REPORTS

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64, 267 (2009). to H.M.) and a German Ministry of Education and Research
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Map (Oxford Univ Press, Oxford, 1978).
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(2006). www.sciencemag.org/cgi/content/full/335/6075/1506/DC1
Materials and Methods
Acknowledgments: We thank K. Deisseroth for the AAVs, Figs. S1 to S11
References
A. Vogt for help in generating mice, I. Preugschat-Gumprecht
and R. Hinz for their technical assistance, and P. H. Seeburg 28 November 2011; accepted 10 February 2012
for helpful discussions. This work was supported by a European 10.1126/science.1217139

of the threat (17, 18). In one schedule, the pre-

Glucocorticoids Can Induce PTSD-Like sentation of the tone was always followed by the
delivery of the shock (predicting-cue group). In
Memory Impairments in Mice this case, animals identified the tone as the main
predictor of the threat, showing conditioned fear
Nadia Kaouane,1,2,3 Yves Porte,1,2* Monique Valle,2,3 Laurent Brayda-Bruno,1,2,3 when re-exposed to the cue alone but not to the
Nicole Mons,1,2 Ludovic Calandreau,4 Aline Marighetto,1,2,3 context (Fig. 1A). During the second schedule,
Pier Vincenzo Piazza,2,3 Aline Desmedt1,2,3 the tone presentation was never followed by the

Downloaded from http://science.sciencemag.org/ on October 29, 2016

delivery of the shock (predicting-context group).
Posttraumatic stress disorder (PTSD) is characterized by a hypermnesia of the trauma and by In this case, animals identified the conditioning
a memory impairment that decreases the ability to restrict fear to the appropriate context. context as the correct predictor of the threat,
Infusion of glucocorticoids in the hippocampus after fear conditioning induces PTSD-like memory showing conditioned fear when re-exposed to the
impairments and an altered pattern of neural activation in the hippocampal-amygdalar circuit. context alone but not to the cue (Fig. 1A). As
Mice become unable to identify the context as the correct predictor of the threat and show expected, in both conditions fear responses to the
fear responses to a discrete cue not predicting the threat in normal conditions. These data correct predictor progressively increased as a
demonstrate PTSD-like memory impairments in rodents and identify a potential pathophysiological function of the threat intensity.
mechanism of this condition. Corticosterone (10 ng per side) was infused
into the dorsal hippocampus immediately after
ituations surrounding threatening events are Animal models of traumatic memories and conditioning with three footshock intensities (0.3,

S better remembered than the ones accom-

panying neutral ones. This hypermnesia for
environments and cues predicting threats is im-
portant for adaptation because it increases the
probability of survival in uncontrolled environ-
ments. In humans, the exposure to threatening sit-
uations can also result in memory impairments
culminating in severe pathological states such as
posttraumatic stress disorder (PTSD) (1). In this
case, a hypermnesia for the core traumatic event
is associated with a memory deficit for peritrau-
matic contextual cues (2, 3), impairing the capacity
of the subject to identify the correct predictors
of the threat and restrict fear to the correct place
and/or to the correct cues. This deficit contributes
to the intrusive recollectionre-experiencing the
fear response in safe situationsthat character-
izes PTSD.
1
CNRS UMR 5228, Centre de Neurosciences Intgratives et
Cognitives, 33405 Talence, France. 2Department of Life Science,
Universit de Bordeaux, 33077 Bordeaux, France. 3INSERM
U862, Neurocentre Magendie, 146 rue Leo Saignat, 33077
Bordeaux, France. 4Institut National de la Recherche Agrono-
mique (INRA) Centre de Tours Nouzilly, Physiologie de la
Reproduction et des Comportements, CNRS UMR 6175, INRA
UMR 85, Universit de ToursHaras Nationaux, 37380
Nouzilly, France.
*Present address: Institut des Maladies Neurodgnratives,
CNRS UMR 5293, Universits Bordeaux 1 et 2, Avenue des
Facults, 33405 Talence, France.
Present address: Institut de Neurosciences Cognitives et
Intgratives dAquitaine, CNRS UMR 5287, Universits Bor-
deaux 1 et 2, Avenue des Facults, 33405 Talence, France.
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: aline.
desmedt@inserm.fr (A.D.); pier-vincenzo.piazza@inserm.fr (P.V.P.)
PTSD principally focus on the quantitative aspect
of fear memories: an increased and persistent fear
response (4). In contrast, the critical landmark of
PTSDthe inability of the subject to restrict fear
responses to the appropriate predictorsis large-
ly neglected. As a consequence, the biological
mechanisms of pathological PTSD-like memo-
ries remain largely unknown.
To address this issue, we analyzed whether
PTSD-like memory impairments can be observed
in mice. We therefore injected the stress hor-
mone corticosterone, the major glucocorticoid in
rodents, into the hippocampus of mice submitted
to a fearful situation. Glucocorticoids increase in
response to stress, enhance stress-related memo-
ries (58), and have been involved in the patho-
physiology of PTSD (9, 10). The hippocampus
plays an important role in memory (11), is the
major brain target of glucocorticoids (12, 13),
and seems impaired in PTSD (14, 15).
We then developed a behavioral model that
allows evaluating the ability of the individuals to
restrict fear responses to the appropriate predictor
of the threatening stimulus. Mice were first sub-
mitted to a threatening situation, the delivery of
an electric footshock, when exposed to a discrete
cue (a tone) in a specific context (conditioning
cage). Twenty-four hours after this conditioning
procedure, animals were re-exposed first to the cue
alone in a familiar and safe environment and then
to the conditioning context without the cue (16).
We used two distinct conditioning schedules
that contained exactly the same nature and quan-
tities of environmental stimuli but, differing in
their associations, identified different predictors
0.5, and 0.8 mA). In the predicting-cue group,
corticosterone did not significantly modify fear
responses (Fig. 1B). This is not surprising because
the hippocampus is necessary for contextual con-
ditioning but is dispensable for cue conditioning
(19, 20). In animals in which the context predicted
the threat (predicting-context group), as expected
(6, 7) corticosterone administered after the lowest
shock intensity (0.3 mA) enhanced conditioned
fear to the context (Fig. 1B). However, when cor-
ticosterone followed the highest shock intensity
(0.8 mA) PTSD-like memory impairments ap-
peared. Animals did not show fear in response to
the correct predictor of the threat, the context, but
in response to the tone (Fig. 1B), which is nor-
mally not a relevant predictor of the threat for
them. Animals infused with corticosterone also
showed a fear response to a previously unexperi-
enced cue (2 kHz tone) at some extent similar to
the one (1 kHz tone) experienced during con-
ditioning (Fig. 1C), but not in response to a com-
pletely different cue (white noise). In contrast, the
fear response in the predicting-cue group was ex-
clusively restricted to the conditioning cue. In con-
clusion, hippocampal corticosterone infusions
impaired the ability of the subject to restrict fear
responses to the appropriate predicting cues.
In physiological conditions, corticosterone in-
creases systemically in response to stress. We then
analyzed whether the exposure to a second stress,
the restraint in a cylinder for 20 min, could also
induce PTSD-like memory impairments. Similar
to intrahippocampal corticosterone infusions,
when the second stress followed the low shock
intensity (0.3 mA) conditioned fear to the context

1510 23 MARCH 2012 VOL 335 SCIENCE www.sciencemag.org

 REPORTS
increased (Fig. 2A). However, when the second effects of stress are attributable to stress-induced (from 0.75 to 2.5 mg/kg) that encompasses the
stress followed the high shock intensity (0.8 mA) corticosterone secretion. Thus, systemic (intraperi- increase in corticosterone induced by several types
PTSD-like memory impairments appeared. These toneal) corticosterone injections, in a range of doses of stress (fig. S1B), increased fear responses to

Fig. 1. Corticosterone infusion in the hippocampus induces

PTSD-like memory impairments. (A) Increasing shock intensity
progressively produced higher fear responses to the right
predictor of the threat [all F > 4.67, P < 0.01]: in the predicting-
cue groups to the cue alone (left) and in the predicting-context
groups to the context alone (right). (B) In the context-predicting
group, corticosterone (CORT) infusions in the hippocampus in-
creased fear response to the context for a low-intensity threat
(0.3 mA). After a high-intensity threat (0.8 mA), corticosterone
induced PTSD-like memory impairments, suppressing the re-
sponse to the correct predictor (the context) and increasing the
fear response for the wrong predictor (the cue). (C) Corticoster-
one increased the response to a cue similar (2 kHz tone) to the
one used for conditioning (1 kHz cue) but not to a very different
cue (white noise). *P < 0.05, **P < 0.01, group comparisons; P <

Downloaded from http://science.sciencemag.org/ on October 29, 2016

0.05, P < 0.01 versus 0.3 mA; #P < 0.05, aCSF versus CORT;
P < 0.01, P < 0.001 versus 1 kHz cue [Fishers partial least-
squares difference (PLSD)].

Fig. 2. Stress and systemic corticosterone injec-

tion induce PTSD-like memory impairments in the
predicting-context group. (A) A second stress after
conditioning with a low-intensity threat (0.3 mA
shock) increased fear responses to the context.
Stress after a high-intensity threat (0.8 mA shock)
induced PTSD-like memory impairments, suppressing
the response to the correct predictor (the context)
and increasing the fear response for the wrong pre-
dictor (the cue). (B) Corticosterone (CORT) levels in
the plasma and dorsal hippocampus (dHPC) were
higher in the high-threat group and further in-
creased after exposure to stress. (C) Intraperitoneal
(i.p.) corticosterone injection after conditioning in-
creased fear responses to the context for a low-intensity
threat and induced PTSD-like memory impairments for
a high-intensity threat. Ba, basal conditions; *P < 0.05,
**P < 0.01, ***P < 0.001, versus control or 0 mg/kg
CORT or low-intensity threat; #P < 0.05, ###P < 0.001,
versus high-intensity threat (Fishers PLSD).

www.sciencemag.org SCIENCE VOL 335 23 MARCH 2012 1511

 REPORTS
Fig. 3. PTSD-like memories
were associated with an al-
tered neural activity within
the hippocampal-amygdalar
circuit. In the control predicting-
context group, c-Fos expres-
sion was high in the dentate
gyrus (DG) of the hippocam-
pus and low in the right amyg-
dala [lateral (LA), basolateral
(BLA), and central (CEA) nuclei].
The opposite pattern was ob-
served in the predicting-cue
group. Corticosterone (CORT)
infusion in the predicting-
context group decreased c-Fos
expression in the dorsal CA1
and the ventral DG, whereas
it increased c-Fos expression
in the amygdala. *P < 0.05,
**P < 0.01, Predicting-cue ver-
sus Predicting-context groups;
#
P < 0.05, ##P < 0.01, ###P <
0.001, aCSF versus CORT
(Students t test).
the context when injected after conditioning with
a low threat (0.3 mA). In contrast, corticosterone,
in the same range of concentrations, induced
PTSD-like memory impairments when injected
after conditioning with an intense threat (0.8 mA)
(Fig. 2C). These differences between groups were
maintained over the entire dose-response func-
tion of corticosterone, which included quite high
doses (5 and 10 mg/kg) encompassing the entire
range of corticosterone behavioral effects. Plas-
ma and hippocampal corticosterone levels were
higher in animals conditioned with the high
shock intensity than in the ones conditioned with
the low shock intensity (Fig. 2B). Stress or cor-
ticosterone injections increased corticosterone
above the levels observed in the high shock in-
tensity group, but differences between groups
were suppressed (Fig. 2B), and this occurred
even when the ED100 dose for the behavioral
effects of corticosterone injections was studied
(S1A). These results indicate that glucocorticoids
induce PTSD-like memory impairments in a state-
dependent manner. Corticosterone levels need to
go above a certain threshold, and the threat needs
to reach a certain intensity, for PTSD-like memory
impairments to appear. These findings extend to
PTSD statedependent effects of glucocorticoids
already described for the ability of these hormones
to enhance the sensitivity to drugs of abuse (21),
suggesting that this could be a general mechanism
in the pathophysiology of stress-related disorders.
During acquisition of fear conditioning, the
selection of the best predictor of the shock (tone
versus context) requires different activations of
the hippocampal-amygdalar circuit (17, 22). The
1512 23 MARCH 2012
activation of these circuits, measured by the ex-
pression of the c-Fos protein, was analyzed 90
min after intrahippocampal infusion of either
corticosterone (10 ng per side) or vehicle [arti-
ficial cerebrospinal fluid (aCSF)] in animals in
the predicting-context group conditioned with the
high shock intensity (0.8 mA). Because animals
in the predicting-context group infused with cor-
ticosterone behaved similarly to control animals
in the predicting-cue group, the latest group also
was studied. In vehicle-infused mice, the correct
identification of the context as predictor of the
shock (predicting-context group) was associated
with high levels of c-Fos expression in the dentate
gyrus (DG) of the hippocampus and low levels of
c-Fos expression in the amygdala. At the oppo-
site, the identification of the cue as the correct
predictor (predicting-cue group) was associated
with low c-Fos levels in the DG and high c-Fos
levels in the amygdala (Fig. 3). No significant
differences between the two groups were ob-
served in CA1 and CA3 (Fig. 3 and fig. S2). As
previously observed (23), in the amygdala the re-
sponse was completely lateralized and present
only in the right hemisphere (Fig. 3 and fig. S2).
Intrahippocampal corticosterone infusions in the
predicting-context group decreased c-Fos expres-
sion in the dorsal CA1 and the ventral DG, whereas
it increased c-Fos expression in the right amyg-
dala. Thus, the pattern of c-Fos expression in the
predicting-context group infused with corticoster-
one approximated the one observed in control ani-
mals for which the correct predictor was the cue.
During conditioning with an intense threat, an
increase in glucocorticoid level in the hippocam-
VOL 335 SCIENCE www.sciencemag.org
pus can generate PTSD-like memory impair-
ments in mice. Animals in the predicting-context
group infused with corticosterone after condi-
tioning with the highest shock intensity did not
show conditioned fear in response to the con-
ditioning context, the correct predictor of the threat.
These animals showed instead a fear response to
salient cues that did not predict the threat in nor-
mal conditions: a tone that was part of the stress-
ful experience but was never associated with shock
delivery, and even a tone resembling the previous
one but never experienced before. This impair-
ment is very similar to the one observed in PTSD
patients in which contextual peritraumatic cues
are often forgotten, whereas salient but irrelevant
ones are strongly remembered. These salient cues,
and others more or less similar to them, can then
induce a strong fear response in contexts different
from the traumatic one (1, 2).
Downloaded from http://science.sciencemag.org/ on October 29, 2016
PTSD-like memory impairments were asso-
ciated with a switch in neural activation within
the hippocampal-amygdalar circuit. In controls,
the identification of the context as the right pre-
dictor of the threat was associated with low amyg-
dalar activation and high activation in the DG,
whereas the opposite pattern was observed in
animals identifying the cue as the correct pre-
dictor. After corticosterone infusions, when the
animals in the predicting-context group identified
the cue instead of the context as the predictor of
the threat, the activation of the right amygdala
increased, whereas it decreased in the ventral DG
and the dorsal CA1 of the hippocampus. This
hippocampal subregion selectivity is consistent
with both the critical role of the dorsal CA1 in the
processing of contextual information and with
the high sensitivity of the ventral DG to stress
(24, 25). The observed alterations in neural acti-
vation are also very similar to those observed in
PTSD patients, showing an impaired hippocam-
pal function, which is sometimes associated with
decreased hippocampal volume (14), and an amyg-
dalar hyperactivation in response to trauma-related
cues (26), in particular in the right hemisphere
(27, 28). The relevance of an imbalance between
the activity of the right and the left amygdala is
also supported by the development of PTSD in a
patient in which the left amygdala was surgically
ablated (29).
These results provide solid evidence for the
existence of PTSD-like memory impairments
in rodents and identify one of the potential patho-
physiological mechanisms of this condition.
Understanding the molecular mechanisms
through which high levels of glucocorticoids in
the hippocampus can modify neural activation in
the hippocampal-amygdalar circuit could open
new avenues for the development of innovative
treatments of PTSD.
References and Notes
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J. Trauma. Stress 8, 527 (1995).
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material on Science Online.
17. L. Calandreau et al., J. Neurosci. 26, 13556 (2006).
18. A. Desmedt, R. Garcia, R. Jaffard, J. Neurosci. 18,
480 (1998).
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25. M. R. Hunsaker, R. P. Kesner, Neurobiol. Learn. Mem.
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28. L. M. Shin et al., Am. J. Psychiatry 156, 575 (1999).
29. S. D. Smith, B. Abou-Khalil, D. H. Zald, J. Abnorm.
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REPORTS
Acknowledgments: We thank F. Naneix for helpful discussions
and C. Dupuy, A. Faugere, A. Grel, and F. Roug-Pont for
technical help. N.K., A.D., and P.V.P. conceived and
designed the experiments. N.K., M.V., N.M., Y.P., L.B.B.,
L.C., and A.D. performed the experiments. N.K., M.V.,
and A.D. analyzed the data. N.K., A.M., A.D., and P.V.P.
wrote the manuscript. This work was supported by Centre
National de la Recherche Scientifique, Institut National
de la Sant et de la Recherche Mdicale, Fondation pour la
Recherche sur le Cerveau, Conseil Rgional dAquitaine,
Ministre de lEnseignement suprieur et de la Recherche,
and University of Bordeaux.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1207615/DC1
Materials and Methods
Figs. S1 and S2
References
28 April 2011; accepted 9 February 2012
Published online 23 February 2012;
10.1126/science.1207615

Downloaded from http://science.sciencemag.org/ on October 29, 2016

can be used to control the specific time window
Generation of a Synthetic Memory Trace in which active neurons are genetically tagged
with hM3Dq by modulating tTA-driven transcrip-
Aleena R. Garner,1,2 David C. Rowland,3 Sang Youl Hwang,1 Karsten Baumgaertel,1 tion (11, 13). To test the kinetics of CNO-based
Bryan L. Roth,4 Cliff Kentros,3 Mark Mayford1,2* neural activation in these animals, we performed
in vivo recording in the hippocampus of anesthe-
We investigated the effect of activating a competing, artificially generated, neural representation tized animals. We found an increase in neuronal
on encoding of contextual fear memory in mice. We used a c-fosbased transgenic approach activity that reached a maximum intensity be-
to introduce the hM3Dq DREADD receptor (designer receptor exclusively activated by designer drug) tween 30 and 40 min after CNO injection (Fig.
into neurons naturally activated by sensory experience. Neural activity could then be specifically 1D). To examine the increase in neural activity
and inducibly increased in the hM3Dq-expressing neurons by an exogenous ligand. When an more broadly, we used endogenous c-fos expres-
ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a sion as an indicator of neural activity (Fig. 1, E
distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the and F). Relative to controls, we found significant
artificially stimulated network within the conditioning context was required for retrieval of the increases (by a factor of 2 to 20) in c-fos
memory, and the memory was specific for the spatial pattern of neurons artificially activated labeling across multiple brain regions in CNO-
during learning. Similar stimulation impaired recall when not part of the initial conditioning. injected hM3Dqfos transgenic mice (table S1).
Labeling for c-fos was found in both hM3Dq-
irect electrical stimulation can be used to ural sensory stimuli (710). How does this inter- positive and hM3Dq-negative neurons, with 91 T

D define functional domains in the brain,

elicit stereotyped behavioral responses,
drive self-stimulation behavior, and serve as con-
ditioned or unconditioned stimuli in conditioning
paradigms (14). This type of stimulation has
typically been focal, using either microelectrodes
or, more recently, genetically encoded mediators
of neural excitability such as channelrhodopsin
(5, 6). Although such discrete, temporally coor-
dinated, focal stimulation can drive behavior, we
know much less about the effects of stimulating
broadly distributed neural networks. The mam-
malian cortex displays substantial nonrandom,
spontaneous neural activity that is internally gen-
erated rather than arising from sensory inputs,
and this activity influences the processing of nat-
1
Department of Cell Biology and Dorris Neuroscience Center,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA. 2Neurosciences Graduate Program,
University of California, San Diego, 9500 Gilman Drive, La
Jolla, CA 92037, USA. 3Department of Psychology, Institute of
Neuroscience, University of Oregon, Eugene, OR 97403, USA.
4
Departments of Pharmacology, Chemical Biology, and Medic-
inal Chemistry and Program in Neuroscience, University of
North Carolina Chapel Hill Medical School, Chapel Hill, NC
27599, USA.
*To whom correspondence should be addressed. E-mail:
mmayford@scripps.edu
nally generated activity influence the formation
of a new memory representation?
To investigate this question, we used trans-
genic mice (Fig. 1A) in which the hM3Dq receptor
is expressed in an activity-dependent manner by
a c-fos promoterdriven tTA transgene (hM3Dqfos
mice) (11, 12). hM3Dq is a Gq-coupled receptor
that responds specifically to clozapine-N-oxide
(CNO) and produces strong depolarization and
spiking in pyramidal neurons (12). Transgenic
mice exposed to a particular environmental stim-
ulus will express hM3Dq in those neurons that are
sufficiently active to induce the c-fos promoter,
and this naturally occurring neural ensemble can
be subsequently reactivated artificially in the trans-
genic mice by delivery of CNO. Artificial activi-
ty induced in this manner will retain the spatial
character of the neural ensemble, but will not
preserve the temporal dynamics achieved by
natural stimuli.
The expression of hM3Dq is widely distrib-
uted in the brain of hM3Dqfos double transgenic
mice in the absence of doxycycline (Dox),
enabling tTA-driven transcription (Fig. 1, B
and C). Within a given brain area, expression is
limited to a fraction of excitatory neurons that are
sufficiently active to drive the c-fos promoter. Dox
2% of hM3Dq-positive neurons in CA1 colabeled
with c-fos (fig. S2).
In standard contextual fear conditioning, an-
imals develop a memory for the conditioning
chamber in which they receive a footshock. The
ability to form the context association is depen-
dent on the hippocampus, which participates in
encoding a representation of the environment
(14, 15). To test the effects of competing circuit
activation on the formation of a memory trace,
we designed the fear-conditioning protocol out-
lined in Fig. 2A. On day 1, hM3Dqfos mice were
exposed to a novel context (ctxA) in order to
drive expression of the hM3Dq transgene into
neurons activated in that context. On day 2, mice
were injected with Dox to inhibit further hM3Dq
receptor expression and with CNO to stimulate
activity in the spatial pattern of neurons that
expressed the receptor. The mice were then fear-
conditioned in a distinct context (ctxB), and 24
hours later, memory performance was tested in
the absence and presence of CNO. Thus, we fired
the neurons active in ctxA while the mice were
fear-conditioned in ctxB.
We anticipated three potential outcomes. The
strong synthetic activation of ctxA neurons could
be dominant and serve as a conditioned stimulus

www.sciencemag.org SCIENCE VOL 335 23 MARCH 2012 1513

 Glucocorticoids Can Induce PTSD-Like Memory Impairments
in Mice
Nadia Kaouane, Yves Porte, Monique Valle, Laurent
Brayda-Bruno, Nicole Mons, Ludovic Calandreau, Aline
Marighetto, Pier Vincenzo Piazza and Aline Desmedt (February 23,
2012)
Science 335 (6075), 1510-1513. [doi: 10.1126/science.1207615]
originally published online February 23, 2012

Downloaded from http://science.sciencemag.org/ on October 29, 2016

Editor's Summary

Remembering Stressful Events

Situations surrounding emotional events are better remembered than others that accompany
neutral events. However, in severe pathological states such as posttraumatic stress disorder (PTSD),
exposure to threatening situations can also result in memory impairment. In this case, a hypermnesia for
a salient trauma-related cue is associated with loss of memory for important aspects of the traumatic
event. The memory for the core traumatic event is enhanced, but the capacity to place it in the right
place and in response to the right cues is reduced. Kaouane et al. (p. 1510, published online 23
February) associated a high-intensity threat with the infusion of corticosterone in the hippocampus to
induce PTSD-like memory impairments in mice. The animals became unable to identify the threat
context as the right predictor of the threat, and they showed a fear response for discrete salient cues
normally identified as safe. The neural activation patterns in the amygdala and hippocampal regions of
these mice were similar to those observed in human PTSD.

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