Conditioned place preference training prevents hippocampal depotentiation in an orexin-dependent manner
Lu et al. Journal of Biomedical Science
Conditioned place preference training prevents hippocampal depotentiation in an orexin-dependent manner
Guan-Ling Lu 1
Hau-Jie Yau 0
Lih-Chu Chiou 0 1 2 3
0 Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University , Taipei , Taiwan
1 Graduate Institute of Pharmacology, College of Medicine, National Taiwan University , Taipei , Taiwan
2 Reserach Center for Chinese Medicine & Acupuncture, China Medical University , Taichung , Taiwan
3 Department of Pharmacology, College of Medicine, National Taiwan University , No. 1, Jen-Ai Rd., Section 1, Taipei 100 , Taiwan
Background: Long-term potentiation (LTP) is well recognized as a cellular-correlated synaptic plasticity of learning and memory. However, its reversal forms of synaptic plasticity, depotentiation, is less studied and its association with behaviors is also far from clear. Previously, we have shown that nanomolar orexin A can prevent the depotentiation induced by low frequency stimulation (LFS) following theta burst stimulation-induced LTP, namely inducing re-potentiation, at hippocampal CA1 synapses in vitro. Here, we explored the functional correlate of this orexin-mediated hippocampal re-potentiation. Methods and results: We found that intraperitoneal (i.p.) injection process-paired contextual exposures during the conditioned place preference (CPP) task in mice resulted in re-potentiation at CA1 synapses of hippocampal slices, regardless of whether the CPP behavior is expressed or not. Simply exposing the mouse in the CPP apparatus, or giving the mouse consecutive i.p. injections of saline in its home cage or a novel cage did not lead to hippocampal re-potentiation. Besides, this CPP training process-induced hippocampal re-potentiation was prevented when mice were pretreated with TCS1102, a dual orexin receptor antagonist. These results suggest that the expression of hippocampal re-potentiation is orexin-dependent and requires the association of differential spatial contexts and i.p. injections in the CPP apparatus. Conclusions: Together, we reveal an unprecedentedly orexin-mediated modulation on hippocampal depotentiation by the training process in the CPP paradigm.
Orexin; Depotentiation; Conditioned place preference; Hippocampus
Orexin A and orexin B [
], also named hypocretin 1 and
hypocretin 2 [
], are a pair of neuropeptides derived from
prepro-hypocretin, which is expressed only in the
perifornical area and lateral hypothalamus (LH). There are two
orexin receptors, OX1Rs and OX2Rs [
]. OX1Rs display
similar affinity for orexin A and orexin B while OX2Rs have
higher affinity for orexin B [
]. Both OX1Rs and OX2Rs are
widely distributed throughout the brain [
], including the
], a crucial brain area involved in learning
and memory [
] and exhibits several forms of synaptic
plasticity, including long-term potentiation (LTP),
longterm depression (LTD) and depotentiation [
]. LTP and
LTD can be induced by high frequency stimulation (HFS)
and low frequency stimulation (LFS), respectively. Both
forms of hippocampal synaptic plasticity are believed to be
the cellular correlates of memory and oblivion (forgetting),
]. Depotentiation is one form of LTD
induced by LFS after HFS while its functional role remains
unclear. Orexins have been shown to modulate LTP in the
hippocampus in vivo and in vitro [
]. Previously, we
found that orexin A can attenuate theta bust stimulation
(TBS)-induced LTP at micromolar concentrations while
prevented LFS-induced depotentiation, namely inducing
re-potentiation, at sub-nanomolar concentrations at
Schaffer collateral-CA1 synapses of hippocampal slices, via
OX1Rs and OX2Rs [
]. The latter re-potentiation effect of
sub-nanomolar orexin can occur under physiological
conditions. We, therefore, further explore its physiological
significance, i.e. under what situations; orexins will be
released to induce hippocampal re-potentiation.
Several lines of evidence indicate that orexins are
involved in the conditioned place preference (CPP)
induced by abusing substances [
] or food . CPP
is a contextual learning paradigm requiring associative
learning between the reward and its spatial context [
and is wildly used to explore the reinforcing potential of
abusing substances [
]. It is a hippocampus-dependent
task since lesion and inactivation of dorsal hippocampus
impaired food and cocaine CPP, respectively [
Recently, the finding of Rashidy-Pour et al.  is
especially noted that intra-hippocampal blocking OX1Rs or
OX2Rs prevented LH stimulation-induced CPP. This
suggests that endogenous orexins in the hippocampus
are required for the development of CPP. Combining
our previous finding that orexin induced hippocampal
], we therefore hypothesized that CPP
development can modify hippocampal synaptic properties
in an orexin-dependent manner. Here, we have tested this
hypothesis by examining the modulation of cocaine CPP
on orexin-induced re-potentiation at Schaffer
collateralCA1 synapses of hippocampal slices. To our surprise, we
found that orexin-induced hippocampal re-potentiation
appears to be a shared cellular correlate specific to an
association of intraperitoneal (i.p.) injections-paired
contextual exposures during the CPP training process, regardless
whether cocaine CPP is expressed or not. Our findings
reveal an unprecedentedly cocaine-dissociated but CPP
training process-specific and orexin-dependent
modulation on hippocampal depotentiation.
All animal experiments adhere to the guidelines and
were approved by the Institutional Animal Care and Use
Committee of College of Medicine, National Taiwan
University. Male C57BL/6JNarl mice were housed under
a 12-h light/dark cycle in a climate-controlled room with
ad libitum access for food and water. On the day for
conducting in vivo experiments, mice were moved to
and acclimated in the behavior room for at least 1 h. All
efforts were made to minimize the number of animals
used and their suffering.
The CPP paradigm
A bias CPP paradigm with a 3 day-training protocol was
used to induce cocaine CPP in mice (8–12 weeks) as
described previously [
] and as shown in Fig. 1a. Briefly,
on Day 1 (the pretest stage), the mouse was allowed to
move freely for 10 min in the CPP apparatus, which
consists of black and white arenas with different floor
features separated by an intermediate compartment. The
time that each mouse spent in each arena was used for
grouping the mice with approximately equal bias of
black or white arena preference. Mice were excluded if
they spent more than 4 min in the neutral chamber or
the time spent difference between white and black
chambers was greater than 100 s. On each day of Days
2–4, the mouse was given an i.p. injection of saline and
placed in its preferred arena for 30 min. Six hours later,
the same mouse was given cocaine hydrochloride
(20 mg/kg, i.p.) (the cocaine-conditioned group) or
saline (the saline-conditioned group) and placed in its
non-preferred arena for 30 min. Drug-paired arenas
were randomized among all groups. On Day 5 (the test
stage), the mouse was allowed to move freely in the CPP
apparatus as the procedure on Day 1. The preference
score in each mouse was calculated by subtracting the
time spent in the saline-paired arena from the time
spent in the cocaine-paired arena.
Saline-conditioning in different contexts
To differentiate whether the change in hippocampal
synaptic plasticity is CPP context-specific, we repeated the
saline-conditioning procedure as in the CPP training
process but changed the conditioning context. The CPP
apparatus was replaced with the home cage
(47*26*21 cm) of the tested mouse or a large novel
bedded cage (30*19*13 cm).
Extracellular recordings of field excitatory postsynaptic
potentials (fEPSPs) were performed at Schaffer collateral-CA1
synapses of mouse hippocampal slices (300 μm) with an
MED64 multichannel recording system (Alpha MED
sciences Co., Ltd., Tokyo, Japan) as described previously [
Briefly, the mouse was sacrificed after the behavioral
operant and coronal hippocampal slices were dissected from the
mouse and equilibrated at room temperature for at least
1.5 h in the artificial cerebral spinal fluid (aCSF). It consisted
of (mM) NaCl 117, KCl 4.5, CaCl2 2.5, MgCl2 1.2, NaH2PO4
1.2, NaHCO3 25 and glucose 11. When performing
recording, the slice was placed on a 8 × 8 multi-electrode dish
probe (MED-P515A; Alpha MED sciences Co., Ltd.) and
perfused with aCSF at the rate of 1.0 ~ 1.5 ml/min. One of
64 electrodes over the Schaffer collateral/commissural fiber
path in the CA1 region was chosen as the stimulating point.
The sharpest and largest fEPSP detected from one of other
63 electrodes in the CA1 stratum radiatum of each
hippocampal slice was recorded. The slope of the fEPSP was
measured via the Conductor® software.
fEPSPs were evoked at 0.03 Hz and the slope of every
fEPSP, which represents the synchronization of
postsynaptic responses upon presynaptic stimulation and
reflects the magnitude of synaptic transmission, was
recorded and the average of 20 fEPSP slopes recorded
10 min before LTP was taken as the baseline of synaptic
transmission. LTP and depotentiation of fEPSPs were
induced and analyzed as reported previously [
]. LTP was
induced by TBS [
], and its magnitudes was
measured by the averaged slope of 20 fEPSPs recorded
50 ~ 60 min after TBS. Depotentiation was induced by
LFS (1 Hz, 15 min) at 1 min after TBS, and its
magnitude was measured by the averaged slope of 20 fEPSPs
recorded 50 ~ 60 min after LFS, and expressed as % of
the baseline slope of fEPSPs.
Cocaine hydrochloride was purchased from the Division of
Controlled Drugs, Food and Drug Administration,
Department of Health, Executive Yuan, Taiwan. TCS1102,
N[1,1′-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2yl)thio]acetyl-2-pyrrolidinedicarboxamide, was purchased
from Tocris Bioscience (Bristol, UK). For in vivo studies,
cocaine hydrochloride was dissolved in 0.9% sodium
chloride (NaCl). TCS1102 was dissolved in 0.9% normal
saline containing 50% v/v PEG-200.
Data are presented as the mean ± S.E.M. The n and N
numbers indicate the number of tested slices (n) and
animals (N), respectively. Two-way repeated-measures
Analysis of Variance (ANOVA) with Bonferroni’s post
hoc test was used for the comparison in the CPP test.
For electrophysiological data, statistical comparison was
performed by one-way ANOVA with the Newman-Keuls
multiple comparison test for groups of 3 or more, and
Student’s t-test or paired t-test was used for groups of 2.
P < 0.05 was considered to be of significant difference.
LFS failed to induce hippocampal depotentiation in both cocaine- and saline-conditioned groups in the CPP paradigm
Fig. 1a depicts the protocol of a 3-day cocaine CPP
training paradigm in mice. The result showed that
cocaine-conditioned, but not saline-conditioned, mice
had a significantly higher CPP score on Day 5 (the test
stage) than that on Day 1 (the pretest stage) (Fig. 1b),
suggesting this task paradigm has successfully
established cocaine CPP in mice. A two-way ANOVA with
repeated measures showed a significant interaction
between treatment and stage [F(1,12) = 14.4, p = 0.003].
Post hoc Bonferroni analysis showed a significance
difference in CPP scores between saline- or
cocaineconditioned groups (p < 0.001).
After the CPP test, hippocampal slices were prepared
from these two groups of mice for extracellular
recordings of synaptic plasticity. In slices isolated from naïve
mice, the average slope of the fEPSP, as measured in the
last 10 min of the 60 min recording period following
LFS, was not significantly different from that in the
baseline period [Fig. 1c and d, 100.5 ± 4.1%, N (number
of animals) = 6, n (number of slices) = 6, p = 0.9, paired
t-test]. This suggests LFS completely attenuates
TBSelicited LTP, in the hippocampal Schaffer collateral-CA1
pathway of naïve mice, as reported in our previous study
], i.e. LFS successfully induce depotentiation in the
naïve group. On the other hand, in slices from
cocaineCPP mice, LFS failed to induce depotentiation (Fig. 1c
and d). To our surprise, LFS also failed to induce
depotentiation in slices from the saline-conditioned group
(Fig. 1c and d). This suggests that despite the mice
learned to distinguish cocaine from saline administration
after conditioning (Fig. 1b), LFS failed to induce
depotentiation in these mice, regardless of saline or cocaine
were conditioned (Fig. 1c and d). The average fEPSP
slopes of saline- and cocaine-conditioned groups were
137.9 ± 8.9% (N = 5, n = 5, p = 0.013, paired t-test) and
144.2 ± 10.6% (N = 5, n = 5, p = 0.014, paired t-test) of
baseline, respectively (Fig. 1c). One-way ANOVA
showed a significant difference among these three
groups [F(2,13) = 9.3, p = 0.003]. A post hoc
NewmanKeuls multiple comparison showed a significance
difference between naïve and saline-conditioned groups as
well as naïve and cocaine-conditioned groups (p < 0.01
and p < 0.01, respectively) (Fig. 1d).
The failure of LFS to de-potentiate TBS-induced LTP
suggests the existence of an antagonizing mechanism of
depotentiation, named “re-potentiation” [
]. Naïve mice
did not receive the CPP training and displayed
depotentiation (i.e. no re-potentiation occurred). However,
the saline group did receive the CPP training but did not
develop CPP, and did not display de-potentiation (i.e.
generating re-potentiation). The cocaine group
developed CPP and generated re-potentiation. Therefore, the
re-potentiation (as seen in the saline- and
cocaineparing groups) is dependent on the CPP training
process, but independent of the establishment of CPP.
Therefore, this “re-potentiation” following TBS-LFS at
the hippocampal Schaffer collateral-CA1 pathway is
dissociated from pharmacological effects of cocaine and
independent on the establishment of CPP.
Saline or cocaine injections in home-caged mice did not induce re-potentiation
To further examine whether the observed hippocampal
re-potentiation is a context-specific phenomena, we
performed the CPP training process in the mouse home
cage. Two groups of mice received the same 3-day
consecutive i.p. saline and cocaine injections, respectively, at
their home cages as in the CPP training process. Mice
were sacrificed on Day 4 and their hippocampal slices
were isolated (Fig. 2a). In home-caged mice, LFS was not
able to induce hippocampal re-potentiation in both
either saline- or cocaine-injection groups (Fig. 2b, c). The
average fEPSP slopes of saline- and cocaine-injection
groups were 114.5 ± 9.0% (N = 5, n = 5, p = 0.18, paired
t-test) and 105.4 ± 9.7% (N = 5, n = 5, p = 0.61, paired
ttest) of baseline, respectively (Fig. 2c). One-way ANOVA
showed no significant difference among naïve,
salineinjection and cocaine-injection groups [F(2,13) = 0.87,
p = 0.44] (Fig. 2c). The home-caged mice in either
saline- or cocaine-injection group were able to show LTP
following TBS, as in the naïve group (the saline group:
147.3 ± 6.7% of baseline, N = 4, n = 6; the cocaine
group: 161.3 ± 8.4% of baseline, N = 3, n = 6; the naïve
group: 141.9 ± 4.3% of baseline, N = 6, n = 6;
Additional file 1: Figure S1). Thus, the failure to induce
repotentiation is not due to that the hippocampal Schaffer
collateral-CA1 synapses of these mice were unable to
potentiate. These results suggest that the injection
process-paired contextual exposure in the CPP
apparatus is important for developing re-potentiation at
hippocampal Schaffer collateral-CA1 synapses.
The injection procedure-paired contextual exposures in the CPP apparatus is required for re-potentiation
To examine if the novelty introduced by the contextual
exposures in the CPP apparatus may contribute to the
development of hippocampal re-potentiation, a larger
novel cage was used to replace the familiar home cage
for the conditioning process in the previous experiment.
We found that the novelty introduced by a novel larger
cage was not able to produce hippocampal
repotentiation (Fig. 3b and e, the average fEPSP slope was
118.0 ± 9.7% of baseline, N = 4, n = 5, p = 0.13, paired
t-test) or to affect TBS-LTP (Additional file 1: Figure
S2B, S2E). The failure to induce re-potentiation in the
novel cage group is not due to the failure of LTP
induction since the magnitude of LTP in this group is similar
to that in the naïve group (the novel cage group:
153.1 ± 6.4% of baseline, N = 3, n = 6, p = 0.2, t-test v.s.
We further investigated whether the association
between i.p. injections and differential contextual
exposures during the CPP training process is required and
sufficient to induce hippocampal re-potentiation. In the
experimental group, mice were daily exposed to white
and black arenas of the CPP apparatus, respectively, and
received saline injections in each arena for three days
(Fig. 3c), as the 3-day training stage in the CPP task (Fig.
1a). On the other hand, the control group was exposed
to the CPP apparatus only and did not receive saline
injection. Interestingly, simply exposing the mice to the
CPP apparatus not only did not develop a preference
between black and white arenas (Additional file 1: Figure
S3) and was not enough to produce hippocampal
repotentiation (Fig. 3d and e, the average fEPSP slope was
119.2 ± 7.5% of baseline, N = 4, n = 5, p = 0.06, paired
t-test,). The failure to induce re-potentiation in this
group is not due to the failure of LTP induction since it
displayed significant LTP following TBS (Additional file 1:
Figure S2D, S2E). Therefore, the association between
contextual exposures and i.p. injections during CPP
training is required to produce hippocampal
repotentiation (Fig. 3d and e, the average fEPSP slope was
151.1 ± 7.9% of baseline, N = 4, n = 5, p = 0.003, paired
Taken together, here we revealed that it is the
association of repetitive differential context exposures and i.p.
injections during the CPP training process that can
enable hippocampal Schaffer collateral-CA1 synapses to
resist LFS-induced depotentiation.
Endogenous orexins are involved in CPP training-induced hippocampal re-potentiation
Previously, we have demonstrated that sub-nanomolar
orexin A can prevent LFS- induced hippocampal
depotentiation in vitro and this effect is mediated by OX1Rs
and OX2Rs [
]. We, therefore, are intrigued to examine
whether endogenous orexins may mediate the CPP
training-induced hippocampal re-potentiation described
above. To validate this hypothesis, mice were pretreated
with a dual OXR antagonist, TCS1102 (20 mg/kg, i.p.),
30 min before undergoing the CPP training process
(Fig. 4a). TCS1102 and its vehicle pretreatments did not
affect the time spent difference between white and black
arenas in mice (Additional file 1: Figure S4). However,
TCS1102 pretreatment significantly inhibited CPP
training-induced hippocampal re-potentiation (Fig. 4b
and c; the average fEPSP slope of the baseline: TCS1102
group, 141.0 ± 5.3%, N = 4, n = 5; vehicle group,
106.8 ± 13.7%, N = 3, n = 5; p = 0.047, unpaired t-test).
These results suggest that endogenous orexins are
released during the CPP training process, even without
developing CPP, can prevent LFS from inducing
depotentiation at Schaffer collateral-CA1 synapses via OXRs;
i.e. keeping synaptic transmission remained potentiated.
The present study investigated the modulation of CPP
task on the hippocampal synaptic properties, specifically
assessed by an orexin-dependent hippocampal
repotentiation. During CPP training, the mouse was
exposed to two different arenas of the CPP apparatus and
passively given an i.p. injection in each arena for three
consecutive days. Although the mice showed behavioral
preference to the arena previously paired with cocaine
i.p. injection, we did not detect a cocaine-specific
synaptic adaption in hippocampal CA1 synapses, assayed by
the TBS-LFS protocol. On the contrary, both saline- and
cocaine-paired groups of mice showed similar
hippocampal re-potentiation, which was not detected in naïve
mice. These results indicate that the CPP training
process has introduced a drug-independent synaptic
modification in the hippocampal circuits, which disables
LFS to induce depotentiation of TBS-elicited LTP.
Since the drug of choice is not the cause of the CPP
task-dependent synaptic modification, shown as
hippocampal re-potentiation, we focused on the context where
CPP training takes place. During CPP training, the
contextual experience in mice can be broken down into
differential contextual exposures and i.p. injections. We
found that mice experiencing i.p. injection-free exposures
in the CPP apparatus did not develop hippocampal
repotentiation. Moreover, mice receiving i.p. injections in
the home cage or in a novel cage also did not develop
hippocampal re-potentiation. These results suggest that an
association between i.p. injections and differential
contextual exposures at the CPP training stage is required for the
development of hippocampal re-potentiation.
Considering using an analogy of Pavlovian
conditioning, the differential contextual exposures during CPP
training may serve as a conditioned stimulus (CS), which
contains a variety of sensory stimuli. The i.p. injection
can serve as an unconditioned stimulus (US), which
brings the distress associated with the injection process
]. The present study suggests that, after repeatedly
pairing, the association of CS-US during the CPP
training period emerges, in a cocaine-independent manner,
and impacts the synaptic properties of hippocampal
circuits. It is revealed as the resistance to LFS-induced
depotentiation of TBS-elicited LTP, which keeps
hippocampal synaptic transmission remained potentiated.
Similarly, enhanced excitatory transmission was also
demonstrated in vivo in the hippocampus of mice in a
classical Pavlovian conditioning session [
The finding that TCS1102, a dual OXR antagonist, can
prevent the CPP training-induced hippocampal
repotentiation, suggests that orexins are released during
the CPP training process. Orexins can be released
through activating hypothalamic orexin neurons under
various conditions, such as stress [
14, 24, 25
] or emotional changes [
]. During the CPP
training period, the association of the arousal from
differential context exposures and the stress from the
paired i.p. injection process may activate hypothalamic
orexin neurons to release orexins, ultimately modulating
hippocampal synaptic properties.
Although the results in a previous CPP test [
showed that the number of activated orexin neurons
was not significantly increased in saline-paired rats,
our previous study has demonstrated that orexin at
the concentration as low as 1 pM can completely
prevent LFS-induced hippocampal depotentiation in mice
]. It is likely that only a few orexin neurons
activated during the CPP training are enough to release
the amount of orexins required for modulating
hippocampal depotentiation. Since we did not detect
hippocampal re-potentiation in the groups of mice placed
in home cage or a novel larger cage paired with
saline injections, these results suggest little or no orexin
release in these conditions. In this regard, the
difference in the degree of stress and arousal between the
CPP training group and other groups may determine
the amount of orexins released. The complexity of
the spatial contexts may be an important determinant
of the contextual experience. In our experimental
preparation, the novel cage is similar to the home
cage of mice in terms of material, bedding and shape,
except the size. However, the CPP arena has a more
restricted spatial compartment with a different wall
color and floor structure from the home cage. It
provides not only more novel spatial information but also
tactile stimulation. Therefore, mice in the CPP
apparatus may encounter a higher degree of arousal than
in the home cage and, accompanied with the injection
stress, have more orexin released, ultimately
developing hippocampal re-potentiation.
Similar to our finding here in C57BL/6JNarl mice, LFS
also failed to induce depotentiation at hippocampal
Schaffer Collateral-CA1 synapses in F344 rats after
chronically treated with saline by either i.p. injection for
7 days [
] or self-administration for 20 days [
contrast, LFS did induce hippocampal depotentiation in
LEW rats, another inbred rat strain, in a concurrent test.
F344 rats, compared to LEW rats, are less vulnerable to
abusing substances while have a higher responsiveness
to stress [
]. It will be interesting to examine whether
F344 rats are more vulnerable to the stress-induced
arousal than LEW rats and hence have elevated orexins
that can prevent LFS-induced depotentiation as we
observed in the present study. In this regards, it will be
also interestingly to examine whether there is an
association between the orexin system activity and the
addiction vulnerability among subjects.
In this study, we have revealed that differential
contextual exposures conditioned with i.p. injections during the
CPP training process can modulate hippocampal
synaptic plasticity, revealed as the resistance to depotentiation
by TBS-LFS application at hippocampal Schaffer
collateral-CA1 synapses. This synaptic modulation
occurs regardless of whether CPP is expressed. To the best
of our knowledge, this is the first report revealing that
the CPP training process per se can modulate
hippocampal synaptic plasticity. Importantly, this CPP
trainingspecific hippocampal re-potentiation is mediated by
endogenous orexins through both OX1Rs and OX2Rs.
Additional file 1: Supplementary data. (DOC 848 kb)
aCSF: Artificial cerebral spinal fluid; CPP: Conditioned place preference;
fEPSPs: Field excitatory postsynaptic potentials; i.p.: Intraperitoneal; LFS: Low
frequency stimulation; LH: Lateral hypothalamus; LTP: Long-term
potentiation; OX1Rs: Orexin receptors 1; OX2Rs: Orexin receptors 2;
OXR: Orexin receptor; TBS: Theta bust stimulation
This study was supported by the grants from the Ministry of Science and
Technology (MOST104–2745-B002–004, MOST104–2325-B002–010,
MOST104–2314-B002–053-MY3 and MOST 105–2325-B002–004), Taiwan.
Availability of data and materials
All data generated or analyzed during this study are included in this
G.L.L and L.C.C designed the experiments. G.L.L performed the experiments
and analyzed the data. All authors wrote the main manuscript.
All animal experiments adhere to the guidelines and were approved by the
Institutional Animal Care and Use Committee of College of Medicine,
National Taiwan University.
Consent for publication
The authors declare that they have no competing interests.
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