Psychoneuroendocrinology (2012) 37, 1531—1545
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
Psychosocial animal model of PTSD produces
a long-lasting traumatic memory, an increase
in general anxiety and PTSD-like glucocorticoid
abnormalities
Phillip R. Zoladz a, Monika Fleshner b, David M. Diamond c,d,*
a
Department of Psychology & Sociology, Ohio Northern University, Ada, OH, USA
Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO, USA
c
Research and Development Service, VA Hospital, Tampa, FL, USA
d
Departments of Psychology and Molecular Pharmacology & Physiology, Center for Preclinical & Clinical Research on PTSD,
University of South Florida, Tampa, FL, USA
b
Received 10 August 2011; received in revised form 3 February 2012; accepted 14 February 2012
KEYWORDS
Stress;
Trauma;
Glucocorticoids;
HPA axis;
Memory;
Dexamethasone;
Animal model;
Fear conditioning
Summary Post-traumatic stress disorder (PTSD) is characterized by a pathologically intense
memory for a traumatic experience, persistent anxiety and physiological abnormalities, such as
low baseline glucocorticoid levels and increased sensitivity to dexamethasone. We have
addressed the hypothesis that rats subjected to chronic psychosocial stress would exhibit
PTSD-like sequelae, including traumatic memory expression, increased anxiety and abnormal
glucocorticoid responses. Adult male Sprague-Dawley rats were exposed to a cat on two occasions
separated by 10 days, in conjunction with chronic social instability. Three weeks after the second
cat exposure, the rats were tested for glucocorticoid abnormalities, general anxiety and their
fear-conditioned memory of the two cat exposures. Stressed rats exhibited reduced basal
glucocorticoid levels, increased glucocorticoid suppression following dexamethasone administration, heightened anxiety and a robust fear memory in response to cues that were paired with
the two cat exposures. The commonalities in endocrine and behavioral measures between
psychosocially stressed rats and traumatized people with PTSD provide the opportunity to
explore mechanisms underlying psychological trauma-induced changes in neuroendocrine systems and cognition.
# 2012 Elsevier Ltd. All rights reserved.
1. Introduction
* Corresponding author at: Department of Psychology, 4202 E.
Fowler Ave. (PCD 4118G), University of South Florida, Tampa, FL
33620, USA. Tel.: +1 813 974 0480; fax: +1 813 974 4617.
E-mail address: ddiamond@usf.edu (D.M. Diamond).
Individuals exposed to intense, life-threatening trauma are
at significant risk for developing post-traumatic stress disorder (PTSD). People who develop PTSD respond to a traumatic experience with intense fear, helplessness and horror
0306-4530/$ — see front matter # 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.psyneuen.2012.02.007
1532
(American Psychiatric Association, 1994) and subsequently
endure chronic psychological distress by repeatedly reliving
their trauma through intrusive, flashback memories (Ehlers
et al., 2004; Hackmann et al., 2004; McFarlane, 1992; Reynolds and Brewin, 1998, 1999; Speckens et al., 2006, 2007).
These intrusive memories are triggered by cues which were
associated with the trauma and can, in extreme cases, lead
to panic attacks. Therefore, PTSD patients make great
efforts to avoid stimuli that remind them of their trauma.
The re-experiencing and avoidance symptoms of the disorder
can hinder everyday functioning in PTSD patients and foster
the development of additional debilitating symptoms,
including persistent anxiety, exaggerated startle, cognitive
impairments and diminished extinction of conditioned fear
(Brewin et al., 2000; Elzinga and Bremner, 2002; Geuze et al.,
2009; Graham and Milad, 2011; Milad et al., 2009; Nemeroff
et al., 2006; Newport and Nemeroff, 2000; Stam, 2007).
PTSD is also characterized by an aberrant biological profile
in different endocrine and physiological systems (Krystal and
Neumeister, 2009; Pervanidou and Chrousos, 2010; Vidovic
et al., 2011). One of the most extensively researched endocrine systems in people with PTSD is the hypothalamic-pituitary-adrenal (HPA) axis. Empirical investigations of the
adrenal hormone, cortisol, have often reported abnormally
low baseline cortisol levels in people with PTSD (for reviews,
see Yehuda, 2005, 2009). One explanation for the presence of
low baseline cortisol levels in people with PTSD is that trauma
induces an enhancement of negative feedback inhibition of
the HPA axis. For example, studies have reported that people
with PTSD display an increased number and sensitivity of
glucocorticoid receptors (Rohleder et al., 2004; Stein et al.,
1997; Yehuda et al., 1991, 1993a, 1995) and an increased
suppression of cortisol and adrenocorticotropic hormone
(ACTH) following the administration of dexamethasone, a
synthetic glucocorticoid (Duval et al., 2004; Goenjian et al.,
1996; Grossman et al., 2003; McFarlane et al., 2011; Newport
et al., 2004; Stein et al., 1997; Yehuda et al., 1993b, 1995,
2002, 2004). Some studies have also observed greater
increases in ACTH levels of PTSD patients, relative to controls, following the administration of metyrapone. This finding may be the result of metyrapone reducing the enhanced
negative feedback inhibition present in PTSD patients (Otte
et al., 2006; Yehuda et al., 1996).
Studies have also employed the dexamethasone-corticotropin releasing hormone (CRH) challenge paradigm to study
abnormal HPA axis functioning in people with PTSD (de Kloet
et al., 2006). An advantage of this paradigm is that the
subjects are treated with dexamethasone prior to CRH
administration, thereby activating negative feedback
mechanisms before acute HPA axis stimulation. Studies have
generally reported reduced ACTH levels in dexamethasonetreated PTSD patients who were subsequently treated with
CRH. These findings support the notion that PTSD patients
exhibit reduced sensitivity to CRH stimulation (Rinne et al.,
2002; Strohle et al., 2008).
Overall, extensive research indicates that PTSD is characterized by reduced basal levels of cortisol, reduced CRH
receptor sensitivity and/or enhanced glucocorticoid negative
feedback at the level of the pituitary. However, the literature
in this area is not entirely consistent, which likely reflects the
heterogeneity in the manifestation of trauma and the measurement of PTSD in different patient populations (Begic and
P.R. Zoladz et al.
Jokic-Begic, 2007; Bonne et al., 2003; Hamner et al., 2004;
Klaassens et al., 2012; Marshall and Garakani, 2002; Metzger
et al., 2008; Pitman and Orr, 1990; Radant et al., 2001; Shalev
et al., 2008).
Our understanding of how trauma affects the HPA axis in
people may be enhanced by animal models that generate
PTSD-like behavioral and physiological abnormalities. To this
end, we have developed an animal model of PTSD that
includes trauma induction procedures which are analogous
to those that induce PTSD in people, including a threat to
survival, a lack of control, an intrusive re-experiencing of a
traumatic event and social instability (Roth et al., 2011;
Zoladz et al., 2008; Zoladz and Diamond, 2010). Specifically,
our animal model of PTSD is based on a combination of acute
traumatic experiences (two 1-h periods of inescapable confinement of rats in close proximity to a cat) embedded within
a 1 month-long period of social stress. We reported that rats
administered this psychosocial stress regimen exhibited
changes in physiology and behavior in common with people
diagnosed with PTSD, including heightened anxiety, exaggerated startle, impaired cognition, increased cardiovascular
reactivity and an exaggerated response to yohimbine administration (Brewin et al., 2000; Elzinga and Bremner, 2002;
Nemeroff et al., 2006; Newport and Nemeroff, 2000; Stam,
2007). Moreover, we recently demonstrated that our psychosocial predator stress model of PTSD produced hippocampusspecific increases in DNA methylation (Roth et al., 2011), a
finding which may be relevant toward understanding how
traumatic memories can persist for a lifetime (Yehuda and
Bierer, 2009).
The purpose of the present experiments was to extend our
animal model of PTSD to determine if rats administered
psychosocial stress would exhibit two hallmark features of
PTSD: (1) a long-lasting memory of the traumatic event
(inescapable live cat exposure); and (2) abnormalities in
glucocorticoid levels under baseline conditions and in
response to stress and dexamethasone administration.
2. Methods
2.1. Subjects
Experimentally-naı̈ve adult male Sprague-Dawley rats (225—
250 g upon delivery) obtained from Charles River laboratories
(Wilmington, MA) were used in all experiments. The rats were
pair-housed on a 12-h light/dark schedule (lights on at
0700 h) in standard Plexiglas cages with free access to food
and water. The colony room temperature and humidity were
maintained at 20 1 8C and 60 3%, respectively. After the
rats were given a 1-week vivarium acclimation period, their
weights increased to 304 g (2.3 g), which was when all
experimental manipulations began. All procedures were
approved by the Institutional Animal Care and Use Committee at the University of South Florida.
2.2. Psychosocial stress paradigm
Following the 1-week acclimation phase, rats were brought
to the laboratory and randomly assigned to ‘‘psychosocial
stress’’ or ‘‘no psychosocial stress’’ groups. Rats in the
psychosocial stress groups were given two 1-h cat exposures,
Psychosocial stress produces PTSD-like sequelae in rats
separated by 10 days, in conjunction with daily social stress in
the form of randomized housing, as described previously
(Zoladz et al., 2008). During each of the two cat exposures,
rats in the psychosocial stress groups were immobilized in
plastic DecapiCones (Braintree Scientific; Braintree, MA) and
placed in a perforated wedge-shaped Plexiglas enclosure
(Braintree Scientific; Braintree, MA; 20 cm 20 cm 8 cm).
cm). The rats, still immobilized in the plastic DecapiCones
within the Plexiglas enclosure, were taken to the cat housing
room where they were placed in a metal cage
(61 cm 53 cm 51 cm) with an adult female cat for 1 h.
The Plexiglas enclosure prevented any physical contact
between the cat and rats, but enabled the rats to be exposed
to all non-tactile sensory stimuli associated with the cat.
Canned cat food was smeared on top of the Plexiglas enclosure to increase cat motor activity because a moving cat
provokes a greater fear response in rats than a non-moving
cat (Blanchard et al., 1975).
The two cat exposures were separated by 10 days, with
the first exposure taking place during the light cycle
(between 0800 h and 1300 h), and the second exposure taking
place during the dark cycle (between 1900 h and 2200 h).
Beginning on the day of the first cat exposure, rats in the
psychosocial stress group were exposed to unstable housing
conditions for the next 31 days. Rats in the psychosocial
stress group were housed two rats per cage, with their cohort
pair combination changed on a daily basis during the entire
31-day stress period. That is, rats in the stress groups were
never housed with the same rat on consecutive days. Rats in
the no psychosocial stress group remained in their home
cages in the laboratory instead of receiving the 1-h acute
stress sessions, and these rats were housed with the same
cage cohort for the duration of the experiment.
2.3. Experiment 1: Traumatic memory
expression and general anxiety
Fig. 1 provides a summary of the timeline and procedures for
the two experiments in this study. In Experiment 1, 20 rats
were assigned to ‘‘psychosocial stress’’ (n = 10) or ‘‘no psychosocial stress’’ (n = 10) groups and exposed to the stress
manipulations described above. Since a major component of
PTSD is the persistent memory of a traumatic experience, we
have developed a method with which to measure a rat’s
memory for the cat exposure experiences. To accomplish this
goal, rats in the psychosocial stress group were given a predator-based form of fear conditioning. The rats were placed in
a chamber for 3 min immediately prior to each of the two cat
exposures. The chamber (26 cm 30 cm 29 cm; Coulbourn
Instruments; Allentown, PA) consisted of two aluminum sides,
an aluminum ceiling and clear Plexiglas on the front and back
walls and speaker on one wall. The floor of the chamber
consisted of 18 stainless steel rods, spaced 1 cm apart. A
74 dB, 2500 Hz tone was presented during the last 30 s of each
chamber exposure. Rats in the no psychosocial stress group
were also given the 3-min chamber and tone exposures, but
without subsequent immobilization and cat exposure.
It is important to emphasize that the rats in both groups
were not given any noxious stimulation, such as foot shock,
while they were in the chamber. It is also important to
emphasize that the tone was delivered to the rats while they
1533
were in the chamber, and then they were removed from the
chamber and then immobilized and brought to a different
room, where the traumatic experience (immobilization during cat exposure) occurred.
Three weeks following the second cat exposure, the rats
were tested for their conditioned fear memory by assessing
their freezing response (degree of immobility) when they
were returned to the chamber and exposed to the tone. Rats
were placed in the chamber, which had been previously
paired with the 2 cat exposures, for 5 min (context test).
One hour later, the rats were placed in a novel box for 6 min,
with a 74 dB, 2500 Hz tone presented during the last 3 min of
the exposure (cue test). The novel box exposure consisted of
a chamber (25 cm 23 cm 33 cm; Coulbourn Instruments,
Allentown, PA) with two aluminum sides, an aluminum ceiling
and Plexiglas front and back. Unlike the conditioning chamber, which contained metal rods on the floor, the cue-testing
chamber had a solid metal floor. Also, a house light was on
while the rats were in the cue-testing chamber. During the
context and cue tests, a 24-cell infrared activity monitor
(Coulbourn Instruments; Allentown, PA) mounted on top of
the chambers detected the infrared body heat image from
the animals to detect their movement. Immobility in the
chambers was operationally defined as continuous periods of
inactivity lasting at least 7 s.
Twenty-four hours after fear conditioning memory testing,
the rats were placed on an elevated plus maze (EPM) for
5 min. The EPM is a routine test of anxiety in rodents (Korte
and De Boer, 2003) and consists of two open arms
(11 cm 50 cm) and two closed arms (11 cm 50 cm) that
intersect each other to form the shape of a plus sign. At the
beginning of each trial, the rats were placed in the intersection area of the EPM, facing one of the open arms. Rat
behavior on the EPM was monitored by computer from 48
infrared photobeams located along the perimeter of the open
and closed arms (Motor Monitor, Hamilton Kinder; San Diego,
CA). The primary dependent measures of interest were the
amount of time rats spent in the open arms and their overall
ambulations. An arm entry was scored by the computer
program only when a rat’s entire body moved from one
arm into a new arm. An ambulation was scored by the
computer program each time a rat crossed a photobeam
sensor.
2.4. Experiment 2: Basal glucocorticoid levels
and dexamethasone suppression test
The rats used in Experiment 2 were not administered any
post-psychosocial stress behavioral testing. Instead, these
rats were used solely for the purpose of obtaining blood
samples at the conclusion of the psychosocial stress regimen
to evaluate corticosterone levels under undisturbed baseline, acute stress and dexamethasone injection conditions
(see timeline; Fig. 1). Twenty days after the second cat
exposure, the hind legs of all rats were shaved to allow
access to their saphenous veins. The rats were then taken
back to the housing room and left undisturbed for the
remainder of the day. The hind legs of all rats were shaved
1 day prior to blood sampling to minimize the amount of time
it took the experimenter to obtain baseline blood samples on
the following day.
1534
P.R. Zoladz et al.
Fig. 1 Experimental timeline and procedures. In Experiment 1, rats were placed in a chamber where a tone was delivered, followed
by immobilization of the rat during cat exposure, which occurred in another room. Ten days later, the predator-based fear conditioning
procedure was repeated. Beginning with the first day of cat exposure and continuing for a total of 31 days, the psychosocial stressed
rats were given social instability, composed of pseudorandom daily changes in cage cohorts. The ‘‘no psychosocial stress’’ group was
also administered chamber and tone exposure, which was then followed by placement in their home cages. These rats had the same
cage cohorts throughout the testing period. On Day 32, all rats were re-exposed to the conditioning chamber and then administered the
tone in a second chamber. On the following day, all rats were tested in the elevated plus maze (EPM). In Experiment 2, the
‘‘psychosocial stress’’ and ‘‘no psychosocial stress’’ groups received the same stress/no stress treatments as in Experiment 1 on Days 1—
32, except there was no chamber exposure included. On Day 32, the rats were administered no injection, vehicle or dexamethasone,
followed 6 h later with by basal blood sampling, 20 min of subsequent restraint stress and 2 post-stress blood samples. Additional
experimental details are provided in the Section 2.
The next day, between 1100 h and 1400 h, a subset of the
rats was administered subcutaneous injections of dexamethasone (10 mg/kg, 25 mg/kg, 50 mg/kg; 1 ml/kg) or vehicle. These doses of dexamethasone were chosen because
previous work indicated that they produce a modest suppression of corticosterone levels in rats (Lurie et al., 1989). Ten
rats from each of the psychosocial stress and no psychosocial
stress groups were assigned to receive an injection of one of
the three doses of dexamethasone or the vehicle solution.
Dexamethasone (Sigma—Aldrich; St. Louis, MO) was dissolved
in a vehicle solution consisting of sodium sulfite (1 mg/ml)
and sodium citrate (19.4 mg/ml), which were both dissolved
in distilled water. Immediately following the administration
of dexamethasone or vehicle, the rats were returned to the
housing room until the commencement of blood sampling. An
additional ten rats from each of the psychosocial stress and
no psychosocial stress groups were not injected to allow for
the analysis of undisturbed baseline corticosterone levels.
Six hours following the injections (or at an equivalent time
point for uninjected rats, between 1700 h and 2000 h), the
rats were taken individually to a procedure room for blood
sampling (Lurie et al., 1989). Petroleum jelly was applied to
each rat’s hind leg to reduce clotting while the blood sample
was being collected. The saphenous vein of each rat was
punctured with a sterile, 27-gauge syringe needle. A 0.2 cc
sample of blood was then collected from each rat in a
Psychosocial stress produces PTSD-like sequelae in rats
microcentrifuge tube. The first blood sample was considered
a baseline measure of corticosterone and was collected
within 2 min after the rats were removed from the housing
room. After obtaining this sample, the rats were immobilized
in plastic DecapiCones for 20 min. The rats were then
removed from the DecapiCones, and another 0.2 cc sample
of blood was collected in a microcentrifuge tube via saphenous vein venipuncture. This blood sample served to examine
the hormonal responses of rats to acute immobilization
stress. We employed this manipulation because in previous
work utilizing the single prolonged stress paradigm (Kohda
et al., 2007), it was necessary to stress the rodents after
dexamethasone administration to observe an exaggerated
suppression of corticosterone in single prolonged stressexposed animals. In addition, examining stress-induced
changes in corticosterone levels provides an assessment of
HPA axis functioning comparable to the one used in dexamethasone-CRH challenge paradigms in PTSD patients.
After the second blood sample was collected, the rats
were returned to their home cages. One hour later, a final
blood sample was collected from all rats to examine corticosterone levels following the termination of the acute
immobilization stress. Once the blood samples had clotted
at room temperature, they were centrifuged (3000 rpm for
8 min), and the serum was extracted and stored 80 8C until
assayed for corticosterone with an Enzyme ImmunoAssay kit
from Assay Design, Inc. (cat#901-097, Ann Arbor, MI). All
samples were diluted 1:50 and assayed per kit instructions.
2.5. Body and organ weights
1535
test and the amount of time spent in the open arms of the
EPM between the psychosocial stress and no psychosocial
stress groups. A two-way mixed-model ANOVA was used to
analyze the degree of immobility by rats during the cue
test, with psychosocial stress (psychosocial stress, no psychosocial stress) serving as the between-subjects factor
and tone (no tone, tone) serving as the within-subjects
factor.
In Experiment 2, two-way between-subjects ANOVAs were
used to analyze the growth rates, adrenal gland weights and
thymus weights, with psychosocial stress (psychosocial
stress, no psychosocial stress) and injection condition (no
injection, vehicle, 10 mg/kg, 25 mg/kg, 50 mg/kg) serving as
the between-subjects factors. A three-way mixed-model
ANOVA was used to analyze corticosterone levels, with the
psychosocial stress and injection condition serving as the
between-subjects factors and time point (0 min, 20 min,
80 min) serving as the within-subjects factor.
3. Results
3.1. Experiment 1: Fear conditioning and
anxiety testing
3.1.1. Growth rates and organ weights
The psychosocial stress group exhibited a significantly lower
growth rate, t(17) = 3.43, significantly larger adrenal glands,
t(14) = 2.24, and a significantly smaller thymus, t(16) = 2.78,
than the no psychosocial stress group ( p’s < 0.05; Table 1).
2.6. Statistical analyses
3.1.2. Traumatic memory expression
The psychosocial stress group exhibited significantly greater
immobility than the no psychosocial stress group during the
context test, t(14) = 4.55, p < 0.001. The analysis of the cue
test revealed significant main effects of psychosocial stress,
F(1,16) = 6.26, and tone, F(1,16) = 12.59, as well as a significant Psychosocial Stress Tone interaction, F(1,16) = 7.62
( p’s < 0.05). The psychosocial stress group demonstrated
significantly greater immobility than the no psychosocial stress
group in the novel environment only when the tone was
presented (Fig. 2).
Alpha was set at 0.05 for all analyses, and Holm-Sidak post
hoc comparisons were employed when an omnibus F test
indicated a significant ANOVA. Outlier data points greater
than 3 standard deviations from the exclusive group means
were eliminated from the analyses (less than 1% of the data
were outliers).
In Experiment 1, independent samples t-tests were used
to compare growth rates, adrenal glands weights, thymus
weights, degree of immobility during the 5-min context
3.1.3. General anxiety
The analysis of EPM behavior revealed that the psychosocial
stress group spent significantly less time in the open arms
than the no psychosocial stress group, t(15) = 2.44, p < 0.05,
thus corroborating our previously-reported anxiogenic
effects of the psychosocial stress paradigm (Zoladz et al.,
2008). There was no significant difference between the two
groups in their overall movement (i.e., number of ambulations) on the EPM, t(16) = 0.16, p > 0.05 (Fig. 3).
In each experiment, body weights were recorded on the day
of the first cat exposure and on the first day of behavioral/
physiological testing. Average growth rates (g/day) were
calculated for statistical analysis. At the end of each experiment, the rats were euthanized, and the adrenals (left and
right adrenals were pooled) and thymus were removed and
weighed. Organ weights were expressed as mg/100 g body
weight.
Table 1
Average growth rates and organ weights (SEM) for Experiment 1.
Group
Growth rate
(g/day)
Adrenal gland weight
(mg/100 g b.w.)
Thymus gland weight
(mg/100 g b.w.)
No psychosocial stress
Psychosocial stress
5.68 (0.53)
3.88* (0.13)
10.26 (0.25)
11.51* (0.50)
108.25 (8.03)
93.01* (5.28)
*
p < 0.05 relative to no psychosocial stress.
1536
P.R. Zoladz et al.
Context Memory
Cue Memory
80
60
*
60
50
40
30
20
Pre-Tone
Tone
50
% Immobility
% Immobility
70
*
40
30
20
10
10
0
No Psychosocial
Stress
0
Psychosocial
Stress
No Psychosocial
Stress
Psychosocial
Stress
Fig. 2 Chronic psychosocial stress resulted in the expression of a traumatic memory. The psychosocial stress group exhibited
significantly greater immobility than the no psychosocial stress group in response to the chamber (context memory; left) and tone (cue
memory; right) that were previously paired with the two cat exposures. Context and cue fear memory were assessed three weeks
following the second cat/home cage exposure. Data are presented as mean SEM. *p < 0.05 relative to the no psychosocial stress
group.
Open Arm Exploration
200
40
30
*
20
Locomotor Activity
150
100
50
10
0
Ambulations
% Time in Open Arms
50
No Psychosocial
Stress
Psychosocial
Stress
0
No Psychosocial
Stress
Psychosocial
Stress
Fig. 3 Chronic psychosocial stress resulted in heightened anxiety. The psychosocial stress group spent significantly less time in the
open arms of the elevated plus maze than the no psychosocial stress group (left), despite there being no difference between the two
groups in overall movement (right). Rat behavior on the elevated plus maze was examined 24 h after the context and cue fear memory
assessments. Data are presented as mean SEM. *p < 0.05 relative to the no psychosocial stress group.
3.2. Experiment 2: Influence of psychosocial
stress on basal glucocorticoid levels and
dexamethasone suppression test
3.2.1. Growth rates and organ weights
Each of the growth rate and organ weight analyses revealed
significant main effects of psychosocial stress, indicating that
the psychosocial stress groups exhibited significantly lower
growth rates, F(1,90) = 13.65, significantly larger adrenal
glands, F(1,88) = 16.53, and a significantly smaller thymus,
F(1,86) = 36.77, than the no psychosocial stress groups
( p’s < 0.001; Table 2).
3.2.2. Serum corticosterone levels
The analysis of serum corticosterone levels revealed a significant main effect of time point, F(2,158) = 122.58,
p < 0.001. Rats demonstrated a significant increase in
corticosterone levels following 20 min of immobilization,
and these levels significantly declined, yet still remained
elevated relative to baseline, 1 h later ( p’s < 0.001). There
was a significant main effect of injection condition,
F(4,79) = 54.99, p < 0.001, indicating that, relative to vehicle- and non-injected groups, dexamethasone led to significantly lower corticosterone levels. The Time Point Injection
Condition, F(8,158) = 6.35, and Time Point Psychosocial
Stress Injection Condition, F(8,158) = 3.10, interactions
were also significant ( p’s < 0.01). The non-injected psychosocial stress group displayed significantly lower corticosterone
levels than the non-injected no psychosocial stress group at
the 0 min time point ( p < 0.01).
Following administration of 10 mg/kg dexamethasone, the
psychosocial stress group exhibited a greater suppression of
post-immobilization corticosterone levels than the no psychosocial stress group. Additionally, 25 mg/kg dexamethasone prevented the immobilization-induced increase in
Psychosocial stress produces PTSD-like sequelae in rats
Table 2
1537
Average growth rates and organ weights (SEM) for Experiment 2.
Group
No psychosocial stress
No injection
Vehicle
DEX — 10 mg/kg
DEX — 25 mg/kg
DEX — 50 mg/kg
Psychosocial stress
No injection
Vehicle
DEX — 10 mg/kg
DEX — 25 mg/kg
DEX — 50 mg/kg
Growth Rate
(g/day)
Adrenal Gland Weight
(mg/100 g b.w.)
Thymus Gland Weight
(mg/100 g b.w.)
4.75
5.88
5.23
5.69
4.76
(0.26)
(0.24)
(0.31)
(0.39)
(0.38)
7.45
9.57
9.20
9.98
9.35
(0.64)
(0.86)
(0.56)
(0.45)
(0.82)
115.18
122.22
122.29
105.73
105.66
(7.31)
(6.94)
(4.10)
(6.35)
(5.67)
3.73
4.75
4.95
4.52
4.38
(0.43)
(0.13)
(0.25)
(0.35)
(0.49)
10.66
11.28
10.57
12.27
11.15
(0.44)
(1.06)
(0.96)
(0.42)
(0.52)
96.47
87.52
95.13
97.87
80.31
(4.98)
(4.18)
(4.36)
(5.28)
(3.91)
corticosterone levels in the psychosocial stress group only.
Administration of 50 mg/kg dexamethasone suppressed baseline and post-immobilization corticosterone levels equivalently in the psychosocial stress and no psychosocial stress
groups ( p > 0.05; Fig. 4).
4. Discussion
The overall goal of our research program has been to
develop an animal model of PTSD based on clinicallyrelevant features of the disorder. To this end, we previously demonstrated that two episodes of inescapable cat
exposure, in conjunction with daily social instability,
caused rats to exhibit heightened anxiety, exaggerated
startle, impaired cognition, increased cardiovascular reactivity and an exaggerated response to yohimbine administration (Zoladz et al., 2008; Zoladz and Diamond, 2010), all
of which are commonly observed symptoms in people with
PTSD (Brewin et al., 2000; Elzinga and Bremner, 2002;
Nemeroff et al., 2006; Newport and Nemeroff, 2000; Stam,
2007). In the present work, we have extended our animal
model of PTSD by demonstrating that rats exposed to two
acute predator stress experiences, embedded within a 31day period of social instability, resulted in a long-lasting,
classically-conditioned fear memory for the predator exposure experiences. We have also shown that rats exposed to
the psychosocial stress regimen exhibited increased
general anxiety and a significant reduction of glucocorticoid levels at baseline and following dexamethasone
administration.
4.1. Predator-based fear conditioning
In Experiment 1, we exposed rats to a unique chamber
(context) and tone (cue), which served as the two conditioned stimuli (CSs). The CSs were presented immediately
prior to immobilization in conjunction with cat exposure,
which served as the unconditioned stimulus (US) (Pavlov,
1928). The use of a live moving cat, alone, is well-established
as a powerful and unlearned fear-provoking stimulus to rats
(Blanchard et al., 1975, 1990; Blanchard et al., 1991; Pentkowski et al., 2006). Psychosocially stressed rats expressed a
fear conditioned memory, as indicated by significant
immobility, upon their re-exposure, three weeks later, to
the context and cue that were temporally associated with the
two cat exposures (Fig. 2). Importantly, during the cue test,
the psychosocially stressed rats did not exhibit significant
immobility in the novel environment until the tone was
presented. This finding indicated that their fear response
during the context test was not an indication of a nonspecific
increase in anxiety, but was, instead, a selective anxiogenic
response to the contextual stimuli that were associated with
cat exposure.
The expression of learned fear that the psychosocially
stressed rats exhibited to the conditioned stimuli in this study
can be considered analogous to the fear and panic that
people with PTSD display when they are exposed to a cue
that reminds them of their trauma (Garakani et al., 2006;
Izquierdo et al., 2004; Redgrave, 2003). These findings confirm that our animal model of PTSD involves a fear conditioning (traumatic memory) component, which is central to the
expression of PTSD in people (Bryant et al., 2007; Debiec and
LeDoux, 2006; Elzinga and Bremner, 2002; Johnson et al.,
2012; Jovanovic and Ressler, 2010; Kolb, 1984; Liberzon and
Sripada, 2008). The present paradigm, therefore, may reveal
mechanisms involved in the formation and persistence of
intrusive memories in traumatized people. For example, in
recent work, we reported that the same psychosocial stress
regimen used here produced selective epigenetic alterations
(methylation) of the hippocampal brain-derived neurotrophic factor (BDNF) gene (Roth et al., 2011). We have also
demonstrated that cat exposure impaired memory-related
functions of the hippocampus (Diamond et al., 1999, 2007;
Mesches et al., 1999; Vanelzakker et al., 2011; Vouimba
et al., 2006), and, conversely, enhanced synaptic plasticity
(Vouimba et al., 2006) and phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), a critical
molecular component of memory formation and synaptic
plasticity (Cammarota et al., 2002; Lisman et al., 2002),
in the amygdala (Zoladz et al., 2012). These and related
findings on an animal model of intrusive memories (Zoladz
et al., 2010) are consistent with the view that traumatic
memory reactivation involves impaired functioning of the
hippocampus, in conjunction with enhanced functioning of
the amygdala (Brewin, 2001; Debiec and LeDoux, 2006;
Metcalfe and Jacobs, 1998; Milad et al., 2009; Nadel and
Jacobs, 1998).
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P.R. Zoladz et al.
Corticosterone (µg/dL)
Undisturbed Baseline (No Injection)
No Psychosocial Stress
Psychosocial Stress
14
12
10
8
6
4
*
2
0
0 min
20 min
80 min
Corticosterone (µg/dL)
Dexamethasone/Vehicle Injection
Vehicle
14
12
10
10
8
8
6
6
4
4
2
2
0
0
Corticosterone (µg/dL)
0 min
20 min
80 min
25 µg/kg
14
12
0 min
80 min
50 µg/kg
10
8
6
6
4
4
2
2
0
0
20 min
20 min
14
8
0 min
*
12
*
10
10 µg/kg
14
12
80 min
0 min
20 min
80 min
Fig. 4 Chronic psychosocial stress resulted in significantly lower corticosterone levels at baseline and following dexamethasone
administration. The non-injected psychosocial stress group exhibited significantly lower corticosterone levels than the no psychosocial
stress group at the 0 min time point (top). Following the administration of 10 mg/kg dexamethasone, the psychosocial stress group
displayed a more rapid recovery of post-immobilization corticosterone levels than the no psychosocial stress group (middle right;
80 min time point). Following the administration of 25 mg/kg dexamethasone, there was a shift in the response pattern indicating that
dexamethasone prevented the immobilization-induced increase in corticosterone levels in the psychosocial stress group only (bottom
left; 20 min time point). Administration of 50 mg/kg dexamethasone resulted in an equivalent suppression of corticosterone levels in
the two groups (bottom right). Blood sampling occurred three weeks following the second cat/home cage exposure between 1700 h and
2000 h. Data are presented as mean SEM. The dark bar from 0 min to 20 min indicates the time when rats were immobilized.
*p < 0.05 relative to the psychosocial stress group.
In related work, Cohen and colleagues (Cohen et al., 2006,
2008; Matar et al., 2009; Zohar et al., 2008) incorporated a
fear conditioning-like component into their animal model of
PTSD. These investigators exposed rats to well-soiled cat
litter (predator scent stress) and subsequently measured
their freezing behavior in response to fresh, unused cat litter.
They found that predator scent stress-exposed rats exhibited
significant freezing behavior upon exposure to unused cat
litter, which suggested that the rats had a fear-provoking
memory of the predator scent stress experience. Their work
Psychosocial stress produces PTSD-like sequelae in rats
is important because it potentially provides insight into how a
fear-provoking experience produces a long-term change in
rat behavior. However, their approach did not provide evidence that the stressed rats had formed an explicit association between a previously neutral cue (CS) and a biologically
relevant, arousing stimulus (US), which is an essential feature
of classical conditioning (Pavlov, 1928). The increased freezing their stressed rats exhibited in response to clean litter
may have developed as a result of increased generalized fear
to all novel stimuli. Thus, the possibility that the predator
scent stress experience produced a non-associative sensitization of stress responses was not addressed in their work.
Other investigators have also studied different forms of
fear memory testing in rodents based on their forming an
association between neutral stimuli and exposure to a predator (Adamec, 1997; Adamec et al., 2004, 2011) or predator
odor (Blanchard et al., 2003a,b, 2001; Hubbard et al., 2004;
Munoz-Abellan et al., 2009; Rosen et al., 2008; Takahashi
et al., 2008). Unlike the other approaches, we embedded
predator-based fear conditioning within a prolonged (31-day)
period of chronic social stress. As such, our work mimics a
clinically relevant situation in which a person is exposed to
acute trauma as a component of prolonged periods of daily
anxiety. The combination of acute traumatic experiences
delivered in conjunction with chronic daily stress may explain
why our model, unlike some predator odor-based work
(Munoz-Abellan et al., 2009; Zangrossi and File, 1992), generates a persistent fear-based memory, as well as a longlasting increase in behavioral anxiety.
It is important to note that unlike conventional classical
conditioning training, in the current work, the CS (context/
cue) and US (immobilization during cat exposure) occurred in
completely different locations. That is, in traditional classical conditioning, the CS and US are always presented
together in the same context. For example, in typical fear
conditioning training, rats are administered foot shock and a
tone in the same context (Fanselow and Gale, 2003; Rudy
et al., 2004). A rat’s memory for the shock is then tested by
observing the rat’s behavior when it is returned to the same
environment where the shock occurred. We have shown here
that rats can associate two neutral stimuli (CSs; chamber and
tone) with an aversive experience (US; immobilization during
predator exposure) that occurred in two different places.
That is, the rats were removed from the chamber and brought
to another room, where cat exposure occurred, and yet, the
rats exhibited fear when they were returned to the chamber
or exposed to the tone. Thus, our demonstration that rats can
associate cues that occurred across time and space is unique,
and potentially relevant toward understanding how traumatic stress can produce powerful, long-lasting and context-independent intrusive memories and phobias in
people (Bryant and Harvey, 1996; Cuthbert et al., 2003;
Jacobs and Nadel, 1985; Wild et al., 2007).
4.2. PTSD-like HPA axis alterations
In Experiment 2, psychosocially stressed rats exhibited
abnormal, PTSD-like endocrine profiles, including significantly lower corticosterone levels at baseline and following
dexamethasone administration (Fig. 4). Although investigations of HPA axis function in PTSD patients have produced
1539
mixed results (Bonne et al., 2003; Hawk et al., 2000; Klaassens et al., 2012; McFarlane et al., 1997, 2011; Metzger
et al., 2008; Pitman and Orr, 1990; Shalev et al., 2008),
numerous studies have reported that people with PTSD exhibit abnormally low baseline cortisol levels (for reviews, see
Yehuda, 2005, 2009), an increased number and sensitivity of
glucocorticoid receptors (Rohleder et al., 2004; Stein et al.,
1997; Yehuda et al., 1991, 1993a, 1995) and increased suppression of cortisol and ACTH following the administration of
dexamethasone (Duval et al., 2004; Goenjian et al., 1996;
Grossman et al., 2003; Newport et al., 2004; Stein et al.,
1997; Yehuda et al., 1993b, 1995, 2002, 2004). However,
given the heterogeneity of findings in this area of research,
some glucocorticoid abnormalities may be present only in a
subtype of the disorder under restricted conditions (e.g.,
combat trauma in males versus sexual assault in females). It
is also possible that such glucocorticoid abnormalities may
occur as a result of trauma, per se, rather than being tied
specifically to the diagnosis of PTSD (de Kloet et al., 2007),
which may explain the difficulty in considering glucocorticoid
abnormalities to be ubiquitous biomarkers of all forms of
PTSD (Klaassens et al., 2012). Thus, inclusion of other biomarkers, perhaps at the molecular level (Kolassa et al., 2010;
Su et al., 2009; Xie et al., 2009; Zhang et al., 2008), may
identify measures unique to trauma-induced psychopathology.
Animal studies involving chronic stress have frequently
reported significant elevations of baseline glucocorticoid
levels (Blanchard et al., 1993; Kant et al., 1987; Lepsch
et al., 2005; Marin et al., 2007; Mizoguchi et al., 2001;
Patterson-Buckendahl et al., 2001; Touyarot and Sandi,
2002). Few studies, however, have produced abnormally
low baseline glucocorticoid levels similar to those reported
here. Those animal models that have reported significantly
reduced baseline glucocorticoid levels have employed either
the single prolonged stress or a stress—restress paradigm,
consisting of situational reminders of the original stress
experience (Diehl et al., 2007; Harvey et al., 2003; Harada
et al., 2008; Iwamoto et al., 2007; Kohda et al., 2007;
Liberzon et al., 1997; Takahashi et al., 2006; Wang et al.,
2008). The present experiment, therefore, extends these
findings by demonstrating that similar HPA axis abnormalities
can be produced in rats by exposure to two acute predator
stress episodes, in conjunction with daily social instability,
three weeks after the last predator exposure occurred.
It is important to note that we observed significantly lower
baseline corticosterone levels only in the uninjected psychosocially stressed rats (Fig. 4). This baseline effect is contrasted with the lack of a psychosocial stress effect on
‘‘baseline’’ corticosterone in the rats that were injected
with vehicle 6 h before the baseline blood sample was
obtained (Fig. 4). These findings illustrate the importance
of obtaining blood samples from completely undisturbed rats
to obtain a true measure of baseline HPA axis activity. This
finding also illustrates the sensitivity of corticosterone levels
to relatively mild environmental manipulations, such as an
intraperitoneal injection. This finding may also be relevant to
inconsistent findings in the PTSD literature as single time
point basal HPA and cardiovascular measures may be
affected, for example, by how long subjects spend in an
experimental (e.g., hospital) environment before a baseline
measure is obtained (McFall et al., 1992).
1540
We did not find that corticosterone levels declined to
baseline 60 min after the termination of 20 min of acute
immobilization stress. The persistent elevation of corticosterone levels 1 h post-stress could have resulted, in part, because
of the time of day that we initiated blood sampling. We began
blood sampling in the early evening hours, at the time when
lights are off and corticosterone levels rise in rats. This timing
of blood sampling was designed to increase the likelihood that
we could observe group differences in baseline corticosterone
levels. The increase in corticosterone levels in the rat’s dark
cycle could have interacted with the acute immobilization
stress response to prevent a full recovery of corticosterone
levels to baseline at the 80 min time point.
As expected, dexamethasone-treated animals displayed
significantly lower baseline corticosterone levels than vehicle-treated animals. However, there was no effect of psychosocial stress on baseline corticosterone levels following
dexamethasone administration. The reason why we did not
observe group differences in baseline corticosterone levels is
because each of the three doses of dexamethasone produced
an almost complete suppression of baseline corticosterone
levels in the stress and control groups. Additional study with
lower doses of dexamethasone may reveal a subtle influence
of psychosocial stress on the dexamethasone-induced suppression of baseline corticosterone levels.
In contrast to equivalent baseline corticosterone levels in
dexamethasone-treated groups, we found that the 25 mg/kg
dose of dexamethasone blocked the immobilization-induced
increase in corticosterone levels in the psychosocial stress
group. This finding replicates observations by Kohda et al.
(2007), who found significantly lower corticosterone levels in
rats exposed to the single prolonged stress paradigm following the administration of dexamethasone. Akin to the present
study, Kohda et al. (2007) exposed rats to an acute stressor
following dexamethasone administration to observe group
differences in corticosterone levels. We also found that
psychosocially stressed rats exhibited significantly lower
post-immobilization (80 min time point) corticosterone
levels than the no psychosocial stress group following administration of 10 mg/kg of dexamethasone. This dose of dexamethasone did not selectively blunt the immobilizationinduced increase of corticosterone levels in psychosocially
stressed rats, as there were no significant group differences
in corticosterone levels at the 20 min time point. However,
following termination of the immobilization stress, psychosocially stressed rats displayed a significantly greater decline
of corticosterone levels 60 min later.
The finding of reduced corticosterone levels in psychosocially stressed animals following dexamethasone administration supports the hypothesis that our PTSD regimen generates
enhanced negative feedback of the HPA axis. We may further
speculate that dexamethasone prevented the immobilization-induced increase (25 mg/kg) and exacerbated the postimmobilization recovery (10 mg/kg) of corticosterone levels
in the psychosocial stress groups because the rats in these
groups had a greater number and/or sensitivity of glucocorticoid receptors or reduced sensitivity of CRH receptors in the
pituitary. It is also possible that rather than enhanced negative feedback of the HPA axis, reduced adrenal output could
explain the reduced corticosterone levels that were observed
in the dexamethasone-treated stressed groups. Arguing
against this interpretation is the finding that the psychosocial
P.R. Zoladz et al.
stress groups exhibited normal levels of corticosterone in
response to acute stress in the uninjected and saline-treated
groups (Fig. 4). Moreover, we found that psychosocial stress
produced adrenal hypertrophy (Tables 1 and 2), which would
seem inconsistent with adrenal insufficiency as an explanation of reduced corticosterone responses in the dexamethasone-treated psychosocial stress groups. However, previous
work has demonstrated that chronic psychosocial stress in
rodents can produce adrenal hypertrophy in conjunction with
reduced ACTH responsiveness of the adrenal glands (Reber
et al., 2007). Therefore, future work will need to be performed to identify the neuroendocrine basis of the psychosocial stress-induced disturbance of HPA axis function we
have observed here, including an examination of CRH and
glucocorticoid receptor expression, levels of circulating
ACTH and adrenal gland responsiveness to ACTH.
4.3. Clinical relevance
The importance of the current work is that our psychosocial
stress regimen generated, in rats, three cardinal features of
PTSD: evidence of a long-lasting traumatic memory, persistent anxiety and hormonal abnormalities. One feature of our
work which may appear inconsistent with clinical research is
that psychosocial stress produced PTSD-like sequelae in
most, if not all, rats, but only a subset (10—25%) of traumatized people develops PTSD (Aupperle et al., 2012; Delahanty
and Nugent, 2006; Marmar et al., 2006; Skelton et al., 2012;
Yehuda and Flory, 2007). In this context it is important to
point out that our animal model of PTSD was explicitly
designed to expose rats to conditions which are known to
maximize the likelihood of PTSD developing in people. Specifically, DSM-IV criteria for the diagnosis of PTSD includes the
following three conditions: (1) PTSD can be triggered by an
event that involves threatened death or a threat to one’s
physical integrity; (2) a person’s response to the event
involves intense fear, helplessness or horror; and (3) in the
aftermath of the trauma, the person feels as if the traumatic
event were recurring, including a sense of reliving the
experience (American Psychiatric Association, 1994). All of
these components of the DSM-IV criteria for PTSD have been
incorporated into our animal model of PTSD. That is, rats
exhibit an intense fear response when exposed to a cat
(Adamec et al., 2005, 2011; Blanchard et al., 2005; Hubbard
et al., 2004), which is a threat to their survival. The immobilization component of our animal model is a rodent analogue to a loss of control over traumatic conditions, which is
known to exacerbate behavioral and physiological responses
to stress (Amat et al., 2005; Bland et al., 2006, 2007;
Kavushansky et al., 2006; Maier et al., 1993; Maier and
Watkins, 2005; Shors et al., 1989). The re-experiencing the
rats were exposed to with the second cat exposure was
designed to be relevant to the increased likelihood of PTSD
developing with multiple traumatic experiences (Koenen
et al., 2002; Kolassa et al., 2010; Xie et al., 2009) and the
unstable psychosocial component of our paradigm is based on
the well-described finding of a link between a lack of social
support reported by people who progress from short-term to
long-lasting PTSD (Andrews et al., 2003; Boscarino, 1995;
Brewin et al., 2000; Solomon et al., 1989; Ullman and Filipas,
2001; Vogt et al., 2011).
Psychosocial stress produces PTSD-like sequelae in rats
Taken together, the basis of the high rate of PTSD-like
endocrine and behavioral effects we have reported here
and in previous studies (Roth et al., 2011; Zoladz et al.,
2008; Zoladz and Diamond, 2010) can be ascribed to the
explicit design of our psychosocial stress manipulations to
mimic clinical features of trauma that are known to increase
the likelihood that persistent PTSD will occur in people. This
approach, therefore, is a tool with which to identify mechanisms that are activated specifically in the subset of individuals
who are exposed to environmental conditions that are most
likely to progress from an acute stress state to chronic PTSD.
5. Concluding remarks
We have developed an animal model of PTSD that includes
trauma induction procedures which are analogous to those
that induce PTSD in people, including a threat to survival, a
lack of control, an intrusive reminder of a traumatic experience and social instability. Rats administered this psychosocial
stress regimen exhibited changes in physiology and behavior in
common with people diagnosed with PTSD, including heightened anxiety, exaggerated startle, impaired cognition,
increased cardiovascular reactivity and an exaggerated
response to yohimbine administration (Roth et al., 2011;
Zoladz et al., 2008; Zoladz and Diamond, 2010). In the current
work we have extended our model to demonstrate that psychosocially stressed rats exhibited a powerful and long-lasting
fear memory for the context and cue which were temporally
associated with immobilization and predator exposure. We
also observed significant changes in HPA activity, specifically,
reductions in basal glucocorticoid levels and enhanced dexamethasone-induced inhibition of glucocorticoid levels, which
have been shown to occur in traumatized people. Overall, the
numerous commonalities in stress-induced changes in physiology and behavior in traumatized people and in the psychosocially stressed rats studied here further validates the use of our
animal model of PTSD to explore cognitive and neuroendocrine
mechanisms underlying emotional trauma-induced changes in
brain and behavior.
Conflicts of interest
All other authors declare that they have no conflicts of
interest.
Contributors
David Diamond designed the study and contributed to the
editing of the manuscript. Phillip Zoladz contributed to the
design of the study, conducted all laboratory procedures and
wrote the first draft of the manuscript. Monika Fleshner
contributed to the design of the study, conducted the corticosterone assays and contributed to the editing of the manuscript. All authors contributed to and have approved the final
manuscript.
Role of the funding source
Funding for this study was provided by the Department of
Veterans Affairs; the VA had no role in study design, in the
1541
collection, analysis and interpretation of data, in the writing
of the report, and in the decision to submit the paper for
publication.
Acknowledgements
This research was supported by Research Career Scientist and
Merit Review Awards from the Department of Veterans Affairs
to David Diamond.
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