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Behavioural Brain Research 250 (2013) 81– 90
Contents lists available at SciVerse ScienceDirect
Behavioural Brain Research
j ourna l h om epage: www.elsev ier .com/ locate /bbr
esearch report
hronic unpredictable mild stress alters an anxiety-related defensive
esponse, Fos immunoreactivity and hippocampal adult neurogenesis
.S. de Andradea, I.C. Céspedesa, R.O. Abrãoa, T.B. dos Santosa, L. Dinizb, L.R.G. Brittob,
.C. Spadari-Bratfischa, D. Ortolania, L. Melo-Thomasa, R.C.B. da Silvaa, M.B. Vianaa,∗
Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil
Institute of Biomedical Sciences, Department of Physiology and Biophysics, University of São Paulo (USP), São Paulo, SP, Brazil
 i g h l i g h t s
Chronic stress facilitates elevated T-maze avoidance, not altering escape.
Avoidance increases Fos-ir in the cortex, amygdala, hippocampus.
Escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus.
Chronic stress activates avoidance but not escape-related structures.
Chronic stress decreases doublecortin cells and increases corticosterone levels.
a r t i c l e i n f o
rticle history:
eceived 12 March 2013
eceived in revised form 16 April 2013
ccepted 20 April 2013
vailable online 30 April 2013
eywords:
npredictable chronic mild stress
levated T-maze
os immunoreactivity
eurogenesis
orticosterone
a b s t r a c t
Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint.
Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an impor-
tant factor influencing these results, we investigated the effects of unpredictable chronic mild stress
(UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir)
was used to map areas activated by stress exposure in response to ETM avoidance and escape perfor-
mance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of
migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum
levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape.
In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus
(dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueduc-
tal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were
observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dor-
sal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were
observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased
the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone
serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of
specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the
hypothalamus–pituitary–adrenal axis and decreases hippocampal adult neurogenesis.
. Introduction
Stress was originally defined by Hans Selye [1] as a non-specific
esponse of the body to any demand for change. The stimulus
hat initiates the stress response, the so-called stressor, is aversive
nd potentially harmful to the organism and may either elicit
∗ Corresponding author at: Av. Ana Costa, 95, 11060-001 Santos, SP, Brazil.
el.: +55 11 38683203; fax: +55 11 38683203.
E-mail addresses: mviana@unifesp.br, milenabv@gmail.com (M.B. Viana).
166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
ttp://dx.doi.org/10.1016/j.bbr.2013.04.031
© 2013 Elsevier B.V. All rights reserved.
an acute or a chronic stress response [2]. Stress responses include
a series of physiological alterations, one of the most important
being the activation of the hypothalamus–pituitary–adrenal axis
(HPA) [3,4] with release of stress hormones in the blood stream.
Furthermore, exposure to stress also results in a series of important
behavioral changes, i.e. inhibition of exploratory activity, aversive
conditioning and anxiety-related responses. Although responses to
short-term or acute stress are adaptive and prepare the organism
to deal with an infection or injury, the stress response might be
potentially hazardous if the stressor is too intense or continuous.
Thus, chronic stress has been associated with a greater risk for
dx.doi.org/10.1016/j.bbr.2013.04.031
http://www.sciencedirect.com/science/journal/01664328
http://www.elsevier.com/locate/bbr
http://crossmark.dyndns.org/dialog/?doi=10.1016/j.bbr.2013.04.031&domain=pdf
mailto:mviana@unifesp.br
mailto:milenabv@gmail.com
dx.doi.org/10.1016/j.bbr.2013.04.031
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2 J.S. de Andrade et al. / Behaviou
ifferent clinical conditions, including psychiatric disorders, such
s depression and anxiety [5].
To better study the consequences of stress on behavior, animal
odels have been developed. Nevertheless, results from studies
esting anxiety-related reactions induced by prior exposure to
tress are quite ambiguous. While some authors have reported
ncreases in anxiety, others have found no effects or even a decrease
n anxiety-related responses after exposure to different kinds of
tressors [6–15].
In a prior study [16] we investigated the consequences of previ-
us exposure to acute restraint in the elevated T-maze (ETM) model
f anxiety (for details on this experimental model see [17–21]). The
TM was developed as an attempt to establish a correspondence
etween specific behavioral tasks and different subtypes of anx-
ety disorders. The model allows the measurement, in the same
at, of two defensive responses: avoidance and escape. Based on
xtensive behavioral and pharmacological validations these defen-
ive responses have been related in terms of psychopathology to
eneralized anxiety and panic disorders, respectively [17,19–21].
orroborating previous observations [22] our results showed that
ats exposed to acute restraint displayed anxiogenic-like behavior,
videnced by facilitation of ETM avoidance responses. In contrast,
TM escape was unaltered by restraint. Since these tasks seem to
ctivate distinct sets of brain structures, we further suggested that
he differences observed were due to particularities in the neurobi-
logical mechanisms, which modulated these defensive responses
16].
However, another possible explanation for the effects observed
16] might rely on the magnitude of the stressor used. It is pos-
ible, for instance, that acute restraint was not strong enough to
lter ETM escape. In this sense it remained to be investigated how
hronic stress alters ETM avoidance and escape responses. Thus, in
he present study, animals were either unstressed or exposed for
 weeks to an unpredictable chronic mild stress paradigm (UCMS)
nd subsequently tested in the avoidance or in the escape task of the
TM (Experiment 1). The UCMS model presents good face validity
nd has been broadly used to investigate some of the physiological
nd behavioral consequences of chronic stress [14,23–26]. Briefly,
n this test, rodents are exposed to a variety of relatively mild stress-
rs (i.e. restriction, inversion of the light–dark cycles, water/food
eprivation, damp sawdust) intermittently, usually for two to three
eeks [14,23–26].
The behavior of unstressed and stressed animals submitted to
he ETM was furthercompared to the behavior of animals exposed
o an enclosed T-maze, an apparatus already used in our earlier
tudy [16] and that possesses all three arms enclosed by walls. As
reviously shown, exposure of animals to this apparatus controls
he effects of handling by the experimenter, the novelty of the expo-
ition and the locomotor activity of the animals while exploring the
aze [16].
In order to understand the neurobiological mechanisms respon-
ible for the behavioral effects obtained, in the present study Fos
rotein immunoreactivity (Fos-ir) was also used to map areas acti-
ated by previous UCMS exposure (Experiment 2). For comparison
easons, the same regions previously analyzed in response to acute
tress [16] were investigated in the present study. As formerly
oted, the product of the immediate-early gene c-Fos is expressed
hroughout the brain in response to a variety of tasks, thus making
t a powerful instrument to study intracellular responses of neurons
o different stimuli [27]. Since previous evidence shows that stress
s a potent inhibitor of adult neurogenesis (for a review see [28]) and
aking into account that adult neurogenesis seems to be involved in
everal behavioral alterations, including certain types of anxiety-
elated reactions [29], we also evaluated the effects of UCMS on
he number of cells expressing the marker of migrating neurob-
asts doublecortin (DCX) in the dorsal and ventral hippocampus
ain Research 250 (2013) 81– 90
(Experiment 3). It has been previously shown that quantification of
DCX-expressing cells provides an accurate measurement of adult
neurogenesis [30]. In order to verify the effectiveness of the UCMS
procedure in activating the HPA axis, corticosterone serum levels
were measured in an independent group of unstressed and stressed
animals (Experiment 4).
2. Materials and methods
2.1. Animals
One day after their arrival to the laboratory, male Wistar rats (250–300 g) were
assigned either to the unstressed or to the UCMS group. Unstressed animals were
housed in groups of 4–6 per cage (50 cm × 60 cm × 22 cm). Room temperature was
maintained at 22 ± 1 ◦C with lights on from 0700 to 1900 h. Food and water were
freely available throughout the experiments. UCMS animals were housed under
the same conditions except during the periods they were exposed to some of the
mild stressors (i.e. food and water restriction/deprivation, inversion of the light/dark
cycle). All procedures were conducted in conformity with the Brazilian Society of
Neuroscience and Behavior Guidelines for Care and Use of Laboratory Animals,
which are also in compliance with international laws and policies. All efforts were
made to minimize animal suffering.
2.2. Apparatus
The ETM was made of wood and had three arms of equal dimensions
(50 cm × 12 cm). One arm, enclosed by walls of 40 cm high, was perpendicular to
two opposed open arms. To avoid falls, a 1 cm high Plexiglas rim surrounded the
open arms. The whole apparatus was elevated 50 cm above the floor.
The enclosed T-maze used as control for the effects of handling, novelty and
locomotion had all three arms (50 cm × 12 cm) surrounded by 40 cm high wooden
walls.
Luminosity at the level of the mazes’ arms was 60 lux. After each experimental
session, the mazes were cleaned with a 10% ethanol solution.
2.3. Unpredictable chronic mild stress (UCMS) procedure
The UCMS protocol was performed as described previously [23,24] (see Table 1).
Rats were subjected to different kinds of stressors, which varied from day to day,
for 14 consecutive days. There were a total of seven stressors: (1) periods of
1 h of restraint in a small acrylic cylinder (16 cm × 7.5 cm × 7.0 cm), as previously
described [23,24]; (2) lights on overnight; (3) food deprivation overnight, followed
by 2 h access to restricted food (resulting from the scattering of pellets of 45 mg in
the cage); (4) water deprivation overnight, followed by 1 h contact with an empty
water bottle; (5) food restriction for 2 h; (6) damp sawdust overnight; (7) inversion
of the light/dark cycle from Friday night to Monday morning.
2.4. Elevated T-maze (ETM) and enclosed T-maze procedure
Twenty-four hours after the end of the UCMS protocol (or 15 days after their
arrival to the laboratory for unstressed rats), all animals were pre-exposed to one of
the open arms of the ETM for 30 min. A wooden barrier mounted on the border of the
open arm, between the maze’s central area and the arm’s proximal end, isolated this
arm from the rest of the maze. It has been shown that this pre-exposure procedure
shortens escape latencies, rendering it more sensitive to the effects of treatment
[20,21,31].
On the next day, independent groups of unstressed and stressed animals (N = 8
per treatment group) were tested in the avoidance or escape tasks of the ETM or in
the enclosed T-maze.
For ETM avoidance measurements, each rat was placed at the end of the enclosed
arm, and the time taken to exit this arm with all four paws was recorded (baseline
latency). The same measurement was then repeated in two subsequent trials (avoid-
ance 1 and 2) at 30 s intervals. The time rats remain in the enclosed arm, in a second
and third exposure to this arm, usually increases due to these animals’ innate fears
to height and openness [17,18,20,32]. For escape measurements, rats were placed
on the open arm on which they had been pre-exposed and the latency to leave this
arm with the four paws was recorded for three consecutive times (escape 1, 2 and
3), again at 30 s intertrial intervals. A cutoff time of 300 s was established for the
avoidance and escape latencies.
The same procedure described above was employed for the enclosed T-maze,
except that animals were placed either at the distal end of the stem arm or at the
distal end of the transversal arm of the maze.
2.5. Fos protein immunohistochemistry
At 2 h after the tests with the ETM or enclosed T-maze, six randomly chosen
animals from each of the treatment groups described above were anesthetized
with ketamine/xylazine 2:1 (1 ml/kg) and perfused with ≈100 ml of 0.9% saline
for approximately 1 min, followed by 500–700 ml of 4% formaldehyde (from
J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90 83
Table 1
Unpredictable chronic mild stress (UCMS) protocol.
Period Monday Tuesday Wednesday Thursday Friday
Morning Restraint (30 min) Restraint (30 min) Foodrestricition for
2 h
Empty water bottle
(60 min);
Restraint (30 min)
Restraint (30 min)
Afternoon Restraint (30 min) Restraint (30 min) Restraint (30 min) Restraint (30 min)
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Night Lights on during the night Water/food
deprivation
overnight
araformaldehyde heated to 60–65 ◦C) and H2O at 4 ◦C, pH 9.5, for approximately
5 min. The brains were post-fixed for 1 h in the same fixative, plus 20% sucrose,
t 4 ◦C. Regularly spaced series (5 × 1-in-5) of 30 �m-thick frozen sections were
ut in the coronal plane, collected in ethylene glycol-based cryoprotectant solution
nd stored at −20 ◦C for later determination of Fos-ir. Fos-ir cells were identified by
sing a polyclonal anti-serum raised in rabbit against synthetic human Fos (anti-Fos,
:20,000; Oncogene, Cambridge, MA, USA). Immunohistochemistry was performed
sing a conventional avidin–biotin immunoperoxidase protocol [33] and Vectastain
lite reagents (Vector Laboratories, Burlingame, CA, USA). Tissue was pretreated
ith hydrogen peroxide (0.3%; Sigma, St. Louis, MO, USA) before addition of the pri-
ary antibody to quench endogenous peroxidase activity in the tissue. The reaction
ith diaminobenzidine (DAB) (0.05%; Sigma) was amplified using nickel ammonium
ulfate. The sections were then mounted on gelatin-coated slides, allowed to dry for
pproximately 18 h and counterstained with 0.25% thionin in order to visualize the
abeled cells within the borders of each nucleus.
The same structures previously analyzed [16] were included in the presenttudy. We quantified Fos-ir cells in sections, having as reference the following AP
oordinates [34]: Bregmas: Hippocampus: +2.28 mm; cingulate cortex: +1.68 mm;
eptum: +0.96 mm; amygdala: −2.92 mm; anterior hypothalamus: −1.80 mm;
orso and ventromedial hypothalamus: −3.12 mm; dorsal and median raphe nuclei:
7.56 mm; periaqueductal gray: −7.68 mm; locus ceruleus: −9.72 mm, under
right-field illumination using the Image-Pro Plus software (Media Cybernetics, Sil-
er Spring, MD, USA). Sections were analyzed by an observer blind to the treatment
onditions. Cells were considered Fos immunoreactive if their nuclei contained dark,
unctate gray-black immunolabeling, and were counted using constant minimum
nd maximum OD and object size criteria, which were validated with visual counts.
.6. DCX
Two independent groups of animals (N = 6 per group) were used for DCX
mmunoreactivity: an unstressed group (that was kept under standard laboratory
onditions during 15 days before euthanasia) and a group submitted to the UCMS
rotocol. These animals were not tested in the ETM or in the enclosed T-maze.
n the 15th day after their arrival to the laboratory (or one day after UCMS expo-
ure for stressed rats) animals were intra-cardiacally perfused as described above.
ections containing the ventral (−5.2 to −6.7 mm) and dorsal (−1.8 to −5.2 mm) por-
ions of the dentate gyrus [35] were preincubated for one hour in a solution of 10%
ormal donkey serum (NDS) (Jackson ImmunoResearch Lab, USA) diluted in 0.1 M
hosphate buffer (PB) containing 0.3% Triton X-100. Subsequently, sections were
ncubated with goat polyclonal primary antibody (1:100, goat anti-doublecortin,
anta Cruz Biotechnology Inc., USA). Forty-eight hours later, sections were incubated
ith a secondary antibody (1:200, donkey anti-goat, Jackson ImmunoResearch Lab.,
SA) in 0.1 M PB containing 0.3% Triton X-100 for two hours, followed by a two-hour
ncubation with the ABC complex (ABC, ABC Elite Kit, Vector Labs, USA). Sections
ere then reacted in 0.05% DAB in a 0.03% hydrogen peroxidase solution with 0.1 M
B and mounted on gelatinized slides, intensified by 0.05% osmium tetroxide in
ig. 1. Left panel: Latencies (mean ± SEM) taken by unstressed rats to withdraw from t
levated T-maze in three consecutive trials (L1, 2 and 3). Right panel: Latencies (mean ± SE
avoidance) or open (escape) arms of the elevated T-maze in three consecutive trials (L1, 
n the unstressed group (ANOVA followed by the Tukey test).
ater deprivation
ernight
Damp sawdust
overnight
Inversion of the
light/darkcycle over
the weekend
water, dried and covered with a coverslip using Permount (Fisher, USA). For each ani-
mal, DCX-positive cells (cell bodies) from two pre-determined areas (623.000 �m2)
of the subgranular zone of the dentate gyrus (ventral and dorsal hippocampus),
created with the help of Image Pro Plus 6.0 (Media Cybernetics Inc., USA), were
manually counted.
2.7. Blood sampling
Another group of rats (N = 5) was submitted to the UCMS protocol and twenty-
four hours later euthanized by decapitation. Trunk blood was collected (from 8:00
to 10:00 a.m.) and centrifuged for 20 min at 4000 rpm, at 4 ◦C. Aliquots of serum
were then removed and stored at −20 ◦C until assayed. Samples from one ani-
mal were discarded due to storage problems. Serum corticosterone concentrations
were determined by enzyme immunoassay (ELISA) using a commercial kit (Assay
Designs, Inc., Ann Arbor, USA). Unstressed animals (N = 5) were left undisturbed
under standard laboratory conditions, for 14 days. On the 15th day, these animals
were also euthanized and their trunk blood collected and analyzed as described for
stressed animals.
2.8. Statistical analysis
To normalize data, behavioral measurements were submitted to a reciprocal
transform. A three-factor design was then applied, with the testing protocol and
task as the independent factors (factor 1 (testing protocol): no stress × UCMS; fac-
tor 2 (task): enclosed T-maze, avoidance or escape) and trials as the dependent factor
(latencies 1, 2 and 3). In case of significant effects, group comparisons were made by
the Tukey post hoc test. For Fos-ir, data was also analyzed by a three-factor design,
with testing protocol and task as the independent factors, and region as the depend-
ent factor. In case of significant results, the Tukey post hoc test was used to analyze
differences in each region. For DCX and corticosterone measurements, unpaired Stu-
dent’s t-test was used to evaluate significant differences between unstressed and
stressed animals. Values of P ≤ 0.05 were considered significant.
3. Results
3.1. Behavioral measurements
Fig. 1 shows the behavior of unstressed (left panel) and stressed
(right panel) rats submitted to the avoidance or escape tasks of the
ETM or to the enclosed T-maze (control group). Three factor ANOVA
did not show a significant effect of trials [F(2,84) = 0.240; P > 0.05]
or a significant testing protocol by task interaction [F(2,42) = 1.36;
P > 0.05]. On the other hand, three factor ANOVA showed a
he enclosed T-maze or from the closed (avoidance) or open (escape) arms of the
M) taken by stressed rats to withdraw from the enclosed T-maze or from the closed
2 and 3). N = 8 animals per treatment group. *P < 0.05 compared with the same trial
84 J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90
Table 2
Average number (mean ± SEM) of Fos immunoreactive cells in pre-determined areas of different brain regions after exposure to unpredictable mild chronic stress and T-maze
performance.
Regions No stress Stress
Control Avoidance Escape Control Avoidance Escape
CC 60.83 ± 10.88 149.5 ± 9.0*,# 68.3 ± 6.8 80.33 ± 14.09 333.2 ± 18.1*,#,+ 217.7 ± 12.9*,#,+
DLSEP 34.83 ± 4.99 39.2 ± 2.1 39.3 ± 2.2 43.50 ± 7.58 62.3 ± 6.6 54.5 ± 9.5
INTSEP 35.50 ± 5.15 41.0 ± 4.3 34.7 ± 3.8 55.17 ± 5.91 62.0 ± 3.3#,+ 43.0 ± 3.4
VLSEP 49.67 ± 10.43 69.5 ± 14.8 47.7 ± 6.0 67.00 ± 10.20 134.8 ± 25.7*,#,+ 61.2 ± 6.6
Hip. CA 13.00 ± 4.37 15.2 ± 2.9 14.3 ± 1.3 19.00 ± 4.47 37.5 ± 4.4*,#,+ 16.0 ± 1.5
Hip. DG 4.83 ± 0.79 30.8 ± 3.9*,# 15.7 ± 1.6 7.00 ± 1.15 44.2 ± 3.6*,#,+ 16.0 ± 3.4
ANH 31.17 ± 4.67 30.5 ± 5.4 22.5 ± 2.3 33.83 ± 5.03 90.0 ± 9.2*,#,+ 50.5 ± 5.1+
DMH 43.83 ± 4.92 88.5 ± 13.2 59.7 ± 3.5 65.67 ± 8.79 169.2 ± 18.1*,#,+ 90.8 ± 9.3
VMH 34.17 ± 5.52 35.2 ± 6.3 46.7 ± 7.7 55.67 ± 4.09 111.2 ± 17.2*,#,+ 55.0 ± 5.3
MeAMG 14.83 ± 1.30 30.7 ± 7.2 18.7 ± 4.7 20.00 ± 1.44 58.7 ± 3.2*,#,+ 24.5 ± 2.3
CeAMG 7.67 ± 0.80 13.8 ± 2.0 13.5 ± 2.0 8.67 ± 0.95 28.7 ± 2.5*,#,+ 14.2 ± 1.7
BmAMG 14.67 ± 2.08 45.5 ± 6.5*,# 25.0 ± 4.3 18.50 ± 3.12 71.7 ± 4.3*,#,+ 31.2 ± 3.3
BlAMG 30.33 ± 4.77 49.2 ± 8.6 19.3 ± 3.9 39.67 ± 6.90 74.3 ± 9.8*,# 26.0 ± 5.3
LAMG 23.83 ± 4.00 61.3 ± 12.0 18.7 ± 2.1 24.83 ± 5.42 106.2 ± 19.7*,#,+ 33.3 ± 2.9
DmPAG 25.33 ± 3.81 29.6 ± 1.2 44.7 ± 9.3 28.17 ± 5.46 33.8 ± 3.6 80.8 ± 8.1*,#,+
DlPAG 29.00 ± 6.16 29.2 ± 1.6 53.2 ± 6.1*,# 34.83 ± 7.46 44.2 ± 4.9 70.3 ± 4.1*,#
LPAG 26.83 ± 2.99 27.5 ± 2.8 30.8 ± 4.8 29.67 ± 6.91 33.0 ± 1.8 50.5 ± 3.0*,#,+
VlPAG 35.00 ± 3.94 45.7 ± 2.2 50.5 ± 5.2 36.33 ± 8.57 47.0 ± 2.5 80.8 ± 7.2*,#,+
DRN 18.83 ± 2.65 19.3 ± 2.6 12.3 ± 1.9 18.17 ± 3.11 56.5 ± 5.9*,#,+ 37.3 ± 3.7#,+
MRN 24.83 ± 1.76 39.7 ± 4.7 26.5 ± 4.2 24.33 ± 1.69 84.0 ± 9.4*,#,+ 38.2 ± 4.2
LC 19.00 ± 1.15 9.2 ± 1.3 36.7 ± 7.2*,# 21.50 ± 3.26 19.5 ± 1.9 40.7 ± 2.7*,#
CC, cingulate cortex; DLSEP, dorsolateral septum; INTSEP, intermediate septum; VLSEP, ventrolateral septum; Hip. CA, hippocampus (Cornus Ammon); HIP. DG, hippocampus
(dentate gyrus); ANH, anterior hypothalamus; DMH, dorsomedial hypothalamus; VMH, ventromedial hypothalamus; MeAMG, medial amygdala; CeAMG, central amygdala;
BmAMG, basomedial amygdala; BlAMG, basolateral amygdala; LAMG, lateral amygdala; DmPAG, dorsomedial periaqueductal gray; DlPAG, dorsolateral periaqueductal gray;
LPAG, lateral periaqueductal gray; VlPAG, ventrolateral periaqueductal gray; DRN, dorsal raphe nucleus; MRN, median raphe nucleus; LC, locus coeruleus..
by the
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* P < 0.05, with respect to control in the same group (stress or no stress).
# P < 0.05, with respect to the other task (avoidance or escape) in the same group
+ P < 0.05, with respect to the same task in the no stress group (ANOVA followed 
ignificant effect of trials by testing protocol [F(2,84) = 8.91;
 < 0.001], trials by task [F(4,84) = 28.56; P < 0.001], trials by test-
ng protocol by task [F(4,84) = 6.52; P < 0.001], testing protocol
F(1,42) = 10.38; P < 0.01], and task [F(2,42) = 11.97; P < 0.001]. The
ukey post hoc test showed that latencies 2 and 3 were significantly
reater for stressed animals submitted to the avoidance task when
ompared to unstressed animals (P < 0.05).
.2. Fos protein immunoreactivity
The results obtained with quantitative analyses of Fos-ir in the
tudied brain regions after performance of unstressed and stressed
nimals in the ETM are summarized in Table 2. Three-factor ANOVA
howed a significant effect of region [F(20,560) = 110.40; P < 0.001],
egion by testing protocol [F(20,560) = 19.08; P < 0.001], region by
ask [F(40,560) = 19.67; P < 0.001], region by testing protocol by
ask [F(40,560) = 5.32; P < 0.001], testing protocol [F(1,28) = 101.44;
 < 0.001], task [F(2,28) = 69.71; P < 0.001], and testing protocol by
ask [F(2,28) = 16.49; P < 0.001].
The Tukey post hoc test showed that unstressed animals
ubmitted to the avoidance task presented increases in Fos-ir
n the cingulate cortex (Fig. 2A), hippocampus (dentate gyrus)
Fig. 2B) and basomedial amygdala (Fig. 2C) when compared to the
nstressed control and escape groups (P < 0.05). On the other hand,
nstressed animals submitted to the escape task showed increases
n Fos-ir in the dorsolateral periaqueductal gray (Fig. 2D) and locus
eruleus (Fig. 2E), when compared to the unstressed control and
voidance groups (P < 0.05).
The Tukey post hoc test also showed that stressed animals
ubmitted to the avoidance task presented significant increases
n Fos-ir in the cingulate cortex (Fig. 2A), ventrolateral septum
Fig. 3A), hippocampus (cornus Ammon) (Fig. 3B), hippocampus
dentate gyrus) (Fig. 2B), anterior (Fig. 3C), dorsomedial (Fig. 3D)
nd ventromedial hypothalamus (Fig. 3E), medial (Fig. 4A), central
Fig. 4B), basomedial (Fig. 2C) and lateral amygdala (Fig. 4C), dorsal
Fig. 4D) and median raphe nucleus (Fig. 4E), when compared to
 Tukey test).
unstressed avoidance animals and to stressed control and escape
rats (P < 0.05). Stressed animals submitted to the avoidance task
showed significant increases in Fos-ir in the basolateral amygdala
(Fig. 5A) when compared to stressed control and escape rats. Also
stressed avoidance animals showed significant increases in Fos-
ir in the intermediate lateral septum (Fig. 5B), when compared to
unstressed avoidance and to stressed escape animals (P < 0.05).
Additionally, the Tukey post hoc test showed that stressed
animals submitted to the escape task showed significant increases
in Fos-ir in the cingulate cortex (Fig. 2A), dorsomedial (Fig. 5C),
lateral (Fig. 5D) and ventrolateral periaqueductal gray (Fig. 5E),
when compared to unstressed escape animals and to stressed con-
trol and avoidance rats (P < 0.05). Stressed animals submitted to
the escape task also showed increases in Fos-ir in the dorsolateral
periaqueductal gray (Fig. 2D) and locus ceruleus (Fig. 2E), when
compared to stressed control and avoidance animals; increases in
Fos-ir in the dorsal raphe (Fig. 4D), when compared to unstressed
escape and stressed avoidance animals; and increases in Fos-ir in
the anterior hypothalamus (Fig. 3C), when compared to unstressed
escape animals.
3.3. DCX measurements
Fig. 6 shows the average number per mm2 of DCX-positive
cells (cell bodies) in the dorsal (upper panel) and ventral (lower
panel) hippocampus of unstressed and stressed animals. Unpaired
Student’s t-test showed that the UCMS protocol decreased the num-
ber of DCX-positive cells in both regions: dorsal (T(7.56) = 13.58;
P < 0.001) (Fig. 7A) and ventral hippocampus (T(7.20) = 22.00;
P < 0.001) (Fig. 7B).
3.4. Corticosterone measurements
Fig. 8 shows corticosterone serum levels for unstressed and
stressed animals. Unpaired Student’s t-test showed that stressed
J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90 85
Fig. 2. Photomicrographs of Fos immunoreactive cells (dark spots) in coronal sections through brain regions with significant increases in Fos immunoreactivity after
performance by unstressed and stressed control (enclosed T-maze) and elevated T-maze animals (avoidance and escape). (A) Cingulate cortex, (B) hippocampus (dentate
g ruleus
c
a
e
4
E
u
p
p
F
I
i
h
m
s
t
l
p
d
v
e
o
S
a
s
yrus), (C) basomedial amygdala, (D) dorsolateral periaqueductal gray, (E) locus ce
allosum; **cerebral aqueduct; ***fourth ventricle.
nimals showed a significant increase in serum corticosterone lev-
ls [T(7) = −4.90; P = 0.002].
. Discussion
The present results showed that the UCMS protocol facilitated
TM avoidance responses, an anxiogenic effect. ETM escape was
naltered by pre-exposure to this chronic stress model. Avoidance
erformance increased Fos-ir in the cingulate cortex, hippocam-
us (dentate gyrus) and basomedial amygdala. Escape increased
os-ir in the dorsolateral periaqueductal gray and locus ceruleus.
n stressed animals submitted to ETM avoidance, increases in Fos-
r were observed in the cingulate cortex, ventrolateral septum,
ippocampus, anterior, dorso and ventromedial hypothalamus,
edial, basomedial, basolateral, lateral and central amygdala, dor-
al and median raphe nucleus. In stressed animals submitted
o ETM escape, increases in Fos-ir were observed in the cingu-
ate cortex, dorsomedial, dorsolateral, lateral and ventrolateral
eriaqueductal gray and locus ceruleus. Also, UCMS exposure
ecreased the number of DCX-positive cells in the dorsal and
entral hippocampus and increased corticosterone serum lev-
ls.
The behavioral data obtained are in agreement with a previ-
us study from our laboratory performed with acute restraint [16].
imilar to UCMS exposure, acute restraint selectively altered ETM
voidance. Results observed with other types of stressors (i.e. forced
wim, escapable footshocks) also pointed to the same direction,
. Scale bar: 300 �m; (A) Magnification, 100×; (B–E) Magnification, 200×. *Corpus
suggesting that ETM escape is more resistant than ETM avoidance
to the effects of pre-exposure to different kinds of stressors [22].
In fact, the only stressor capable of altering ETM escape was expo-
sure to inescapable footshocks [22], what led the authors of this
particular study to propose that controllability was a determinant
factor for the results observed. Nevertheless, the stressors to which
the animals were exposed in the present study were neither con-
trollable nor predictable. Thus, it is still not clear why most of the
stressors used did not alter ETM escape. It is possible that, as acute
restraint, forced swim and escapable footshocks, the UCMS proto-
col was just not intense enough to alter this fear-related response.
Aside from that, it has also been previously demonstrated that
different types of stressors present a distinct neurobiological “sig-
nature” [36]. This could explain the ambiguous results observed
after pre-exposure to stress in anxiety models [6–15]. In this sense,
it may be also suggested that both acute restraint and UCMS (and
also possibly forced swim and escapable footshocks) share neuro-
biological mechanisms that are likely akin.
Indeed this possibility seems to be confirmed by the results
observed with Fos-ir. Corroborating previous observations [16],
unstressed animals submitted to the avoidance task showed
increases in Fos-ir in the cingulate cortex, in the dentate gyrus
of the hippocampal formation and in the basomedial amygdala.
Other structures that were activated by acute restraint [16] (i.e.
the dorsomedial hypothalamus and the dorsal raphe) presented
resultsmarginal to statistical significance (P = 0.065 and P = 0.07,
respectively). On the other hand, differently from acute restraint
86 J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90
Fig. 3. Photomicrographs of Fos immunoreactive cells (dark spots) in coronal sections through brain regions with significant increases in Fos immunoreactivity after
performance by unstressed and stressed control (enclosed T-maze) and elevated T-maze animals (avoidance and escape). (A) Ventrolateral septum; (B) hippocampus
( entro
M
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n
S
p
7
b
t
t
l
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p
i
p
t
w
b
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f
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s
[
t
[
p
t
cornus Ammon); (C) anterior hypothalamus; (D) dorsomedial hypothalamus; (E) v
agnification, 200×. *Lateral ventricle; **third ventricle.
16], the basolateral amygdala and the anterior hypothalamus did
ot present significant increases in Fos-ir, as compared to control.
ince, in the present study, unstressed animals remained for a
rolonged period of time in the laboratory (2 weeks versus the usual
 days) before behavioral measurements, the differences in Fos-ir
etween unstressed animals in the two studies may be indicative of
he effects of habituation. It is important to emphasize, for instance,
hat animals used in our study come from a breeding center
ocated approximately 80 km away from our laboratory. As pre-
iously pointed out, although after adequate transportation most
hysiological changes take 1–7 days to normalize, secondary phys-
ological outcomes resulting from transportation are difficult to
redict [37].
Analysis of Fos-ir also showed that exposure to the UCMS pro-
ocol increased the activation of several brain structures involved
ith the modulation of anxiety-related responses, what possi-
ly explains the anxiogenic effects observed. The septum and the
ippocampus are the main structures of the so-called “Behav-
oral Inhibition System” [38–40], activated when the animal is
aced with a threat, which involves approach-avoidance conflict.
t has been previously pointed out that the components of the
epto-hippocampal system directly influence the cingulate cortex
38–40]. In a similar way, all areas of the cingulate cortex project
o the entorhinal cortex, thus influencing the prefrontal cortex
38–40]. In this last regard it is interesting to point out that a
revious study has shown that lesions of the medial prefrontal cor-
ex impaired ETM avoidance performance, without altering escape
medial hypothalamus. Scale bar: 300 �m; (B) Magnification, 100×; (A, C, D and E)
responses [41]. Similar results were also obtained after benzodi-
azepine administration into the lateral septum [42].
The amygdala has also long been implicated with the mod-
ulation of anxiety-related responses [43–45]. Corroborating our
present observations, previous studies have shown that the
inhibition of the basolateral complex (composed of the lat-
eral, basomedial and basolateral amygdala) by administration of
GABA/benzodiazepine agonists impairs ETM avoidance responses,
while not altering escape [46,47]. In a similar way, administration
into the medial amygdala of the GABAA agonist muscimol or of
the benzodiazepine midazolam impaired ETM avoidance [48], in
this case also altering escape responses. At last, although up to
our knowledge the effects of the pharmacological manipulation
of the central amygdala in ETM defensive responses have not yet
been tested, previous results have shown that this region occu-
pies a special position in the organization of stress responses (for
a review see [36]). From the central amygdala, projections are sent
to motor, autonomic and neuroendocrine systems implicated with
the expression of anxiety and fear-related behavior [49].
As the amygdala, almost all of the medial hypothalamic nuclei
participate in the organization of responses to different kinds of
stressors [36]. The anterior hypothalamus, together with the dorso
and ventromedial hypothalamus are part of the hypothalamic sys-
tem implicated with the modulation of defensive responses, and
particularly involved with the integration of innate responses to
environmental threats [50–55]. In a previous study, we showed that
both the anterior and dorsomedial hypothalamus were activated
J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90 87
Fig. 4. Photomicrographs of Fos immunoreactive cells (dark spots) in coronal sections through brain regions with significant increases in Fos immunoreactivity after
p -maze
l ion, 20
b
t
r
l
m
b
m
m
i
F
v
o
s
o
l
p
(
h
o
v
t
t
t
[
t
t
erformance by unstressed and stressed control (enclosed T-maze) and elevated T
ateral amydala; (D) dorsal raphe; (E) median raphe. Scale bar: 300 �m; Magnificat
y ETM avoidance [16]. Furthermore, the pharmacological inhibi-
ion of the ventromedial hypothalamus by GABA/benzodiazepine
eceptors activation decreases avoidance latencies [56], an anxio-
ytic response, which also relates this hypothalamic nucleus to the
odulation of approach-avoidance conflict behavior.
It is important to mention that all the structures activated
y pre-exposure to the UCMS protocol in ETM avoidance ani-
als receive serotonergic innervation arising from the dorsal and
edian raphe. The two nuclei also presented significant increases
n Fos-ir induced by UCMS exposure. Although in the present study
os-ir was not assessed specifically in serotonergic neurons, obser-
ations from a previous study [57] showed high co-localization
f Fos and serotonin immunoreactivities, suggesting increases in
erotonergic neuronal activity after exposure to UCMS. Indeed,
ver-activation of serotonin neurons has also been associated to
earned helplessness behavior [58]. In light of these results, it is
ossible to suggest that serotonin innervation to forebrain regions
cingulate cortex, septum, hippocampus amygdala and medial
ypothalamus) is strongly involved with the increases in anxiety
bserved after UCMS exposure.
The dorsal raphe was also one of the main structures acti-
ated by acute restraint [16]. This observation led us to suggest
hat serotonin release in forebrain structures was also critical for
he anxiogenic effects obtained with acute stress exposure [16],
hus corroborating the hypothesis proposed by Deakin and Graeff
59–61]. According to these authors, the medial forebrain bundle
hat originates in the dorsal raphe facilitates avoidance behaviors
hat occur in response to potential or distal threat, by releasing
 animals (avoidance and escape). (A) Medial amygdala; (B) central amygdala; (C)
0×. *Optic tract; **cerebral aqueduct.
serotonin in forebrain structures, such as the cingulate cortex and
the amygdala.
The median raphe, however, was not significantly activated by
acute restraint [16]. Since Deakin and Graeff [59–61] further sug-
gested that the pathway connecting the median raphe nucleus to
the hippocampus promotes resistance to chronic (not acute) stress,
it remained necessary to investigate how chronic stress inter-
fered with the neuronal pattern of activation of both structures.
Our present results corroborate Deakin and Graeff’s hypothesis,
and implicate the median raphe and the hippocampal formation
(cornus Ammon and dentate gyrus) in the modulation of behav-
ioral responses to chronic stress. In fact, stimulation of serotonin
neurons within the median raphe induces anxiogenic effects in
ETM avoidance, without altering escape responses [62], an effect
blocked by intra-dorsal hippocampus administration of serotonin
1A antagonists. Furthermore, it has also been previously shown
that exposure to another type of chronic stressor, social separa-
tion, increases anxiogenic behavior in the elevated plus-maze and
serotonin turnover in both regions [62]. These behavioral and neu-
rochemical effects were reverted by treatment with the tricyclic
antidepressant imipramine [62].
The results observed with unstressed animals submitted to the
escape task were identical to the ones previously obtained with
acute restraint [16]. When compared to unstressed control and
avoidance rats, escapeanimals showed increases in Fos-ir in the
dorsolateral column of the periaqueductal gray and in the locus
ceruleus, regions that seem to modulate fear (or panic) related-
responses [47,63–66]. Thus, unlike what was observed for the
88 J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90
Fig. 5. Photomicrographs of Fos immunoreactive cells (dark spots) in coronal sections through brain regions with significant increases in Fos immunoreactivity after
performance by unstressed and stressed control (enclosed T-maze) and elevated T-maze animals (avoidance and escape). (A) Basolateral amygdala; (B) intermediate lateral
s ) vent
a
a
l
t
o
p
r
s
s
r
c
t
a
T
i
t
s
d
o
p
t
p
t
E
o
eptum; (C) dorsomedial periaqueductal gray; (D) lateral periaqueductal gray; (E
queduct.
voidance animals, to spend a prolonged period of time under the
aboratory conditions before testing does not seem to interfere with
he neurobiological mechanisms responsible for the performance
f ETM escape.
Furthermore, in animals submitted to the escape task, the UCMS
rotocol increased Fos-ir in fewer brain regions. In fact, although
egions that have traditionally been related to the organization of
tress responses (for a review see [36]) were activated, the two
tructures that seem to be critical for the performance of escape
esponses – the dorsolateral periaqueductal gray and the locus
eruleus – did not significantly alter their activity in response to
he UCMS protocol (that is, the values obtained by stressed animals
re not significantly differently from those of unstressed animals).
his might explain why UCMS did not alter ETM escape responses,
n other words, why UCMS was not panicogenic.
The results observed in ETM avoidance also seem to be related
o the inhibition of migrating neuroblasts induced by UCMS expo-
ure. UCMS decreased the number of DCX-positive cells, both in the
orsal and ventral hippocampus. This data corroborates previous
bservations [57] showing that chronic mild stress decreases cell
roliferation and neurogenesis in the subgranular zone of the den-
ate gyrus. These results are also similar to previous observations
erformed by our research group after chronic treatment with cor-
icosterone [67]. In this particular study, corticosterone facilitated
TM avoidance, while at the same time decreasing the number
f DCX-positive cells in the dentate gyrus [67,68]. Together, these
rolateral periaqueductal gray. Scale bar: 300 �m; Magnification, 200×. *Cerebral
observations also seem to suggest that a decrease in neurogenesis
in the hippocampus is not crucial for escape performance. In other
words, that ETM avoidance and escape responses recruit different
neural substrates.
The increases in serum corticosterone observed in animals
submitted to the UCMS protocol corroborate previous evidence
[69], and suggest that, as expected, chronic stress exposure effec-
tively activates the HPA axis, what is possibly responsible for the
decreases in neuronal migration observed in the hippocampus, as
indicated by previous studies [28,30,69]. Similar increases in cor-
ticosterone serum levels were observed with acute restraint [16].
As mentioned [16], these results also seem to suggest that escape
responses – in clinical terms associated to panic [17,19–21] – are
unrelated to the activation of the HPA axis. In fact, it has been pro-
posed on the basis of experimental and clinical evidence [70–75],
the while anticipatory anxiety and generalized anxiety disorder
are associated to the activation of both the HPA and the sym-
pathoadrenal axes, a panic attack is an atypical emergency fear
reaction related to major sympathetic activation, but with little
effect on the HPA axis. Our data seem to corroborate this propo-
sition.
In conclusion, our results suggest that the anxiogenic effects
observed after chronic stress exposure are related to the activation
of specific neurobiological circuits that modulate anxiety, in par-
ticular forebrain structures (cingulate cortex, septo-hippocampal
formation, amygdala) that receive serotonin innervation from
J.S. de Andrade et al. / Behavioural Brain Research 250 (2013) 81– 90 89
Fig. 6. Number of DCX-immunoreactive cells (cell bodies) per mm2 in the dor-
sal (upper panel) and ventral (lower panel) hippocampus of animals unstressed
a
S
t
r
t
r
c
o
i
r
p
F
s
m
N
nd stressed. Bars represent mean ± SEM for 6 animals/group. *P < 0.05, unpaired
tudent’s t-test.
he dorsal and median raphe nuclei. On the other hand, escape
esponses – which are related, in particular, to the activation of
he dorsolateral periaqueductal gray and locus ceruleus – are more
esistant to the effects of UCMS, possibly because these same neuro-
ircuitries are not significantly altered in response to stress. These
bservations have important implications for a better understand-
ng of the effects of stress exposure on anxiety and fear-related
esponses, and for the physiopathology of generalized anxiety and
anic disorder.
ig. 7. Photomicrographs of DCX-immunoreactive cells (dark spots) in coronal
ections of the dorsal and ventral hippocampus for unstressed and stressed ani-
als. (A) Dorsal hippocampus; (B) ventral hippocampus. Magnification, 100×.
 = 6 animals/group. Scale bar: 300 �m.
[
[
[
[
[
[
[
Fig. 8. Corticosterone serum measurements (ng/ml) for unstressed and stressed ani-
mals submitted to the UCMS protocol. Bars represent mean ± SEM for 5 unstressed
animals and 4 stressed animals. P < 0.05, unpaired Student’s t-test.
Acknowledgements
This work was supported by CNPq and FAPESP (grant numbers:
2011/17471-0 and 2011/01409-4), Brazil.
References
[1] Selye H. A syndrome produced by diverse nocuous agents. Nature 1936;138:32.
[2] Steckler T. The neuropsychology of stress. In: Stecker T, Kalin NH, Reul JMHM,
editors. Handbook of stress and the brain: the neurobiology of stress. Amster-
dam: Elsevier Academic Press; 2005. p. 25–42.
[3] Garcia-Bueno B, Caso JR, Leza JC. Stress as a neuroinflammatory condition in
brain: damaging and protective mechanisms. Neuroscience and Biobehavioral
Reviews 2008;32(6):1136–51.
[4] Joels M, Baram TZ. The neuro-symphony of stress. Nature Reviews Neuro-
science 2009;10:459–66.
[5] Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, et al.
Chronic stress, glucocorticoid receptor resistance, inflammation, and disease
risk. Proceedings of the National Academy of Sciences of the United States of
America 2012;109(16):5995–9.
[6] van Dijken HH, Mos J, van der Heyden JA, Tilders FJ. Characterization of stress-
induced long-term behavioural changes in rats: evidence in favor of anxiety.
Physiology and Behavior 1992;52(5):945–51.
[7] Smagin GN, Harris RB, Ryan DH. Corticotropin-releasing factor receptor antag-
onist infused into the locus ceruleus attenuates immobilization stress-induced
defensive withdrawal in rats. Neuroscience Letters 1996;220(3):167–70.
[8] Rössler AS, Joubert C, Chapouthier G. Chronic mild stress alleviates anx-
ious behaviour in female mice in two situation. Behavioural Processes
2000;49(3):163–5.
[9] Harris RB, Zhou J, Shi M, Redmann S, Mynatt RL, Ryan DH. Over expression
of agouti protein and stress responsiveness in mice. Physiology and Behavior
2001;73(4):599–608.
10] Harris RB, Mitchell TD, Simpson J, Redmann Jr SM, Youngblood BD, Ryan DH.
Weight loss in rats exposed to repeated acute restraint stress is independent
of energy or leptin status. American Journal of Physiology – Regulatory, Inte-
grative and Comparative Physiology 2002;282(1):R77–88.
11] Harris RB, Gu H, Mitchell TD, Endale L, Russo M, Ryan DH. Increased glucocor-
ticoid response to a novel stress in rats that have been restrained. Physiology
and Behavior 2004;81(4):557–68.
12] Griebel G, Simiand J, Serradeil-Le Gal C, Wagnon J, Pascal M, Scatton B, et al.
Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin
V1b receptor antagonist, SSR 149415, suggest an innovative approach for the
treatment of stress-related disorders.Proceedings of the National Academy of
Sciences of the United States of America 2002;99(9):6370–5.
13] Morilak DA, Cecchi M, Khoshbouei H. Interactions of norepinephrine and
galanin in the central amygdala and lateral bed nucleus of the stria ter-
minalis modulate the behavioral response to acute stress. Life Sciences
2003;73(6):715–26.
14] Mineur YS, Belzung C, Crusio WE. Effects of unpredictable chronic mild stress
on anxiety and depression-like behavior in mice. Behavioural Brain Research
2006;175(1):43–50.
15] Schweizer MC, Henniger MS, Sillaber I. Chronic mild stress (CMS) in mice: of
anhedonia, ‘anomalous anxiolysis’ and activity. PLoS One 2009;4(1):e4326.
16] de Andrade JS, Abrão RO, Céspedes IC, Garcia MC, Nascimento JOG, Spadari-
Bratfisch RC, et al. Acute restraint differently alters defensive responses
and fos immunoreactivity in the rat brain. Behavioural Brain Research
2012;232(1):20–9.
http://refhub.elsevier.com/S0166-4328(13)00231-3/sbref0005
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http://refhub.elsevier.com/S0166-4328(13)00231-3/sbref0060
http://refhub.elsevier.com/S0166-4328(13)00231-3/sbref0060
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0 J.S. de Andrade et al. / Behaviou
17] Graeff FG, Viana MB, Tomaz C. The elevated T maze, a new experimental model
of anxiety and memory: effect of diazepam. Brazilian Journal of Medical and
Biological Research 1993;26(1):67–70.
18] Viana MB, Tomaz CAB, Graeff FG. The elevated T-maze: a new animal
model of anxiety and memory. Pharmacology Biochemistry and Behavior
1994;49:549–54.
19] Graeff FG, Netto CF, Zangrossi H. The elevated T-maze as an experimental model
of anxiety. Neuroscience and Biobehavioral Reviews 1998;23(2):237–46.
20] Teixeira RC, Zangrossi H, Graeff FG. Behavioral effects of acute and chronic
imipramine in the elevated T maze model of anxiety. Pharmacology Biochem-
istry and Behavior 2000;65(4):571–6.
21] Poltronieri SC, Zangrossi Jr H, Viana MB. Antipanic-like effect of serotonin
reuptake inhibitors in the elevated T-maze. Behavioural Brain Research
2003;147(1–2):185–92.
22] Vicente MA, Biojone C, Zangrossi Jr H, Guimarães FS, Joca SR. Distinct behav-
ioral consequences of stress models of depression in the elevated T-maze.
Behavioural Brain Research 2011;225(2):590–5.
23] Moreau JL, Borgulya J, Jenck F, Martin JR. Tolcapone: a potential new antidepres-
sant detected in a novel animal model of depression. Behavioural Pharmacology
1994;5(3):344–50.
24] Moreau JL, Bourson A, Jenck F, Martin JR, Mortas P. Curative effects of the atyp-
ical antidepressant mianserin in the chronic mild stress-induced anhedonia
model of depression. Journal of Psychiatry and Neuroscience 1994;19(1):51–6.
25] Willner P, Moreau JL, Nielsen CK, Papp M, Sluzewska A. Decreased hedonic
responsiveness following chronic mild stress is not secondary to loss of body
weight. Physiology and Behavior 1996;60(1):129–34.
26] Pothion S, Bizot JC, Trovero F, Belzung C. Strain differences in sucrose preference
and in the consequences of unpredictable chronic mild stress. Behavioural Brain
Research 2004;155(1):135–46.
27] Hale MW, Bouwknecht JA, Spiga F, Shekhar A, Lowry CA. Exposure to high- and
low-light conditions in an open-field test of anxiety increases c-Fos expres-
sion in specific subdivisions of the rat basolateral amygdaloid complex. Brain
Research Bulletin 2006;71(1–3):174–82.
28] Krugers HJ, Lucassen PJ, Karst H, Joëls M. Chronic stress effects on hippocampal
structure and synaptic function: relevance for depression and normalization by
anti-glucocorticoid treatment. Frontiers in Synaptic Neuroscience 2010;2:24.
29] Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV, et al. Adult
hippocampal neurogenesis is involved in anxiety-related behaviors. Molecular
Psychiatry 2009;14:959–67.
30] Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner
N, et al. Doublecortin expression levels in adult brainreflect neurogenesis.
European Journal of Neuroscience 2005;21(1):1–14.
31] Sena LM, Bueno C, Pobbe RL, Andrade TG, Zangrossi Jr H, Viana MB.
The dorsal raphe nucleus exerts opposed control on generalized anxiety
and panic-related defensive responses in rats. Behavioural Brain Research
2003;142(1–2):125–33.
32] Graeff FG, Zangrossi Jr H. Animal models of anxiety. In: D’Haenen H, Den Boer
JA, Willner P, editors. Biological psychiatry. London: John Wiley & Sons; 2002.
p. 879–93.
33] Hsu SM, Raine L. Protein A, avidin, and biotin in immunohistochemistry. Journal
of Histochemistry and Cytochemistry 1981;29:1349–53.
34] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Amsterdam:
Elsevier Academic Press; 2007.
35] Brummelte S, Galea LA. Chronic high corticosterone reduces neurogen-
esis in the dentate gyrus of adult male and female rats. Neuroscience
2010;168(3):680–90.
36] Pacák K, Palkovits M. Stressor specificity of central neuroendocrine
responses: implications for stress-related disorders. Endocrine Reviews
2001;22(4):502–48.
37] Orbenier JA, Baldwin RL. Establishing an appropriate period of acclimatization
following transportation of laboratory animals. ILAR Journal 2006;47(4):364–9.
38] Gray JA. The neuropsychology of anxiety: an enquiry into functions of the septo-
hippocampal system. Oxford: Oxford University Press; 1982.
39] McNaughton N, Corr PJ. A two-dimensional neuropsychology of defense:
fear/anxiety and defensive distance. Neuroscience and Biobehavioral Reviews
2004;28:285–305.
40] Gray JA, McNaughton N. The neuropsychology of anxiety: an enquiry into the
functions of the septo-hippocampal system. 2nd ed. Oxford: Oxford University
Press; 2001.
41] Blanco E, Castilla-Ortega E, Miranda R, Begega A, Aguirre JA, Arias JL, et al. Effects
of medial prefrontal cortex lesions on anxiety-like behaviour in restrained and
non-restrained rats. Behavioural Brain Research 2009;201(2):338–42.
42] Viana Mde B, Zangrossi Jr H, Onusic GM. 5-HT1A receptors of the lateral septum
regulate inhibitory avoidance but not escape behavior in rats. Pharmacology
Biochemistry and Behavior 2008;89(3):360–6.
43] Ledoux JE. Fear and the brain: where have we been, and where are we going?
Biological Psychiatry 1998;44:1229–38.
44] Ledoux JE. Emotion circuits in the brain. Annual Review of Neuroscience
2000;23:155–84.
45] Shin LM, Liberzon I. The neurocircuitry of fear, stress and anxiety disorders.
Neuropsychopharmacology 2010;35(1):169–91.
46] Zangrossi Jr H, Viana MB, Graeff FG. Anxiolytic effect of intra-amygdala injection
of midazolam and 8-hydroxy-2-(di-n-propylamino)tetralin in the elevated T-
maze. European Journal of Pharmacology 1999;369(3):267–70.
47] Bueno CH, Zangrossi Jr H, Viana MB. The inactivation of the basolateral nucleus
of the rat amygdala has an anxiolytic effect in the elevated T-maze and
[
ain Research 250 (2013) 81– 90
light/dark transition tests. Brazilian Journal of Medical and Biological Research
2005;38(11):1697–701.
48] Herdade KC, Strauss CV, Zangrossi Júnior H, Viana MB. Effects of medial amyg-
dala inactivation on a panic-related behavior. Behavioural Brain Research
2006;172(2):316–23.
49] Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, et al. Amyg-
dala circuitry mediating reversible and bidirectional control of anxiety. Nature
2011;471(7338):358–62.
50] Hess WR, Brugger M. Das subkortikale Zentrum der affektiven abwehrreack-
tion. Helvetica Physiologica et Pharmacologica Acta 1943;1:33–52.
51] Fernandez de Molina A, Hunsperger RW. Organization of the subcortical sys-
tem governing defense and flight reactions in the cat. Journal of Physiology
1962;160:200–13.
52] Silveira MC, Graeff FG. Defense reaction elicited by microinjection of kainic
acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor
agonist. Behavioral and Neural Biology 1992;57(3):226–32.
53] Schmitt P, Di Scala G, Brandao ML, Karli P. Behavioral effects of microinjec-
tions of SR 95103, a new GABA-A antagonist, into the medial hypothalamus
or the mesencephalic central gray. European Journal of Pharmacology
1985;117(2):149–58, 5.
54] Bailey TW, Dimicco JA. Chemical stimulation of the dorsomedial hypothala-
mus elevates plasma ACTH in conscious rats. American Journal of Physiology –
Regulatory, Integrative and Comparative Physiology 2001;280(1):R8–15.
55] Canteras N. The medial hypothalamic defensive system: hodological organi-
zation and functional implications. Pharmacology Biochemistry and Behavior
2002;71:481–91.
56] Bueno CH, Zangrossi Jr H, Viana MB. GABA/benzodiazepine receptors in
the ventromedial hypothalamic nucleus regulate both anxiety and panic-
related defensive responses in the elevated T-maze. Brain Research Bulletin
2007;74(1–3):134–41.
57] Elizalde N, García-García AL, Totterdell S, Gendive N, Venzala E, Ramirez MJ,
et al. Sustained stress-induced changes in mice as a model for chronic depres-
sion. Psychopharmacology 2010;210(3):393–406.
58] Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal
cortex determines how stressor controllability affects behavior and dorsal
raphe nucleus. Nature Neuroscience 2005;8(3):365–71.
59] Deakin JFW, Graeff FG. 5-HT and mechanisms of defence. Journal of Psychophar-
macology 1991;5:305–15.
60] Graeff FG, Guimarães FS, De Andrade TG, Deakin JF. Role of 5-HT in
stress, anxiety, and depression. Pharmacology Biochemistry and Behavior
1996;54(1):129–41.
61] Graeff FG, Zangrossi Jr H. The dual role of serotonin in defense and the mode of
action of antidepressants on generalized anxiety and panic disorders. Central
Nervous System Agents in Medicinal Chemistry 2010;10(3):207–17.
62] dos Santos L, de Andrade TG, Graeff FG. Social separation and diazepam with-
drawal increase anxiety in the elevated plus-maze and serotonin turnover
in the median raphe and hippocampus. Journal of Psychopharmacology
2010;24(5):725–31.
63] Redmond Jr DE. The possible role of locus ceruleus noradrenergic activity in
anxiety-panic. Clinical Neuropharmacology 1986;9(4):40–2.
64] Graeff FG. Neurotransmitters in the periaqueductal gray and animal models of
panic anxiety. In: Briley M, File SE, editors. New concepts in anxiety. London:
MacMillan; 1991. p. 288–312.
65] Fanselow MS. Neural organization of the behaviour system responsible for fear.
Psychological Bulletin Review 1994;1:429–38.
66] Jenck F, Moreau JL, Martin JR. Dorsal periaqueductal gray-induced aversion as a
simulation of panic anxiety: elements of face and predictive validity. Psychiatry
Research 1995;57:181–91.
67] Diniz L, Dos Reis BB, de Castro GM, Medalha CC, Viana MB. Effects of
chronic corticosterone and imipramine administration on panic and anxiety-
related responses. Brazilian Journal of Medical and Biological Research
2011;44(10):1048–53.
68] Diniz L, dos Santos TB, Britto LR, Céspedes IC, Garcia MC, Spadari-Bratfisch
RC, et al. Effects of chronic treatment with corticosterone and imipramine on
fos immunoreactivity and adult hippocampal neurogenesis. Behavioural Brain
Research 2013;238:170–7.
69] Bachis A, Cruz MI, Nosheny RL, Mocchetti I. Chronic unpredictable stress
promotes neuronal apoptosis in the cerebral cortex. Neuroscience Letters
2008;442(2):104–8.
70] Klein DF. False suffocation alarms, spontaneous panics, and related conditions,
an integrative hypothesis. Archives of General Psychiatry 1993;50(4):306–17.
71] Coplan JD, Pine D, Papp L, Martinez J, Cooper T, Rosenblum LA, et al. Uncoupling
of the noradrenergic-hypothalamic–pituitary–adrenal axis in panic disorder
patients. Neuropsychopharmacology 1995;13(1):65–73.
72] Graeff FG. Anxiety, panic and the hypothalamic–pituitary–adrenal axis. Revista
Brasileira de Psiquiatria 2007;29(Suppl. 1):S3–6.
73] Graeff FG, Garcia-Leal C, Del-Ben CM, Guimarães FS. Does the panic attack acti-
vate the hypothalamic–pituitary–adrenal axis? Anais da Academia Brasileira
de Ciencias 2005;77(3):477–91.
74] Terleph TA, Klein RG, Roberson-Nay R,Mannuzza S, Moulton III JL, Wolde-
hawariat G, et al. Stress responsivity and HPA axis activity in juveniles: results
from a home-based CO2 inhalation study. American Journal of Psychiatry
2006;163(4):738–40.
75] van Duinen MA, Schruers KR, Maes M, Griez EJ. CO2 challenge induced HPA
axis activation in panic. International Journal of Neuropsychopharmacology
2007;10(6):797–804.
http://refhub.elsevier.com/S0166-4328(13)00231-3/sbref0085
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	Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult...
	1 Introduction
	2 Materials and methods
	2.1 Animals
	2.2 Apparatus
	2.3 Unpredictable chronic mild stress (UCMS) procedure
	2.4 Elevated T-maze (ETM) and enclosed T-maze procedure
	2.5 Fos protein immunohistochemistry
	2.6 DCX
	2.7 Blood sampling
	2.8 Statistical analysis
	3 Results
	3.1 Behavioral measurements
	3.2 Fos protein immunoreactivity
	3.3 DCX measurements
	3.4 Corticosterone measurements
	4 Discussion
	Acknowledgements
	References