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Oxytocin increases amygdala reactivity to threatening
scenes in females
Alexander Lischkea,b,1,*, Matthias Gamerc,1, Christoph Bergerb,
Annette Grossmannd, Karlheinz Hauensteind, Markus Heinrichse,
Sabine C. Herpertza, Gregor Domese,**
aDepartment of General Psychiatry, University of Heidelberg, Voßstr. 2, D-69115 Heidelberg, Germany
bDepartment of Psychiatry and Psychotherapy, University of Rostock, Gehlsheimerstr. 20, D-18147 Rostock, Germany
cDepartment of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany
dDepartment of Radiology, University of Rostock, Schillingallee 35, D-18055 Rostock, Germany
eDepartment of Psychology, University of Freiburg, Stefan-Meier-Straße 8, D-79104 Freiburg, Germany
Received 4 September 2011; received in revised form 26 January 2012; accepted 26 January 2012
Psychoneuroendocrinology (2012) 37, 1431—1438
behavior, which appear to be mediated by an OT-dependent modulation of amygdala activity in
the context of social stimuli. In humans, OT decreases amygdala reactivity to threatening faces in
males, but enhances amygdala reactivity to similar faces in females, suggesting sex-specific
differences in OT-dependent threat-processing. To further explore whether OT generally
enhances amygdala-dependent threat-processing in females, we used functional magnetic
resonance imaging (fMRI) in a randomized within-subject crossover design to measure amygdala
activity in response to threatening and non-threatening scenes in 14 females following intranasal
administration of OT or placebo. Participants’ eye movements were recorded to investigate
whether an OT-dependent modulation of amygdala activity is accompanied by enhanced explo-
ration of salient scene features. Although OT had no effect on participants’ gazing behavior, it
increased amygdala reactivity to scenes depicting social and non-social threat. In females, OT
may, thus, enhance the detection of threatening stimuli in the environment, potentially by
interacting with gonadal steroids, such as progesterone and estrogen.
# 2012 Elsevier Ltd. All rights reserved.
The neuropeptide oxytocin (OT) is well known for its profound effects on social
* Corresponding author at: Department of Psychiatry and Psychotherapy, University of Rostock, Gehlsheimer Str. 21, D-18147 Rostock,
Germany. Tel.: +49 381 494 4968; fax: +49 381 494 9502.
** Corresponding author. Tel.: +49 761 203 3035; fax: +49 761 203 3023.
E-mail addresses: email@example.com (A. Lischke), firstname.lastname@example.org (G. Domes).
1These authors contributed equally to this work.
Available online at www.sciencedirect.com
j our na l h omepa g e: www.e lse vie r.c om/l oca te/ psyne ue n
0306-4530/$ — see front matter # 2012 Elsevier Ltd. All rights reserved.
Author's personal copy
The neuropeptide oxytocin (OT) is crucially involved in the
regulation of reproductive and social behavior in non-human
mammals (Lee et al., 2009), including parturition, lactation,
parental care, play, bonding and mating. OT also appears to
be a potent modulator of human social behavior (Meyer-
Lindenberg et al., 2011). In humans, OT attenuates anxiety
and stress (Ditzen et al., 2009; Heinrichs et al., 2003),
promotes trust (Kosfeld et al., 2005) and facilitates the
encoding (Guastella et al., 2008; Rimmele et al., 2009)
and recognition of facial expressions (Di Simplicio et al.,
2009; Domes et al., 2007b; Fischer-Shofty et al., 2010;
Lischke et al., 2011; Marsh et al., 2010; Schulze et al., 2011).
With regard to the neurobiological mechanism mediating
the behavioral effects of OT, the amygdala with its cortical
and subcortical projections appears to be a key region (Pitt-
man and Spencer, 2005). OT is released within the rat amyg-
dala (Bosch et al., 2005; Ebner et al., 2005), where it acts on
specific receptors (Huber et al., 2005; Terenzi and Ingram,
2005) to modulate fear (McCarthy et al., 1996) and aggression
(Bosch et al., 2005). Recent evidence suggests that OT
modulates neuronal activity in the human amygdala in a
similar way, especially in response to threatening stimuli
(Baumgartner et al., 2008; Domes et al., 2007a, 2010a;
Gamer et al., 2010; Kirsch et al., 2005; Petrovic et al.,
2008; Singer et al., 2008). Interestingly, OT decreases amyg-
dala reactivity to aversive, threat-related scenes (Kirsch
et al., 2005) and fearful, threat-related faces (Domes
et al., 2007a; Gamer et al., 2010; Kirsch et al., 2005; Petrovic
et al., 2008) in males, but increases amygdala reactivity to
similar faces in females (Domes et al., 2010a). Although sex
differences in neuropeptidergic functioning are well known
in non-human mammals (Carter et al., 2009), they have
rarely been studied in humans. In fact, our initial finding
of enhanced amygdala reactivity to fearful faces in females
receiving OT has not been replicated yet (Domes et al.,
2010a). In addition, it remains unresolved whether the
observed OTeffects are specific to facial stimuli or generalize
to other stimulus classes such as more complex emotional
In consideration of this, the current study examined how
OT modulates amygdala reactivity to negative, positive and
neutral scenes in females. We also measured how OT affects
visual exploration of these scenes because it has been shown
that OT alters visual processing of emotional stimuli in males
(Gamer et al., 2010). Based on our previous findings (Domes
et al., 2010a), we hypothesized that OTspecifically enhances
amygdala activity to negative scenes, potentially by increas-
ing exploration of salient scene features.
Fourteen female adults (age: M = 23.79 years, SD = 2.32
years) participated voluntarily in this study. Exclusion criteria
were medical or mental illness, use of medication, substance
abuse, smoking, pregnancy, and lactation. Exclusion was
determined based on a brief clinical interview and several
self-report questionnaires (see Supplementary Methods). All
participants provided written, informed consent and were
paid for participation. The study was carried out in accor-
dance with the Declaration of Helsinki and was approved by
the Ethics Committee of the University of Rostock.
2.2. Experimental procedure
In a double-blind, placebo-controlled and counter-balanced
within-subject design, participants were tested twice during
the mid-luteal phase of their menstrual cycle within an
interval of approximately four weeks. The mid-luteal phase
was determined by participants’ self-reports and validated
by blood samples drawn on the testing days (see Supplemen-
tary Methods). In addition, pregnancy tests were carried out
to confirm that none of the participants was pregnant at the
time of testing. Following a standardized protocol (Domes
et al., 2010a), participants self-administered a nasal spray
either containing 24 international units (IU) of OT (Syntoci-
non Spray; Novartis, Basel, Switzerland) or placebo (PL;
containing all ingredients except for the neuropeptide)
45 min before the beginning of the functional magnetic
resonance imaging (fMRI). Substance-induced changes in
mood, arousal and wakefulness were tracked by administer-
ing a multidimensional mood questionnaire (MDBF, Steyer
et al., 1997) before and after substance application. Blood
samples were also drawn before and after substance applica-
tion to control for differences in OT assimilation (see Sup-
2.3. Experimental paradigm
During fMRI scanning, participants performed an emotional
arousal rating task while viewing positive, negative and
neutral scenes selected from the International Affective
Picture System (IAPS, Lang et al., 2005; see Supplementary
Methods) via a set of fiber optic goggles (VisuaStim, Reso-
nance Technology, Los Angeles, CA, USA). All scenes of a
particular valence were randomly presented in blocks that
consisted of an 18.6 s viewing and 3 s rating phase. In the
viewing phase, six scenes of the same valence were pre-
sented for 3 s each, with an interstimulus interval of 100 ms.
In the subsequent rating phase, the previously presented
scenes had to be collectively rated on a four-point scale
for emotional arousal (0 = low arousal and 3 = high arousal)
by pressing a corresponding button within 3 s. For each
valence category, four blocks of scenes were presented,
resulting in a total of 12 blocks, whose order was randomly
determined. The interblock interval amounted to 13—
15.75 s. Scene presentation and response registration were
controlled using Presentation 12.1 (Neurobehavioral Sys-
tems, Albany, CA, USA).
During fMRI scanning, participants’ eye movements were
recorded with an MRI compliant infra-red eye-tracker
(VisuaStim, Resonance Technology, Los Angeles, CA, USA)
to control for substance-induced differences in visual atten-
tion. Raw data were collected at a 60 Hz sampling rate with a
spatial resolution of approximately 0.158 for tracking resolu-
tion and 0.25—1.08 for gaze position accuracy. After filtering
A. Lischke et al.
Author's personal copy
of the raw data, fixations were coded when gaze remained
for at least 100 ms within a 14-pixel diameter region. Matlab
7.7 (MathWorks Inc., Natick, MA, USA) was then used to
determine the mean number and duration of fixations for
an entire scene as well as for predefined regions of interests
(see Supplementary Methods). Finally, the relative number
and duration of fixations for these regions compared to the
entire scene was calculated and used for statistical analyses.
Eye tracking and behavioral data were analyzed using a
series of 2 ? 3 repeated measures ANOVAs (Condition ?
Valence). The Greenhouse—Geisser correction was applied
to correct for potential violations of the sphericity assump-
tion whenever appropriate. Partial h2is reported as an effect
2.5. Magnetic-resonance imaging
2.5.1. Data acquisition
Magnetic-resonance imaging was performed on a 1.5-Twhole-
body MR-scanner (Magnetom Avanto, Siemens, Erlangen, Ger-
many) equipped with a standard head coil. Using a T2*-sensi-
tive gradient echo-planar imaging sequence (repetition time,
2670 ms; echo time, 40 ms; flip angel, 908; field of view,
205 mm ? 205 mm; matrix, 64 ? 64; in-plane resolution,
3.2 mm ? 3.2 mm), 36 axial slices (slice thickness, 3.5 mm;
no gap) were acquired covering the whole brain. Additionally,
isotropic high-resolution (1 ? 1 ? 1 mm3) structural images
were recorded using a T1-weighted coronal oriented magne-
tization-prepared rapid gradient echo (MPRAGE) sequence
(repetition time, 1500 ms; echo time, 3.9 ms; flip angle,
158; field of view, 256 ? 256; matrix, 256 mm ? 256 mm) with
160 sagittal slices (slice thickness, 1 mm).
2.5.2. Data analysis
Image preprocessing and statistical data analysis were per-
formed with the Statistical Parametric Mapping software
SPM8 (Wellcome Department of Imaging Neuroscience, Lon-
don, UK). Prior to image preprocessing, the first four images
of each functional series were discarded due to T1 equilibra-
tion effects. The remaining images were then realigned to
the first image in the series and unwarped to account for
movement-related artifacts (Andersson et al., 2001). There-
after, the functional images of both runs (OTand PL) were co-
registered to the T1 image of each participant. The T1 image
was then segmented to determine normalization parameters
which were subsequently used to spatially normalize all
functional images to the standard anatomical Montreal Neu-
rological Institute (MNI) space. Finally, functional images
were smoothed with an isotropic Gaussian kernel (FWHM:
10 mm) and temporally filtered with an autoregressive AR
model (Ashburner, 2007) and a 128 s high-pass filter to
account for serial correlations in the functional series.
For the first-level fixed-effects analysis, scene presenta-
tion was modeled as separate boxcar regressors for each
experimental condition (negative, positive and neutral
valence) and convolved with the hemodynamic response
function (hrf). Subsequently, simple contrasts were calcu-
lated to investigate brain activation in response to positive,
negative and neutral scenes, respectively. The resulting
contrast maps were used to construct a 2 ? 3 design matrix
(repeated measures ANOVA) as a second-level random-effects
analysis. Within this model, we compared brain activation
between negative and neutral as well as positive and neutral
scenes in the PL and OT condition and we calculated interac-
tion contrasts to test whether these differential activations
differed between the PL and OT condition.
Since we were primarily interested in amygdala activa-
tion, we performed a small volume correction with a thresh-
old of p < .05 in predefined anatomical amygdala regions of
interest (Tzourio-Mazoyer et al., 2002). In addition to this
hypothesis-driven region of interest analysis, we performed
an exploratory whole brain analysis with a threshold of
p < .001 (uncorrected) and a cluster threshold of k ? 20
voxels. For illustration purposes, statistical parametric maps
were thresholded at p < .01 (uncorrected) and overlaid on a
representative structural image using MRIcron (http://
3.1. Hormones and mental state
Participants’ progesterone and estrogen levels on the testing
days were in the range typically displayed during the mid-
luteal phase of the menstrual cycle (Nelson, 2005). Paired t-
tests with Bonferroni correction revealed no significant dif-
ferences in participants’ hormone levels between the OTand
PL condition, although estrogen levels tended to be higher in
the OT than in the PL condition (see Table 1). A 2 ? 2
repeated measures ANOVA (Condition ? Time) indicated that
participants’ OT levels before substance application were
not significantly different in the PL and OTcondition, whereas
their OT levels after substance application were significantly
higher in the OT than in the PL condition (see Table 1; main
effect condition: F[1,13] = 6.30, p = .03; main effect time:
F[1,13] = 39.46, p < .001, h2= 0.75; interaction Condi-
tion ? Time: F[1,13] = 26.29, p < .001, h2= 0.67). However,
a series of 2 ? 2 repeated measures ANOVAs (Condi-
tion ? Time) showed that OT application had no effect on
participants’ mood, arousal or wakefulness (all Fs < 1.27, all
ps > .28 for all substance related effects, see Table 1).
3.2. Experimental paradigm
3.2.1. Behavioral data
A 2 ? 3 repeated measures ANOVA (Condition ? Valence) on
the arousal ratings revealed no significant differences
between the OT and PL condition (see Table 1; main effect
condition: F[1,13] = 0.04, p = .84, h2= 0.00; main effect
valence: F[2,26] = 182.41, e = 0.86, p < .001, h2= 0.93;
interaction Condition ? Valence: F[2,26] = 1.12, e = 0.81,
p = .33, h2= 0.08). In both conditions, participants rated
emotional scenes as more arousing than non-emotional ones
(positive vs. neutral scenes: p < .001; negative vs. neutral
scenes: p < .001). Among emotional scenes, negative scenes
yielded higher arousal ratings than positive ones ( p < .001).
3.2.2. Eye tracking data
A series of 2 ? 3 repeated measures ANOVA (Condition ?
Valence) showed no significant differences between the PL
and OT condition with regard to the number of fixations
F[1,11] = 0.11,
Oxytocin increases amygdala reactivity to threatening scenes in females
Author's personal copy
p = .75, h2= 0.10; main effect valence: F[2,22] = 1.97,
e = 0.99, p = .16, h2= 0.15; interaction Condition ? Valence:
F[2,22] = 1.26, e = 0.89, p = .30, h2= 0.10) or duration of
fixations in the predefined ROIs (see Table 1; main effect
condition: F[1,11] = 0.06, p = .81, h2= 0.00; main effect
valence: F[2,22] = 1.10, e = 0.83, p = .34, h2= 0.09; interac-
tion Condition ? Valence: F[2,22] = 0.77, e = 0.80, p = .45,
3.2.3. Imaging data
After PL administration, negative scenes activated the right
amygdala significantly more than neutral ones (Z = 2.92,
p = .031, see Table 2). A similar, albeit non-significant, effect
was found in the left amygdala (Z = 2.49, p = .077, see Table
2). This effect was significant in both amygdalae after OT
administration (left amygdala: Z = 4.46, p < .001; right
amygdala: Z = 5.70, p < .001, see Table 2). Positive relative
to neutral scenes, on the contrary, had no effect on amygdala
activity after PL administration and only on right amygdala
activity after OTadministration (Z = 3.58, p = .004, see Table
2). An interaction analysis directly contrasting the OT with
the PL condition revealed more right-lateralized amygdala
activity to negative relative to neutral scenes after OT than
after PL administration (Z = 3.01, p = .024; see Fig. 1 and
Table 2). A similar, albeit marginally significant effect was
found in the left amygdala (Z = 2.50, p = .075, see Fig. 1 and
Table 2). Contrasting the PL with the OT condition, on the
contrary, revealed no evidence for significant differences in
amygdala activity. The results of this imaging analysis are
summarized in Table 2. The exploratory whole brain analysis
Amygdala activations for negative and positive as compared to neutral scenes in the PL and OT condition.
OT > PL
Note. Activations are reported when pFWE< .10 (small volume correction for anatomical amygdala regions of interest). PL = placebo.
OT = oxytocin. k = cluster size in voxels (voxel size after preprocessing was 2 ? 2 ? 2 mm3). Peak coordinates of each cluster are reported in
Group differences in hormone levels, mental state, arousal ratings and visual attention.
Oxytocin (pg/ml) [pre]
Oxytocin (pg/ml) [post]
Visual attentiona— relative number and duration of fixations
Positive scenes [number]
Positive scenes [duration]
Negative scenes [number]
Negative scenes [duration]
Neutral scenes [number]
Neutral scenes [duration]
t(11) = 0.60
t(10) = 2.05
t(13) = 0.98
t(13) = 3.70
t(13) = 0.19
t(13) = 0.30
t(13) = 0.00
t(13) = 0.66
t(13) = 1.03
t(13) = 0.73
t(11) = 0.23
t(11) = 0.15
t(11) = 1.47
t(11) = 1.04
t(11) = 0.59
t(11) = 0.60
Note. Pre: pre-application; post: post-application.
an = 12.
bn = 11.
**p < .01, two-tailed.
A. Lischke et al.
Author's personal copy
only revealed few brain regions showing a modulatory effect
of OT (see Table S2, Supplementary Results). Although p-
values were not corrected for multiple comparisons in this
analysis, a comparably large cluster in the left anterior
temporal lobe seemed to show a similar activation pattern
as the amygdala.
In order to test whether the marginally significant differ-
ence in estrogen levels between the OT and the PL condition
accounted for the observed OTeffect on amygdala activity, we
performed a correlation analysis between estrogen levels and
activity changes in the amygdala. However, correlating the
difference between estrogen levels in the OTand PL condition
with the percentage signal change of the observed interaction
effect (OTneg-neut> PLneg-neut) in the corresponding peak vox-
els (left amygdala: x = ?22, y = ?8, z = ?14; right amygdala:
x = 24, y = 6, z = ?16), revealed no substantial correlation,
neither for the left (r = .31, t = 0.99, p = .35), nor for the
right (r = ?.16, t = 0.49, p = .64) amygdala.
The aim of the present study was to investigate how OT
modulates amygdala activity during the processing of emo-
tional scenes in females. We found that OT selectively
increased amygdala reactivity to threatening scenes, which
is consistent with a recent report of enhanced amygdala
reactivity to threat-related faces in females receiving OT
(Domes et al., 2010a). Moreover, an exploratory whole brain
analysis revealed a similar response in the left anterior
temporal lobe, a structure that has also been implicated
in social and emotional processing (Olson et al., 2007). These
effects could not be explained by differences in the explora-
tion of salient scene features and they were not evident in
subjective arousal ratings. It has to be mentioned, however,
that arousal ratings were only given on a roughly graded four-
point scale for a series of scenes. Therefore, it seems possible
that these ratings were too insensitive to detect subtle
changes in arousal during scene presentation. Future studies
should, thus, use more sensitive measures (e.g., skin con-
ductance measures) to investigate whether the reported
changes in amygdala activity are accompanied by behavioral
changes. The currently observed effect of enhanced amyg-
dala reactivity to threatening scenes following OT treatment
in females sharply contrasts with the observation of attenu-
ated amygdala activity in response to threat-related scenes
(Kirsch et al., 2005) and faces (Domes et al., 2007a; Gamer
et al., 2010; Kirsch et al., 2005; Petrovic et al., 2008) in
males. Taken together, these findings suggest that OT differ-
entially affects the neural processing of threatening stimuli
in males and females.
The amygdala is crucially implicated in the processing of
potentially threatening stimuli in the environment (Bishop,
2008). The basal and lateral nuclei of the amygdala receive
highly processed sensory information, which enable the
detection of threat-related stimuli. The central nucleus
subsequently initiates fear responses via projections to the
brain stem, allowing the organism to behave appropriately in
a hostile environment. The OT-dependent increase in amyg-
dala reactivity to threatening scenes may thus reflect an
effect of the neuropeptide on female threat-avoidance and
safety seeking behavior. In the present study, the threatening
scenes depicted social and non-social sources of threat (e.g.,
snarling dogs, injured children or exploding cars), which may
lead to the speculation that OT generally enhances threat-
processing in females. In males, on the contrary, the proces-
sing of threat-related stimuli appears to be attenuated by OT
as indicated by a decrease in amygdala reactivity to threa-
tening stimuli following OT administration (Domes et al.,
2007a; Gamer et al., 2010; Kirsch et al., 2005; Petrovic
et al., 2008). As discussed previously (Kirsch et al., 2005),
this reduction in amygdala activity appeared to be more
pronounced in the context of social as compared to non-
social threat, suggesting that OT may selectively attenuate
scenes. (A) Statistical parametric map (coronal plane, y = 4) revealing a statistically significant effect in the right amygdala (peak
voxel: x = 24, y = 6, z = ?16; Z = 3.01; p = .024, FWE-corrected) and a marginally significant effect in the left amygdala (peak voxel:
x = ?22, y = ?8, z = ?14; Z = 2.50; p = .075, FWE-corrected) for the contrast OTneg-neut> PLneg-neut. The anatomical amygdala region of
interest is visualized with a white outline. (B) Percent signal change as a function of condition and picture valence in the right amygdala
(peak voxel: x = 24, y = 6, z = ?16). Error bars depict standard errors of the mean. Note. For interpretation of the references to color in
this figure legend, the reader is referred to the web version of the article.
Region-of-interest analysis for the amygdala. Oxytocin increased amygdala activity to negative as compared to neutral
Oxytocin increases amygdala reactivity to threatening scenes in females
Author's personal copy
social-threat sensitivity in males. Although these findings
suggest a possible sexual-dimorphism in the processing of
social and non-social threat, they should be interpreted very
cautiously as none of the above mentioned studies was
explicitly designed to investigate this issue. For example,
the use of a block design in the present study precluded the
possibility to investigate whether OT differentially affected
the processing of social and non-social scenes. Future studies
should, therefore, employ more sophisticated designs to
investigate the neural effects of OT on social and non-social
threat-processing in males and females.
Sex-specific differences in amygdala reactivity to threat-
related scenes have previously been reported (Domes et al.,
2010b; Mackiewicz et al., 2006), indicating that threat-proces-
sing is generally enhanced in females. Gonadal steroids pre-
sumably contribute to these differences because amygdala
responsiveness to threatening scenes seems to be modulated
by progesterone and estrogen (Andreano and Cahill, 2010;
Goldstein et al., 2005, 2010). Progesterone and estrogen are
also implicated in sex-specific alterations of the OT-system (de
Vries, 2008). Estrogen, in particular, stimulates OTrelease from
hypothalamic neurons (Akaishi and Sakuma, 1985) and pro-
motes OT receptor gene expression (Bale et al., 1995; Qui-
nones-Jenab et al., 1997) as well as OTreceptor binding in the
amygdala (Young et al., 1998). Considering that estrogen levels,
which are generally elevated during the mid-luteal phase
(Nelson, 2005), tended to be higher in the OT compared to
the PL condition, suggests that estrogen may have contributed
to the observed changes in threat-related amygdala activity
after OT administration. However, the present results do not
provide convincing evidence for this notion, which may be due
to the limitations of the present study design. For example, all
participants were investigated during the mid-luteal phase
which may have reduced the variance in estrogen levels that
would have been necessary for the respective correlation
analysis. Future studies should, therefore, investigate the
impact of estrogen on OT induced-changes in amygdala-depen-
dent threat-processing during different cycle phases.
From an evolutionary viewpoint, enhanced processing of
potentially threatening stimuli may be highly adaptive for
females during pregnancy, nursing, and infant care as these
situations render them vulnerable to a broad array of threats.
Accordingly, females may be exceptionally threat-sensitive
during times of increased gonadal steroid concentrations,
such as during times of fertility and pregnancy as suggested
by estrogen and progesterone modulated changes in amyg-
dala-dependent threat-processing (Andreano and Cahill,
2010; Goldstein et al., 2005, 2010). Gonadal steroids are
elevated during pregnancy as well as during the mid-luteal
phase (Nelson, 2005), suggesting that OT may have further
enhanced females’ propensity to detect threatening stimuli
in the environment.
OT-dependent alterations in female threat-detection and
safety-seeking behavior have also been found in non-human
mammals (Bosch, 2011), suggesting that the observed OT-
effects may indeed reflect an evolutionary adaptation to
hostile environments. In female rats, local OT-levels within
the amygdala increase during an intruder—encounter and are
associated with the degree of aggression displayed toward
the intruder (Bosch et al., 2005). Most relevant here, OT
increases aggression toward the intruder but not toward the
offspring, indicating a role for OT in the protection of the
offspring. Interestingly, the observed OT-effects appear to be
mediated by the rats’ innate level of anxiety, suggesting that
anxious rats perceive the encounter as more threatening
than non-anxious ones and consequently display more mater-
nal aggression (Bosch et al., 2005). Besides OT, gonadal
steroids, in particular estrogen, are implicated in rats’
maternal aggression (Lonstein and Gammie, 2002), which
further supports the notion that the observed OT-effects,
which appear to be mediated by estrogen, reflect an evolu-
tionary shaped threat—response.
Taken together, the findings of the present study, which are
consistent with previous ones (Domes et al., 2010a), suggest
that OT promotes female threat-detection by increasing amyg-
dala-dependent processing of threat-related stimuli. In males,
on the contrary, OTappears to attenuate threat-sensitivity by
decreasing amygdala reactivity to threat-related stimuli, par-
ticularly to those depicting social threat (Domes et al., 2007a;
Gamer et al., 2010; Kirsch et al., 2005; Petrovic et al., 2008).
However, these conclusions should be drawn with caution,
considering that we only investigated a relatively small num-
ber of females during the mid-luteal phase. Besides this, we
were unable to test whether social and non-social scenes
differentially affected amygdala-dependent threat-proces-
sing. Moreover, we only focused on the processing of threat-
related stimuli and did not consider the processing of other
aversive stimuli, which may also be affected by OT (Riem
et al., 2011). We suggest that future studies should be expli-
citly designed to investigate amygdala-dependent emotion
processing in males and females after OT administration,
preferably by explicitly considering cyclic variations in gonadal
steroid levels. It, thus, remains an interesting question for
future research to determine whether sex-specific differences
in neuropeptidergic functioning during the processing of emo-
tional, especially threatening, stimuli are indeed mediated by
gonadal steroids (Carter et al., 2009).
Role of funding source
This study was supported by the FORUN program of the
University of Rostock [to G.D.] and a grant from the German
Research Foundation [Do1312/1-1 to G.D. and S.C.H.].
Conflict of interest
We would like to thank Gisela Irmisch for assistance with
analysis of the hormone data.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.psyneuen.
A. Lischke et al.
Author's personal copy
Akaishi, T., Sakuma, Y., 1985. Estrogen excites oxytocinergic, but not
vasopressinergic cells in the paraventricular nucleus of female rat
hypothalamus. Brain Res. 335, 302—305.
Andersson, J.L., Hutton, C., Ashburner, J., Turner, R., Friston, K.,
2001. Modeling geometric deformations in EPI time series. Neuro-
image 13, 903—919.
Andreano, J.M., Cahill, L., 2010. Menstrual cycle modulation of
medial temporal activity evoked by negative emotion. Neuro-
image 53, 1286—1293.
Ashburner, J., 2007. A fast diffeomorphic image registration algo-
rithm. Neuroimage 38, 95—113.
Bale, T.L., Pedersen, C.A., Dorsa, D.M., 1995. CNS oxytocin receptor
mRNA expression and regulation by gonadal steroids. Adv. Exp.
Med. Biol. 395, 269—280.
Baumgartner, T., Heinrichs, M., Vonlanthen, A., Fischbacher, U.,
Fehr, E., 2008. Oxytocin shapes the neural circuitry of trust
and trust adaptation in humans. Neuron 58, 639—650.
Bishop, S.J., 2008. Neural mechanisms underlying selective attention
to threat. Ann. N.Y. Acad. Sci. 1129, 141—152.
Bosch, O.J., 2011. Maternal nurturing is dependent on her innate
anxiety: the behavioral roles of brain oxytocin and vasopressin.
Horm. Behav. 59, 202—212.
Bosch, O.J., Meddle, S.L., Beiderbeck, D.I., Douglas, A.J., Neumann,
I.D., 2005. Brain oxytocin correlates with maternal aggression:
link to anxiety. J. Neurosci. 25, 6807—6815.
Carter, C.S., Boone, E.M., Pournajafi-Nazarloo, H., Bales, K.L., 2009.
Consequences of early experiences and exposure to oxytocin and
vasopressin are sexually dimorphic. Dev. Neurosci. 31, 332—341.
de Vries, G.J., 2008. Sex differences in vasopressin and oxytocin
innervation of the brain. Prog. Brain Res. 170, 17—27.
Di Simplicio, M., Massey-Chase, R., Cowen, P.J., Harmer, C.J., 2009.
Oxytocin enhances processing of positive versus negative emo-
tional information in healthy male volunteers. J. Psychopharma-
col. 23, 241—248.
Ditzen, B., Schaer, M., Gabriel, B., Bodenmann, G., Ehlert, U.,
Heinrichs, M., 2009. Intranasal oxytocin increases positive com-
munication and reduces cortisol levels during couple conflict.
Biol. Psychiatry 65, 728—731.
Domes, G., Heinrichs, M., Glascher, J., Buchel, C., Braus, D.F.,
Herpertz, S.C., 2007a. Oxytocin attenuates amygdala responses
to emotional faces regardless of valence. Biol. Psychiatry 62,
Domes, G., Heinrichs, M., Michel, A., Berger, C., Herpertz, S.C.,
2007b. Oxytocin improves ‘‘mind-reading’’ in humans. Biol. Psy-
chiatry 61, 731—733.
Domes, G., Lischke, A., Berger, C., Grossmann, A., Hauenstein, K.,
Heinrichs, M., Herpertz, S.C., 2010a. Effects of intranasal oxyto-
cin on emotional face processing in women. Psychoneuroendo-
crinology 35, 83—93.
Domes, G., Schulze, L., Bottger, M., Grossmann, A., Hauenstein, K.,
Wirtz, P.H., Heinrichs, M., Herpertz, S.C., 2010b. The neural
correlates of sex differences in emotional reactivity and emotion
regulation. Hum. Brain Mapp. 31, 758—769.
Ebner, K., Bosch, O.J., Kromer, S.A., Singewald, N., Neumann, I.D.,
2005. Release of oxytocin in the rat central amygdala modulates
stress-coping behavior and the release of excitatory amino acids.
Neuropsychopharmacology 30, 223—230.
Fischer-Shofty, M., Shamay-Tsoory, S.G., Harari, H., Levkovitz, Y.,
2010. The effect of intranasal administration of oxytocin on fear
recognition. Neuropsychologia 48, 179—184.
Gamer, M., Zurowski, B., Buchel, C., 2010. Different amygdala
subregions mediate valence-related and attentional effects of
oxytocin in humans. Proc. Natl. Acad. Sci. U.S.A. 107, 9400—9405.
Goldstein, J.M., Jerram, M., Abbs, B., Whitfield-Gabrieli, S., Makris,
N., 2010. Sex differences in stress response circuitry activation
dependent on female hormonal cycle. J. Neurosci. 30, 431—438.
Goldstein, J.M., Jerram, M., Poldrack, R., Ahern, T., Kennedy, D.N.,
Seidman, L.J., Makris, N., 2005. Hormonal cycle modulates
arousal circuitry in women using functional magnetic resonance
imaging. J. Neurosci. 25, 9309—9316.
Guastella, A.J., Mitchell, P.B., Mathews, F., 2008. Oxytocin enhances
the encoding of positive social memories in humans. Biol. Psychi-
atry 64, 256—258.
Heinrichs, M., Baumgartner, T., Kirschbaum, C., Ehlert, U., 2003.
Social support and oxytocin interact to suppress cortisol and
subjective responses to psychosocial stress. Biol. Psychiatry 54,
Huber, D., Veinante, P., Stoop, R., 2005. Vasopressin and oxytocin
excite distinct neuronal populations in the central amygdala.
Science 308, 245—248.
Kirsch, P., Esslinger, C., Chen, Q., Mier, D., Lis, S., Siddhanti, S.,
Gruppe, H., Mattay, V.S., Gallhofer, B., Meyer-Lindenberg, A.,
2005. Oxytocin modulates neural circuitry for social cognition and
fear in humans. J. Neurosci. 25, 11489—11493.
Kosfeld, M., Heinrichs, M., Zak, P.J., Fischbacher, U., Fehr, E., 2005.
Oxytocin increases trust in humans. Nature 435, 673—676.
Lang, P.J., Bradley, M.M., Cuthbert, B.N., 2005. International affec-
tive picture system (IAPS): affective ratings of pictures and
instruction manual. In: Technical Report A-6, University of Flor-
ida, Gainesville, FL.
Lee, H.J., Macbeth, A.H., Pagani, J.H., Young 3rd, W.S., 2009.
Oxytocin: the great facilitator of life. Prog. Neurobiol. 88,
Lischke, A., Berger, C., Prehn, K., Heinrichs, M., Herpertz, S.C., Domes,
G., 2011. Intranasal oxytocin enhances emotion recognition from
dynamic facial expressions and leaves eye-gaze unaffected.
Lonstein, J.S., Gammie, S.C., 2002. Sensory, hormonal, and neural
control of maternal aggression in laboratory rodents. Neurosci.
Biobehav. Rev. 26, 869—888.
Mackiewicz, K.L., Sarinopoulos, I., Cleven, K.L., Nitschke, J.B.,
2006. The effect of anticipation and the specificity of sex differ-
ences for amygdala and hippocampus function in emotional
memory. Proc. Natl. Acad. Sci. U.S.A. 103, 14200—14205.
Marsh, A.A., Yu, H.H., Pine, D.S., Blair, R.J., 2010. Oxytocin improves
specific recognition of positive facial expressions. Psychophar-
macology (Berl) 209, 225—232.
McCarthy, M.M., McDonald, C.H., Brooks, P.J., Goldman, D., 1996. An
anxiolytic action of oxytocin is enhanced by estrogen in the
mouse. Physiol. Behav. 60, 1209—1215.
Meyer-Lindenberg, A., Domes, G., Kirsch, P., Heinrichs, M., 2011.
Oxytocin and vasopressin in the human brain: social neuropep-
tides for translational medicine. Nat. Rev. Neurosci. 12, 524—538.
Nelson, R.J., 2005. An Introduction to Behavioral Neuroendocrinology,
3rd ed. Sinauer Associates, Sunderland.
Olson, I.R., Plotzker, A., Ezzyat, Y., 2007. The Enigmatic temporal
pole: a review of findings on social and emotional processing.
Brain 130, 1718—1731.
Petrovic, P., Kalisch, R., Singer, T., Dolan, R.J., 2008. Oxytocin
attenuates affective evaluations of conditioned faces and amyg-
dala activity. J. Neurosci. 28, 6607—6615.
Pittman, Q.J., Spencer, S.J., 2005. Neurohypophysial peptides:
gatekeepers in the amygdala. Trends Endocrinol. Metab. 16,
Quinones-Jenab, V., Jenab, S., Ogawa, S., Adan, R.A., Burbach,
J.P., Pfaff, D.W., 1997. Effects of estrogen on oxytocin recep-
tor messenger ribonucleic acid expression in the uterus, pitui-
tary, and forebrain of the female rat. Neuroendocrinology 65,
Riem, M.M., Bakermans-Kranenburg, M.J., Pieper, S., Tops, M.,
Boksem, M.A., Vermeiren, R.R., van Ijzendoorn, M.H., Rombouts,
S.A., 2011. Oxytocin modulates amygdala, insula, and inferior
frontal gyrus responses to infant crying: a randomized controlled
trial. Biol. Psychiatry 70, 291—297.
Oxytocin increases amygdala reactivity to threatening scenes in females
Author's personal copy
Rimmele, U., Hediger, K., Heinrichs, M., Klaver, P., 2009. Oxytocin
makes a face in memory familiar. J. Neurosci. 29, 38—42.
Schulze, L., Lischke, A., Greif, J., Herpertz, S.C., Heinrichs, M.,
Domes, G., 2011. Oxytocin increases recognition of masked
emotional faces. Psychoneuroendocrinology 36, 1378—1382.
Singer, T., Snozzi, R., Bird, G., Petrovic, P., Silani, G., Heinrichs, M.,
Dolan, R.J., 2008. Effects of oxytocin and prosocial behavior on
brain responses to direct and vicariously experienced pain. Emo-
tion 8, 781—791.
Steyer, R., Schwenkmezger, P ., Notz, P ., Eid, M., 1997. Der Mehrdimen-
sionale Befindlichkeitsfragebogen (MDBF). Hogrefe, Go ¨ttingen.
Terenzi, M.G., Ingram, C.D., 2005. Oxytocin-induced excitation of
neurones in the rat central and medial amygdaloid nuclei. Neu-
roscience 134, 345—354.
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F.,
Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated
anatomical labeling of activations in SPM using a macroscopic
anatomical parcellation of the MNI MRI single-subject brain.
Neuroimage 15, 273—289.
Young, L.J., Wang, Z., Donaldson, R., Rissman, E.F., 1998. Estrogen
receptor alpha is essential for induction of oxytocin receptor by
estrogen. Neuroreport 9, 933—936.
A. Lischke et al.