior (Cryan et al., 2005). In this animal model, our
of immobility (Estrada-Camarena et al., 2011). The estrous
group (Estrada-Camarena et al., 2011) and others (Frye and
cycle phases were determined by vaginal-cytology during
Walf, 2002) have shown that the reduction in ovarian hor-
two consecutive cycles (4—5 days). Only those animals that
mones — through ovariectomy (OVX) — increases immobility
were in proestrus (characterized by predominantly nucleated
behavior, as compared to that displayed by females in
cell) during the test day were considered for evaluation.
proestrus, with high levels of estrogen and progesterone.
Additionally, in this test, the immobility caused by OVX is
decreased by different kinds of estrogens (Estrada-Camar- 2.2. Forced swimming
ena et al., 2003) and progestins (Andrade et al., 2007).
Interestingly, estrogens, besides producing antidepres- Briefly, animals were placed in Plexiglass cylinders (20 cm in
sant-like effects, enhance cell proliferation, promote diameter and 46 cm tall) filled with a 30-cm layer of water at
Stress by forced swimming decreases cell survival 1409

23  2 8C. The FS consisted of placing rats inside the cylinder 2.6. Experimental design
for 15 min (Porsolt et al., 1977) after which they were
removed and dried with paper towels and placed in heated 2.6.1. Experiment 1. Effects of acute stress induced
cages for 30 min. After this time, all the animals were by FS on cell proliferation in the dentate gyrus of OVX
returned to the home cage until sacrificed or submitted to and proestrous-rats
a second session of FS in which the rats were placed in the In order to compare the impact of gonads’ removal (OVX) and
tank under the same conditions for a 5 min-period (Porsolt the exposure to a single session of forced-swimming (FS) on
et al., 1977). The behavior of the animals in the FSTwas video the number of proliferating cells in the adult dentate gyrus,
recorded and an observer unaware of the animal’s group female rats were divided into two groups: ovariectomized
scored the immobility behavior, which was considered as the (OVX) and sham-operated rats selected in proestrus (Sham).
minimal movements exerted by the animal to keep the head Three weeks after either ovariectomy or false surgery (Fig. 1,
above the water and floating (Porsolt et al., 1977; Detke panel a), the groups were subdivided in control animals
et al., 1997). without FS-stress and animals with FS-stress. Subsequently,
45 min after stress session or handling, the animals were
2.3. Tissue preparation and sacrificed and their brains removed to be processed for
immunohistochemistry immunohistochemistry for Ki67 determinations.

Rats were anesthetized with ketamine/xilacine (i.p.) and 2.6.2. Experiment 2. Effects of exposure to forced
intracardially perfused with 0.9% saline solution, followed swimming at three survival times (2 h, 3 days, and, 14
by 4% p-formaldehyde (PFA) in 0.1 M sodium phosphate days, after BrdU administration) and on corticosterone
buffer (pH 7.4). Subsequently, brains were removed and levels in OVX and proestrous-rats
post-fixed in PFA for 24 h. Then, brains were kept in 30% The characterization of the effects caused by FS exposure on
sucrose in phosphate buffer until sectioned. Brains were early-, short- and long-lasting cell survival was carried out in
cut into 40 mm coronal sections on a vibratome (Microm six groups of OVX or proestrous females: (1—3) control ani-
International, Germany) and stored at 4 8C in a cryopro- mals without stress (WFS) and sacrificed 2 h, 3 and 14 days
tective solution until required. Immunohistochemistry for after a second administration of BrdU and, (4—6) stressed
Ki67 and BrdU detection was performed on every sixth animals, exposed to a single 15-min forced swim session
section, as previously reported (Tanapat et al., 1999; (Fig. 1, panel b) and sacrificed 2 h, 3 or 14 days later. In
Scholzen and Gerdes, 2000; Ramirez-Rodriguez et al., all groups, BrdU was administered twice (75 mg/kg, i.p., 12 h
2009). apart); the second administration was carried out 30 min
before the FS. Animals were sacrificed and the collected
2.4. Quantification of Ki67- and BrdU-labeled blood was used to determine plasma CORT levels. Brains were
cells dissected and processed for immunohistochemistry for BrdU.
In addition in order to evaluate if cell proliferation was
All Ki67- and BrdU-labeled cells were counted every sixth affected at 2 h, 3 and 14 days after stress, immunohsito-
section throughout the rostro-caudal extension of the chemestry for Ki67 was also performed.
hippocampus, using a light microscope (Leica, Germany). To determine the levels of immobility at 3 and 14 days
In the DG, the quantification of BrdU and Ki67-labeled cell after the exposure to the FS, two independent groups (n = 9)
was limited to the granular cell layer (GCL) and subgra- of ovariectomized female rats were subjected to a second
nular cell layer (SGZ). The latter region was defined as a FST at these intervals. As aforementioned, previous data
band limited by three nodes down from the apparent edge (Detke et al., 1997; Estrada-Camarena et al., 2008) have
between the GCL and the hilar region (H). To estimate the revealed that separating the FST for 3, 14, and even 21 days
total amount of Ki67- and BrdU-labeled cells in the DG, does not modify the high levels of immobility. Only ovariec-
labeled cells number was multiplied by 6 (Ramirez-Rodri- tomized females were included in this experiment because,
guez et al., 2009). as aforementioned, ovariectomy increases the levels of
immobility and stress (Dalla et al., 2005) has profound actions
on the regularity of the estrous cycle.
2.5. Determination of corticosterone levels

Corticosterone (CORT) levels were determined from plasma 2.7. Statistical analysis
samples obtained from the different groups. Prior to perfu-
sion, a blood sample was obtained by cardiac puncture from Results are presented as means  standard error of the mean
which roughly 5 ml of blood were collected in a tube. Blood (SEM). Comparisons between groups were done using the
was kept on ice until centrifuged (4000 rpm for 20 min at SigmaStat 3.1 software. For FS, the analysis of the number
4 8C) to allow plasma extraction. Plasma was kept at 20 8C of labeled cells with Ki67 was done with a two way ANOVA
until analysis. Corticosterone levels were determined by considering the factors: stress (factor A) and endocrine con-
taking all the necessary care to prevent degradation and dition (factor B), followed by the Holm—Sidak’s test. The cell
using the corticosterone immunoassay kit (AssayDesigns, survival data and corticosterone levels were analyzed with a
USA) according to the manufacturer’s instructions. Micro- three way ANOVA considering time of sacrifice after stress as
plate was read at 405 nm in an ELISA reader (Bio-Tek, USA). an extra factor (factor C). This analysis was followed by two
Inter- and intra-assay variabilities were 7.8 and 6.6%, way ANOVA’s and by the Holm—Sidak test. To evaluate
respectively. the effects of forced swimming on immobility behavior, a
1410 N.M. Vega-Rivera et al.

Figure 1 Schematic representation of the experimental designs. (a) To compare the impact of gonads’ removal (OVX) and the
exposure to a single session of forced-swimming (FS) on cell proliferation, female rats were randomly divided into two groups: false-
operated (Sham selected in proestrous) and ovariectomized (OVX). Three weeks after either ovariectomy or false surgery rats were
subjected to the FS and sacrificed. (b) Sham- and OVX-animals were administered with bromodexouridine (BrdU; 75 mg/kg, i.p.; 12 h
and 30 min prior to FS) at the beginning of each experiment and divided into six groups: control animals without stress (WFS), which
were sacrificed 2 h, 3 or 14 days after the second BrdU administration, and stressed animals (FS) sacrificed 2 h, 3 or 14 days after FS.

one-way ANOVA was used followed by Student—Newman— (Table 1) (two-way ANOVA test for 3 days, endocrine condi-
Keuls test. Differences were considered statistically signifi- tion: F 1,15 = 2.59, ns; stress: F 1,15 = 1.27, ns; and interaction:
cant at p < 0.05. F 1,15 = 0.19, ns; and for 14 days, endocrine condition:
F 1,13 = 1.67, ns; stress: F 1,13 = 0.002, ns; and interaction:
F 1,13 = 1.38, ns).
3. Results

3.1. Experiment 1. Effects of acute stress 3.2. Experiment 2. Effects of exposure to forced
induced by FS on cell proliferation in the dentate swimming at three survival times (2 h, 3 days,
gyrus of OVX and proestrous-rats and, 14 days, after BrdU administration) and on
corticosterone levels in OVX and proestrous rats
Fig. 2 shows representative photomicrographs of Ki67-
labeled cells (panel a) and their quantification (panel b) of Fig. 3 shows representative photomicrographs of BrdU-
sham (rats selected in proestrus) and OVX rats after a single labeled cells of sham- and OVX-rats exposed to a single FS
exposure to FS. As observed, the number of Ki67-labeled cells session and sacrificed 2 h, 3 or 14 days after stress (panel a).
of sham- and OVX-rats did not vary independently if the rats Quantifications of BrdU-labeled cells of sham- and OVX-rats
were or not exposed to a single FS stress session (panel b; and corticosterone levels are shown in panels b and c,
two-way ANOVA test: endocrine condition: F 1,15 = 0.11, ns; respectively. As can be seen in Fig. 3 quantification of
stress: F 1,15 = 0.88, ns; and interaction: F 1,15 = 0.30, ns). Cell BrdU-labeled cells in proestrous-rats, regardless of their
proliferation was also unmodified after 3 or 14 days after the exposure to stress, showed no-differences in early-, short-
FS exposition regardless of the animal’s endocrine condition or long-term survival (panel b). Ovariectomy per se induced a
Stress by forced swimming decreases cell survival 1411

Figure 2 Effect of acute stress on cell proliferation in the dentate gyrus of OVX and proestrous-rats. (a) Representative images of
coronal sections including the dentate gyrus are shown in panel (a) of Sham selected in proestrous and ovariectomized (OVX) rats. KI67-
labeled cells are shown by arrows. Scale bar = 50 mm. Effect of OVX and acute stress on total number of KI67-positve cells in the dentate
gyrus (DG) (n = 4 for group) (b). Data represent the average of the number of Ki67-labeled cells (mean  S.E.M.). Holm—Sidack test,
*p  0.05; **p  0.01.

decline in the number of BrdU-labeled cells along the three only in the group of OVX rats. In addition, the number of BrdU
time points (2 h, 3 and 14 days after FS) that was not labeled cells were not different between 2 h, 3 and 14 days
statistically different from that shown by non-stressed after FS-exposure in OVX (three way ANOVA: time after stress
sham-rats (Fig. 3, panel b, white bars). In contrast, stress exposition F 2,35 = 2.71, ns), therefore the main stress effect
produced a drastic decrease of early cell survival in the DG was observed already 2 h after the stress and persisted for at
measured 2 h after a single 15-min FS session in OVX-rats. least 14 days.
This reduction was evident after comparison with the non- OVX per se increased 6-fold corticosterone levels as com-
stressed OVX-group (46%). (Fig. 3, panel b) and versus the pared with the basal values in sham-non stressed rats (Fig. 3,
sham-stressed group (63%) (Fig. 3 panel b). Data indicate panel c), such increase remains 2 h, 3 and 14 days after FS
that the absence of hormones causes a decrease in early ( p < 0.05). In addition, within OVX rats, stress produced a
survival of newborn cells. Accordingly the three-way ANOVA further increase of 1.7 in corticosterone levels. The pattern
revealed a significant main effect of endocrine condition, of changes in corticosterone levels between the different
(F 1,35 = 41.364, p < 0.001), and a significant interaction groups did not vary between 2 h, 3 and 14 days after stress. In
between endocrine condition and stress (F 1,35 = 5.772, line, the three way ANOVA revealed significant values for
p = 0.022). Interestingly, the groups sacrificed 3 and 14 days endocrine condition F 1,35 = 219.80, p < 0.001; for stress
after stress showed also a drastic decrease in cell survival F 1,35 = 9.31, p = 0.004 and their interaction condition 

Table 1 Effect of FS on cell proliferation at 3 or 14 days after stress exposition.

Condition Short-survival 3 days after Long-survival 14 days after


Acute stress
Sham
Without stress 1224.00  182.66 1012.00  155.30
With stress 1107.00  82.66 1180  155.30
OVX
Without stress 1024.80  162.38 996.00  109.81
With stress 758.00  149.14 842.40  120.29
The exposition to acute stress session did not modified cell proliferation in the gyrus dentate regardless of the endocrine condition. Data are
expressed as means  SEM.
1412 N.M. Vega-Rivera et al.

Figure 3 Effects of exposure to forced swimming (FS) on early-, short- and long-cell survival and on corticosterone levels in sham-
and ovariectomized-rats. Representative images of BrdU-labeled cells in the dentate gyrus are shown in panel (a). Scale bar = 50 mm.
Effect of a single exposure to FS on number of BrdU-labeled cells at 2 h, 3 and 14 days after FS exposition in the dentate gyrus in OVX and
sham rats with or without stress (b). Effect of a single exposure to FS on corticosterone levels at 2 h, 3, or 14 days after stress in OVX and
proestrous-rats (n = 4 for group) (c). Data represent the mean  standard error of the mean (SEM) of BrdU-labeled cells, corticosterone
levels, respectively. Holm—Sidack test, *p  0.05; **p  0.01.

stress F 1,5 = 12.83, p = 0.001, but not for the time of sacrifice 4. Discussion
F 3,35 = 1.54, ns.
As previously reported (Detke et al., 1997; Estrada- Ovariectomy per se did not change cell proliferation or
Camarena et al., 2008), a second exposure to FST resulted survival, but increased the corticosterone levels. A single
in an increased immobility (compared with those subjects forced swim session in OVX rats markedly reduced cell survi-
that were forced to swim only once) even when the events val at 2 h, 3 and 14 days, further augmented the corticoster-
were separated for 3 or 14 days after the first swim training one levels and promoted depressive-like behaviors, reflected
(110% and 102% increase, respectively; Fig. 4) (F 2,18 = 15.96, as an increased immobility. Such stress did not modify cell
p < 0.001). proliferation.
Stress by forced swimming decreases cell survival 1413

results since acute exposure to stressors, such as the domi-


nant-subordinate test and the resident-intruder test,
decreased cell proliferation using adult marmoset monkeys
and adult male rats (Gould et al., 1998; Tanapat et al., 2001;
Heine et al., 2004). These differences could be related to the
type of stressor, its duration, animal species and sex. Another
factor that contributes to explain these discrepancies is the
use of BrdU as a marker of cell proliferation. Thus, to study
cell proliferation various authors have used BrdU adminis-
tered 2 h before sacrifice (Gould et al., 1998; Lagunas et al.,
2010; Tanapat et al., 2001). Such manipulation, however,
labels cells in S-phase (proliferation) and in post-mitosis
Figure 4 Effects of exposure to forced swimming (FS) on (early survival) veiling specific effects on each stage of the
immobility behavior at 3 and 14 days after stress. Effect of neurogenic process. Specific experiments using different
OVX on immobility behavior in FST (n = 9 for group). White bar thymidine analogs to analyze multiple birth-dating cells
represent the animals without pre-test FS session (15 min) and populations (Llorens-Martin and Trejo, 2011) could help to
darkness bars represent to the animals exposed to pre-test FS clarify this point.
session. Data represent the number of counts of immobility Interestingly, 2 h after swim stress there was a drastic
behavior in 5-min test period. Holm—Sidack test, *p  0.05. decline in early cell survival evidenced by BrdU label. This
initial FS-induced decrease remained for 3 and 14 days,
indicating that the short and long survival of newly generated
4.1. Effect of ovariectomy per se on cells is also diminished. Similar effects have been reported in
proliferation and survival other studies using different acute stressors (Czeh et al.,
2002; Malberg and Duman, 2003; Thomas et al., 2007). The
The present study showed that ovariectomy per se did not decrease in the number of BrdU-labeled cells observed 3 and
alter cell proliferation or survival of newborn cells in the 14 days after FS is most likely the result of the initial decrease
hippocampus when compared with the sham proestrous rats. in early cell survival since no additional changes along time or
Several reports indicate that ovarian hormones regulate on cell proliferation, at any interval, were observed. The
adult neurogenesis (Barker and Galea, 2008), suggesting that finding that the FS-induced stress affected early-survival and
the absence of ovarian hormones affect the neurogenic not cell proliferation suggests that newborn cells are more
process. However, the present results showed that three sensitive to the effects of acute stress. This higher sensitivity
weeks after OVX there were no changes in cell proliferation of these cells could be related with the expression of both
or survival in the DG of the hippocampus. These results glucocorticoid- (GR) and mineralocorticoid receptors (MR) at
contrast with others showing a decrease in cell proliferation this time (Llorens-Martin et al., 2011; Garcia et al., 2004).
in rats one week after OVX (Banasr et al., 2001; Tanapat Various reports indicate that the elevation in corticosterone
et al., 1999, 2005). The difference in the results could rely on levels is a sign of stress and a negative regulator of some
the time of evaluation after OVX: one versus three weeks. aspects of neurogenesis (Cameron et al., 1998; Huang and
Interestingly, one week after OVX the hormonal milieu is Herbert, 2006). In this sense, it has been proposed that the
fluctuating due to ovarian suppression. For example, at this survival of newborn cells in the hippocampus is regulated by
time there are increases in FSH and LH accompanied by high glucocorticoid levels, accompanied by high levels of
oscillations in estradiol levels. Conversely, three weeks after their receptors (Wong and Herbert, 2006), particularly during
OVX, estradiol levels in the hippocampus are low and stable the first 9 days after the mitotic process (Wong and Herbert,
(Barker and Galea, 2010). There is evidence showing that the 2004).
estrogen deficiency, natural in aging rats or induced by OVX,
decreases the synaptic connectivity and reduces the dendri-
4.3. Effect of ovariectomy and acute stress on
tic arborization (Kataria et al., 2010), then OVX could affect
corticosterone levels
the synaptic neuronal plasticity rather than the neurogenic
process. Specific experiments should be done in order to
explore this idea. In the present study we found that ovariectomy per se
increased the corticosterone levels, which were further
augmented by a single forced swimming session. Some
4.2. Effect of acute stress on cell proliferation reports suggest that estrogens act as inhibitory factors of
and survival the HPA stress response (Wood and Shors, 1998; Young et al.,
2001). In fact, physiological doses of estradiol decrease the
In OVX rats a single swim session did not alter cell prolifera- adrenocorticotropic hormone (ACTH) response induced by
tion, evaluated using Ki67 at 2 h, 3 and 14 days after stress, restraint-stress (Young et al., 2001), and estrogen replace-
but drastically reduced cell survival, identified by using BrdU, ment therapy suppresses stress-related Fos-like immunola-
at the same intervals. The finding that FS did not affect cell beling induced by an emotional stressor (noise) and a physical
proliferation is consistent with previous studies showing that stressor (immune challenge by systemic interleukin-1b) in
acute exposure to a social dominance paradigm did not alter female rats (Dayas et al., 2000). In addition, in intact female
the cell proliferation rate of adult male rats (Thomas et al., rats subjected to stress, caused by food-restriction or dehy-
2007, 2006). However, other studies differ from the present dration-induced anorexia, a 40% decrease of estradiol was
1414 N.M. Vega-Rivera et al.

observed with a concomitant increase in corticosterone decreases the synaptic connectivity and reduces the dendri-
levels and anxiety-like behaviors (Jaimes-Hoy et al., tic arborization (Kataria et al., 2010), then, it is possible that
2008). Estradiol also induces an antidepressant-like effect the development of immobility behavior is related with both
in the FST (Estrada-Camarena et al., 2003), probably by a decrease in early survival of newborn cells and synaptic
modulating the HPA axis. Thus, it is possible that the absence plastic changes. All these alterations modify the function of
of ovarian hormones caused by OVX promotes the rats’ neuronal networks, which underlie depressive like behaviors
vulnerability to develop depressive-like behavior reflected (Airan et al., 2007).
as an increased immobility in the FST by activating the HPA A limitation of the present study is that we did not
axis in response to stress (Okada et al., 1997; Bekku et al., analyze the phenotype of newborn cells; hence we cannot
2006; Estrada-Camarena et al., 2011). ascertain conclusively the ratio of new-formed neurons to
A single FS session (15 min) produced higher corticoster- glia. However, recent work has revealed that in intact
one levels than those induced by other stressors such as female mice a single exposure to FS, applied one week after
immobilization, cold, and locomotion (Kirby et al., 1997). cell labeling, affects the survival of the cellular population
Furthermore, Bowers et al. (2008) compared the effect of 2- corresponding to immature new neurons (Llorens-Martin
min FS with 2 h of restriction and both stressors induced a et al., 2011).
marked increase in corticosterone levels, that may be Finally, these data demonstrate that a single episode of
responsible for the changes in the neurogenic process (Garcia stress induced by FS affects the behavior and reduces cell
et al., 2004). In support, present results showed a negative survival in the hippocampus, probably by increasing corti-
correlation between corticosterone levels and the number of costerone levels. Additionally, our data strongly suggest that
BrdU-labeled cells in the hippocampus after FS (r = 0.658, the depressive-like behavior observed in OVX-rats in the FST
p = 0.01) in OVX rats. Furthermore, in no OVX rats tested in and the impact of this type of stress on some aspects of
proestrus, no changes in corticosterone levels or in cell neurogenesis could be a consequence of a decrease in estro-
survival after stress were found, strongly suggesting that gen levels.
OVX increases the vulnerability to corticosterone on cell
survival in the hippocampus. Role of the funding sources
The long lasting (2 h—14 days) increase in corticosterone
levels after stress contrasts with previous results showing
Funding for this study was provided by CONACYT Grant
that after the cessation of the stressful event, corticosterone
104659 and 101316; and a studentship of CONACYT
increase returns to basal levels (Shishkina et al., 2010). One
(216658). The CONACYT had no further role in study design;
possible mechanism mediating such sustained increase could
in the collection, analysis and interpretation of data; in the
be related with the selective estrogens inhibition of the HPA
writing of the report; and in the decision to submit the paper
axis in PVN via the stimulation of ERb (Lund et al., 2006;
for publication.
Weiser and Handa, 2009). In line, the reduction in estradiol
levels by OVX decreases the ERb mRNA in some brain areas
(Jin et al., 2005; Barker and Galea, 2009). These evidences Conflict of interest
suggest that the absence of estrogens promote the sustained
activity of the HPA axis. Another possible explanation may Nelly Maritza Vega-Rivera, Alonso Fernández-Guasti, Gerardo
rely on the observation that the marked increase in corti- Ramirez-Rodriguez and Erika Estrada-Camarena have
costerone levels-induced by FST- reduces the sensitivity to received, except for income received from their primary
their receptors thereby decreasing their negative feedback employer, no financial support or compensation from any
(Rittenhouse et al., 2002). A combination of these two individual or corporate entity for research or professional and
mechanisms may explain the long lasting increase in corti- no financial holdings that could be perceived as constituting a
costerone levels after a single FS session. potential conflict of interest.

4.4. Are the changes in cell survival related with


Acknowledgements
depressive-like behaviors?
This work was supported by CONACYT grant No. CB-104659
and No. CB-101316. NMVR received a fellowship of CONACYT
Present data showed that a single forced swim session (216658). We also thank the technical support of Leonardo
induced a clear increase in immobility behavior 3 and 14 Ortiz-Lopez, Silvia Mejia Mauries and Mario Torres-Pérez.
days later that could be partly associated with the reduction
in the number of BrdU-labeled cells. It has been reported that
castration combined with chronic mild stress produces References
depressive-like behavior at the same time that decreases
proliferation and survival of new born cells and the expres- Airan, R.D., Meltzer, L.A., Roy, M., Gong, Y., Chen, H., Deisseroth, K.,
sion of neuroplastic protein polysialylated neural cell adhe- 2007. High-speed imaging reveals neurophysiological links to
behavior in an animal model of depression. Science 317, 819—
sion molecule in the hippocampus of male rats (Wainwright
823.
et al., 2011). Furthermore, emerging evidence shows that Andrade, S., Silveira, S.L., Gomez, R., Barros, H.M., Ribeiro, M.F.,
the reduction in synaptic plasticity and neuroplastic proteins 2007. Gender differences of acute and chronic administration of
contributes to develop a depressive phenotype in animal dehydroepiandrosterone in rats submitted to the forced swim-
models (Sairanen et al., 2007; Magarinos et al., 1996; Wain- ming test. Prog. Neuropsychopharmacol. Biol. Psychiatry 31,
wright et al., 2011). As mentioned before OVX alone 613—621.
Stress by forced swimming decreases cell survival 1415

Armario, A., Escorihuela, R.M., Nadal, R., 2008. Long-term neuro- reverses the decrease in hippocampal cell survival induced by
endocrine and behavioural effects of a single exposure to stress in chronic mild stress. Behav. Brain Res. 218, 121—128.
adult animals. Neurosci. Biobehav. Rev. 32, 1121—1135. Dalla, C., Antoniou, K., Drossopoulou, G., Xagoraris, M., Kokras, N.,
Banasr, M., Hery, M., Brezun, J.M., Daszuta, A., 2001. Serotonin Sfikakis, A., Papadopoulou-Daifoti, Z., 2005. Chronic mild stress
mediates oestrogen stimulation of cell proliferation in the adult impact: are females more vulnerable? Neuroscience 135 (3),
dentate gyrus. Eur. J. Neurosci. 14, 1417—1424. 703—714.
Barha, C.K., Brummelte, S., Lieblich, S.E., Galea, L.A., 2011. Chron- Dayas, C.V., Xu, Y., Buller, K.M., Day, T.A., 2000. Effects of chronic
ic restraint stress in adolescence differentially influences hypo- oestrogen replacement on stress-induced activation of hypotha-
thalamic-pituitary-adrenal axis function and adult hippocampal lamic—pituitary—adrenal axis control pathways. J. Neuroendo-
neurogenesis in male and female rats. Hippocampus 21, 1216— crinol. 12, 784—794.
1227. de Kloet, E.R., Joels, M., Holsboer, F., 2005. Stress and the brain:
Barker, J.M., Galea, L.A., 2008. Repeated estradiol administration from adaptation to disease. Nat. Rev. Neurosci. 6, 463—475.
alters different aspects of neurogenesis and cell death in the Detke, M.J., Johnson, J., Lucki, I., 1997. Acute and chronic antide-
hippocampus of female, but not male, rats. Neuroscience 152, pressant drug treatment in the rat forced swimming test model of
888—902. depression. Exp. Clin. Psychopharmacol. 5, 107—112.
Barker, J.M., Galea, L.A., 2009. Sex and regional differences in Duncan, G.E., Paul, I.A., Harden, T.K., Mueller, R.A., Stumpf, W.E.,
estradiol content in the prefrontal cortex, amygdala and hippo- Breese, G.R., 1985. Rapid down regulation of beta adrenergic
campus of adult male and female rats. Gen. Comp. Endocrinol. receptors by combining antidepressant drugs with forced swim: a
164 (October (1)), 77—84. model of antidepressant-induced neural adaptation. J. Pharma-
Barker, J.M., Galea, L.A., 2010. Males show stronger contextual fear col. Exp. Ther. 234, 402—408.
conditioning than females after context pre-exposure. Physiol. Estrada-Camarena, E., Fernandez-Guasti, A., Lopez-Rubalcava, C.,
Behav. 99, 82—90. 2003. Antidepressant-like effect of different estrogenic com-
Bekku, N., Yoshimura, H., Araki, H., 2006. Factors producing a pounds in the forced swimming test. Neuropsychopharmacology
menopausal depressive-like state in mice following ovariectomy. 28, 830—838.
Psychopharmacology (Berl.) 187, 170—180. Estrada-Camarena, E., Fernandez-Guasti, A., Lopez-Rubalcava, C.,
Belda, X., Fuentes, S., Nadal, R., Armario, A., 2008a. A single 2004. Interaction between estrogens and antidepressants in the
exposure to immobilization causes long-lasting pituitary—adrenal forced swimming test in rats. Psychopharmacology (Berl.) 173,
and behavioral sensitization to mild stressors. Horm. Behav. 54, 139—145.
654—661. Estrada-Camarena, E., Lopez-Rubalcava, C., Hernandez-Aragon, A.,
Belda, X., Rotllant, D., Fuentes, S., Delgado, R., Nadal, R., Armario, Mejia-Mauries, S., Picazo, O., 2011. Long-term ovariectomy mod-
A., 2008b. Exposure to severe stressors causes long-lasting dys- ulates the antidepressant-like action of estrogens, but not of
regulation of resting and stress-induced activation of the hypo- antidepressants. J. Psychopharmacol. 25, 1365—1377.
thalamic—pituitary—adrenal axis. Ann. N.Y. Acad. Sci. 1148, 165— Estrada-Camarena, E., Rivera, N.M., Berlanga, C., Fernandez-
173. Guasti, A., 2008. Reduction in the latency of action of antide-
Borsini, F., 1995. Role of the serotonergic system in the forced pressants by 17 beta-estradiol in the forced swimming test.
swimming test. Neurosci. Biobehav. Rev. 19, 377—395. Psychopharmacology (Berl.) 201, 351—360.
Bowers, S.L., Bilbo, S.D., Dhabhar, F.S., Nelson, R.J., 2008. Stressor- Frye, C.A., Walf, A.A., 2002. Changes in progesterone metabolites in
specific alterations in corticosterone and immune responses in the hippocampus can modulate open field and forced swim test
mice. Brain Behav. Immun. 22, 105—113. behavior of proestrous rats. Horm. Behav. 41, 306—315.
Cameron, H.A., Tanapat, P., Gould, E., 1998. Adrenal steroids and N- Garcia, A., Steiner, B., Kronenberg, G., Bick-Sander, A., Kemper-
methyl-D-aspartate receptor activation regulate neurogenesis in mann, G., 2004. Age-dependent expression of glucocorticoid- and
the dentate gyrus of adult rats through a common pathway. mineralocorticoid receptors on neural precursor cell populations
Neuroscience 82, 349—354. in the adult murine hippocampus. Aging Cell 3, 363—371.
Campbell, S., Macqueen, G., 2004. The role of the hippocampus in Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A., Fuchs, E., 1997.
the pathophysiology of major depression. J. Psychiatry Neurosci. Neurogenesis in the dentate gyrus of the adult tree shrew is
29, 417—426. regulated by psychosocial stress and NMDA receptor activation. J.
Caspi, A., Sugden, K., Moffitt, T.E., Taylor, A., Craig, I.W., Neurosci. 17, 2492—2498.
Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, Gould, E., Tanapat, P., 1999. Stress and hippocampal neurogenesis.
A., Poulton, R., 2003. Influence of life stress on depression: Biol. Psychiatry 46, 1472—1479.
moderation by a polymorphism in the 5-HTT gene. Science 301, Gould, E., Tanapat, P., McEwen, B.S., Flugge, G., Fuchs, E., 1998.
386—389. Proliferation of granule cell precursors in the dentate gyrus of
Connor, T.J., Song, C., Leonard, B.E., Anisman, H., Merali, Z., 1999. adult monkeys is diminished by stress. Proc. Natl. Acad. Sci.
Stressor-induced alterations in serotonergic activity in an animal U.S.A. 95, 3168—3171.
model of depression. Neuroreport 10, 523—528. Heim, C., Nemeroff, C.B., 1999. The impact of early adverse experi-
Consiglio, A.R., Ramos, A.L., Henriques, J.A., Picada, J.N., 2010. ences on brain systems involved in the pathophysiology of anxiety
DNA brain damage after stress in rats. Prog. Neuropsychophar- and affective disorders. Biol. Psychiatry 46, 1509—1522.
macol. Biol. Psychiatry 34, 652—656. Heine, V.M., Maslam, S., Zareno, J., Joels, M., Lucassen, P.J., 2004.
Cryan, J.F., Valentino, R.J., Lucki, I., 2005. Assessing substrates Suppressed proliferation and apoptotic changes in the rat dentate
underlying the behavioral effects of antidepressants using the gyrus after acute and chronic stress are reversible. Eur. J. Neu-
modified rat forced swimming test. Neurosci. Biobehav. Rev. 29, rosci. 19, 131—144.
547—569. Holmes, M.M., Galea, L.A., 2002. Defensive behavior and hippocam-
Czeh, B., Welt, T., Fischer, A.K., Erhardt, A., Schmitt, W., Muller, pal cell proliferation: differential modulation by naltrexone dur-
M.B., Toschi, N., Fuchs, E., Keck, M.E., 2002. Chronic psychoso- ing stress. Behav. Neurosci. 116, 160—168.
cial stress and concomitant repetitive transcranial magnetic Huang, G.J., Herbert, J., 2006. Stimulation of neurogenesis in the
stimulation: effects on stress hormone levels and adult hippo- hippocampus of the adult rat by fluoxetine requires rhythmic
campal neurogenesis. Biol. Psychiatry 52, 1057—1065. change in corticosterone. Biol. Psychiatry 59, 619—624.
Dagytė, G., Crescente, I., Postema, F., Seguin, L., Gabriel, C., Jaimes-Hoy, L., Joseph-Bravo, P., de Gortari, P., 2008. Differential
Mocaër, E., Boer, J.A., Koolhaas, J.M., 2011. Agomelatine response of TRHergic neurons of the hypothalamic paraventricular
1416 N.M. Vega-Rivera et al.

nucleus (PVN) in female animals submitted to food-restriction or 17beta-estradiol on the tail skin temperature and behavior in
dehydration-induced anorexia and cold exposure. Horm. Behav. the forced swimming test in rats. Jpn. J. Pharmacol. 73, 93—96.
53, 366—377. Porsolt, R.D., Bertin, A., Jalfre, M., 1977. Behavioral despair in mice:
Jayatissa, M.N., Bisgaard, C., Tingstrom, A., Papp, M., Wiborg, O., a primary screening test for antidepressants. Arch. Int. Pharma-
2006. Hippocampal cytogenesis correlates to escitalopram-medi- codyn. Ther. 229, 327—336.
ated recovery in a chronic mild stress rat model of depression. Plümpe, T., Ehninger, D., Steiner, B., Klempin, F., Jessberger, S.,
Neuropsychopharmacology 31, 2395—2404. Brandt, M., Römer, B., Rodriguez, G.R., Kronenberg, G., Kem-
Jin, M., Jin, F., Zhang, L., Chen, Z., Huang, H., 2005. Two estrogen permann, G., 2006. Variability of doublecortin-associated den-
replacement therapies differentially regulate expression of es- drite maturation in adult hippocampal neurogenesis is
trogen receptors alpha and beta in the hippocampus and cortex of independent of the regulation of precursor cell proliferation.
ovariectomized rat. Brain Res. Mol. Brain Res. 142, 107—114. BMC Neurosci. 7, 77—92.
Kataria, S., Varshney, M.K., Kumar, P., Dhar, P., Mehra, R.J., 2010. Ramirez-Rodriguez, G., Klempin, F., Babu, H., Benitez-King, G.,
Role of estrogen in regulation of morphology and synaptic con- Kempermann, G., 2009. Melatonin modulates cell survival of
nectivity in female rat subiculum. J. Anat. Soc. Indian 59, 144— new neurons in the hippocampus of adult mice. Neuropsycho-
149. pharmacology 34, 2180—2191.
Kempermann, G., Jessberger, S., Steiner, B., Kronenberg, G., 2004. Rittenhouse, P.A., Lopez-Rubalcava, C., Stanwood, G.D., Lucki, I.,
Milestones of neuronal development in the adult hippocampus. 2002. Amplified behavioral and endocrine responses to forced
Trends Neurosci. 27, 447—452. swim stress in the Wistar-Kyoto rat. Psychoneuroendocrinology
Kirby, L.G., Chou-Green, J.M., Davis, K., Lucki, I., 1995. The effects 27, 303—318.
of different stressors on extracellular 5-hydroxytryptamine and 5- Sairanen, M., O’Leary, O.F., Knuuttila, J.E., Castrén, E., 2007.
hydroxyindoleacetic acid. Brain Res. 760, 218—230. Chronic antidepressant treatment selectively increases expres-
Kirby, L.G., Lucki, I., 1997. Interaction between the forced swimming sion of plasticity-related proteins in the hippocampus and medial
test and fluoxetine treatment on extracellular 5-hydroxytrypta- prefrontal cortex of the rat. Neuroscience 144, 368—374.
mine and 5-hydroxyindoleacetic acid in the rat. J. Pharmacol. Sapolsky, R.M., 2004. Is impaired neurogenesis relevant to the
Exp. Ther. 282, 967—976. affective symptoms of depression? Biol. Psychiatry 56, 137—139.
Kronenberg, G., Reuter, K., Steiner, B., Brandt, M.D., Jessberger, Sarter, M., Turchi, J., 2002. Age- and dementia-associated impair-
S., Yamaguchi, M., Kempermann, G., 2003. Subpopulations of ments in divided attention: psychological constructs, animal
proliferating cells of the adult hippocampus respond differently models, and underlying neuronal mechanisms. Dement. Geriatr.
to physiologic neurogenic stimuli. J. Comp. Neurol. 467, 455— Cogn. Disord. 13, 46—58.
463. Scholzen, T., Gerdes, J., 2000. The Ki-67 protein: from the known and
Lagunas, N., Calmarza-Font, I., Diz-Chaves, Y., Garcia-Segura, L.M., the unknown. J. Cell. Physiol. 182, 311—322.
2010. Long-term ovariectomy enhances anxiety and depressive- Selye, H., 1976. The stress concept. Can. Med. Assoc. J. 115, 718.
like behaviors in mice submitted to chronic unpredictable stress. Sheline, Y.I., Sanghavi, M., Mintun, M.A., Gado, M.H., 1999. Depres-
Horm. Behav. 58, 786—791. sion duration but not age predicts hippocampal volume loss in
Llorens-Martin, M., Tejeda, G.S., Trejo, J.L., 2011. Antidepressant medically healthy women with recurrent major depression. J.
and proneurogenic influence of environmental enrichment in Neurosci. 19, 5034—5043.
mice: protective effects vs recovery. Neuropsychopharmacology Shishkina, G.T., Kalinina, T.S., Berezova, I.V., Bulygina, V.V., Dygalo,
36, 2460—2468. N.N., 2010. Resistance to the development of stress-induced
Llorens-Martin, Trejo, J., 2011. Mifepristone prevents stress-induced behavioral despair in the forced swim test associated with ele-
apoptosis in newborn neurons and increases AMPA receptor ex- vated hippocampal Bcl-xl expression. Behav. Brain Res. 213, 218—
pression in the dentate gyrus of C57/BL6 mice. PLoS One 6, 224.
e28376. Tanapat, P., Hastings, N.B., Gould, E., 2005. Ovarian steroids influ-
Lund, T.D., Hinds, L.R., Handa, R.J., 2006. The androgen 5alpha- ence cell proliferation in the dentate gyrus of the adult female rat
dihydrotestosterone and its metabolite 5alpha-androstan-3beta, in a dose- and time-dependent manner. J. Comp. Neurol. 481,
17beta-diol inhibit the hypothalamo-pituitary-adrenal response 252—265.
to stress by acting through estrogen receptor beta-expressing Tanapat, P., Hastings, N.B., Reeves, A.J., Gould, E., 1999. Estrogen
neurons in the hypothalamus. J. Neurosci. 26, 1448—1456. stimulates a transient increase in the number of new neurons in
Malberg, J.E., Duman, R.S., 2003. Cell proliferation in adult hippo- the dentate gyrus of the adult female rat. J. Neurosci. 19, 5792—
campus is decreased by inescapable stress: reversal by fluoxetine 5801.
treatment. Neuropsychopharmacology 28, 1562—1571. Tanapat, P., Hastings, N.B., Rydel, T.A., Galea, L.A., Gould, E., 2001.
McEwen, B.S., 2004. Protection and damage from acute and chronic Exposure to fox odor inhibits cell proliferation in the hippocampus
stress: allostasis and allostatic overload and relevance to the of adult rats via an adrenal hormone-dependent mechanism. J.
pathophysiology of psychiatric disorders. Ann. N.Y. Acad. Sci. Comp. Neurol. 437, 496—504.
1032, 1—7. Thomas, R.M., Hotsenpiller, G., Peterson, D.A., 2007. Acute psy-
Magarinos, A.M., McEwen, B.S., Flugge, G., Fuchs, E., 1996. Chronic chosocial stress reduces cell survival in adult hippocampal
psychosocial stress causes apical dendritic atrophy of hippocam- neurogenesis without altering proliferation. J. Neurosci. 27,
pal CA3 pyramidal neurons in subordinate tree shrews. J. Neu- 2734—2743.
rosci. 16, 3534—3540. Thomas, R.M., Urban, J.H., Peterson, D.A., 2006. Acute exposure to
Morilak, D.A., Barrera, G., Echevarria, D.J., Garcia, A.S., Hernan- predator odor elicits a robust increase in corticosterone and a
dez, A., Ma, S., Petre, C.O., 2005. Role of brain norepinephrine in decrease in activity without altering proliferation in the adult rat
the behavioral response to stress. Prog. Neuropsychopharmacol. hippocampus. Exp. Neurol. 201, 308—315.
Biol. Psychiatry 29, 1214—1224. Veena, J., Srikumar, B.N., Raju, T.R., Shankaranarayana Rao, B.S.,
Nestler, E.J., Gould, E., Manji, H., Buncan, M., Duman, R.S., Gre- 2009. Exposure to enriched environment restores the survival and
shenfeld, H.K., Hen, R., Koester, S., Lederhendler, I., Meaney, M., differentiation of new born cells in the hippocampus and ame-
et al., 2002. Preclinical models: status of basic research in liorates depressive symptoms in chronically stressed rats. Neu-
depression. Biol. Psychiatry 52, 503—528. rosci. Lett. 455, 178—182.
Okada, M., Hayashi, N., Kometani, M., Nakao, K., Inukai, T., 1997. Wainwright, S.R., Lieblich, S.E., Galea, L.A., 2011. Hypogonadism
Influences of ovariectomy and continuous replacement of predisposes males to the development of behavioural and
Stress by forced swimming decreases cell survival 1417

neuroplastic depressive phenotypes. Psychoneuroendocrinology adrenal axis via estrogen receptor alpha within the hypothala-
36, 1327—1341. mus. Neuroscience 159, 883—895.
Wong, E.Y., Herbert, J., 2006. Raised circulating corticosterone Wood, G.E., Shors, T.J., 1998. Stress facilitates classical conditioning
inhibits neuronal differentiation of progenitor cells in the adult in males, but impairs classical conditioning in females through
hippocampus. Neuroscience 137, 83—92. activational effects of ovarian hormones. Proc. Natl. Acad. Sci.
Wong, E.Y., Herbert, J., 2004. The corticoid environment: a deter- U.S.A. 95, 4066—4071.
mining factor for neural progenitors’ survival in the adult hippo- Young, E.A., Altemus, M., Parkison, V., Shastry, S., 2001. Effects of
campus. Eur. J. Neurosci. 20, 2491—2498. estrogen antagonists and agonists on the ACTH response to
Weiser, M.J., Handa, R.J., 2009. Estrogen impairs glucocorticoid restraint stress in female rats. Neuropsychopharmacology 25,
dependent negative feedback on the hypothalamic-pituitary- 881—891.

Вам также может понравиться