Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior.
ABSTRACT Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.
- SourceAvailable from: Thomas E Schlaepfer[show abstract] [hide abstract]
ABSTRACT: While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising. Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (+/-SD) length of the current episode was 10.8 (+/-7.5) years; the number of past treatment courses was 20.8 (+/-8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (+/-5.3). Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [+/-2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala. We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes.Biological psychiatry 11/2009; 67(2):110-6. · 8.93 Impact Factor
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ABSTRACT: Ca(2+)-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-kappa B transcription factor by a pathway requiring the Ca(2+)/calmodulin-dependent kinase CaMKII and local submembranous Ca(2+) elevation. The p65:p50 NF-kappa B form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-kappa B. Activated NF-kappa B moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-kappa B nuclear translocation and gene activation.Nature Neuroscience 11/2003; 6(10):1072-8. · 15.25 Impact Factor
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ABSTRACT: Structural plasticity of dendritic spines and synapses is a fundamental mechanism governing neuronal circuits and may form an enduring basis for information storage in the brain. We find that the p65 subunit of the nuclear factor-κB (NF-κB) transcription factor, which is required for learning and memory, controls excitatory synapse and dendritic spine formation and morphology in murine hippocampal neurons. Endogenous NF-κB activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in vitro synaptogenesis, NF-κB enhances dendritic spine and excitatory synapse density and loss of endogenous p65 decreases spine density and spine head volume. Cell-autonomous function of NF-κB within the postsynaptic neuron is sufficient to regulate the formation of both presynaptic and postsynaptic elements. During synapse development in vivo, loss of NF-κB similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-κB activity is low and p65 deficiency no longer attenuates basal spine density. Instead, NF-κB in mature neurons is activated by stimuli that induce demand for new synapses, including estrogen and short-term bicuculline, and is essential for upregulating spine density in response to these stimuli. p65 is enriched in dendritic spines making local protein-protein interactions possible; however, the effects of NF-κB on spine density require transcription and the NF-κB-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-κB in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.Journal of Neuroscience 04/2011; 31(14):5414-25. · 6.91 Impact Factor
Effects of Inhibitor of kB Kinase Activity in the Nucleus
Accumbens on Emotional Behavior
Daniel J Christoffel1, Sam A Golden1, Mitra Heshmati1, Ami Graham2, Shari Birnbaum2, Rachael L Neve3,
Georgia E Hodes1and Scott J Russo*,1
1Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA;2Department of Psychiatry, University of Texas
Southwestern Medical Center, Dallas, TX, USA;3McGovern Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Inhibitor of kB kinase (IkK) has historically been studied in the context of immune response and inflammation, but recent evidence
demonstrates that IkK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases
IkK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IkK signaling
results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IkK in
anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green
fluorescent protein, a constitutively active form of IkK (IkKca), or a dominant negative form of IkK into the NAc. Of all three experimental
groups, only mice expressing IkKca show a behavioral phenotype. Expression of IkKca results in a decrease in the time spent in the non-
periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose
preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine
whether IkK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an
acute social defeat stress. We found that IkKca enhanced social avoidance behavior and promoted thin spine formation. These data
show that IkK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of
immature excitatory synapses.
Neuropsychopharmacology advance online publication, 11 July 2012; doi:10.1038/npp.2012.121
Keywords: anxiety; depression; glutamate; excitatory synapse; medium spiny neuron (MSN); nuclear factor kappa B (NFkB)
The inhibitor of kappaB kinase (IkK)–nuclear factor
kappaB (NFkB) pathway has a central role in inflammation
and immune response, as well as cell growth and survival
(Chen and Greene, 2004; Ha ¨cker and Karin, 2006). More
recently, IkK and NFkB activity has been implicated as an
important regulator of synaptic signaling and neuronal
morphology both in vitro and in vivo (Christoffel et al,
2011a,b; Kaltschmidt et al, 1993; Meffert et al, 2003; O’Mahony
et al, 2006; Russo et al, 2009). The IkK signaling pathway
is activated by extracellular cytokines (such as interleukin
1 beta (IL-1b) and IL-6), infectious agents, glutamate, and
neurotrophins (Israel, 2010; O’Neill and Kaltschmidt, 1997;
Scho ¨lzke et al, 2003). Downstream of IkK, many target
genes of the NFkB transcriptional complex contribute signi-
ficantly to synaptic plasticity, such as NCAM, BDNF, opioid
receptors, glutamate receptors, and neuregulin (Bunting
et al, 2007; Chen et al, 2006; Frensing et al, 2008; Richter
et al, 2002; Saha et al, 2006). Indeed, c-Rel, a member of the
NFkB transcriptional complex, is required for long-term
potentiation in the hippocampus (Ahn et al, 2008). Thus,
IkK is capable of integrating many extracellular signals to
alter gene expression and cause long-lasting changes in
neuronal function and ultimately behavior.
The nucleus accumbens (Nac) is a brain region critical in
evaluating the salience of aversive and rewarding stimuli
to direct behavior (Mogenson et al, 1980). This subcortical
nuclei of the ventral striatum mediates neural communica-
tion between cortical regions and the limbic system in order
to regulate emotion and cognition. The NAc acts as a central
regulator of emotional behaviors, and its function is tightly
modulated by a number of molecular mechanisms, includ-
ing histone deactylases, IkK, and DFosB, among others
(Christoffel et al, 2011a; Covington et al, 2009; Vialou et al,
2010). Importantly, the NAc is a relevant target for thera-
peutic exploration in major depressive disorder, as deep
Received 13 February 2012; revised 8 June 2012; accepted 11 June
*Correspondence: Dr SJ Russo, Fishberg Department of Neuroscience,
Mount Sinai School of Medicine, One Gustave Levy Place, Icahn
10-26A, 10029-6574 New York, NY, USA, Tel: +212 659 5917,
Fax: +212 659 8510, E-mail: email@example.com
Neuropsychopharmacology (2012), 1–9
& 2012 American College of Neuropsychopharmacology.All rights reserved 0893-133X/12
brain stimulation of the NAc reduces anxiety and depres-
sion in previously treatment-resistant major depressive
disorder patients (Bewernick et al, 2010). These findings
highlight the critical role of NAc in emotional behaviors and
suggest that novel modulators of neuronal function in NAc
may improve therapeutic outcomes for psychiatric patients.
Previously, we demonstrated that chronic social defeat
stress induces IkK activity and the formation of immature
dendritic spines on medium spiny neurons (MSNs) in NAc
of susceptible mice. Expression of the susceptible pheno-
type is dependent upon IkK, as inhibition of IkK activity,
through viral mediated gene transfer of a dominant negative
mutant (IkKdn), reverses both social avoidance behavior
and the immature dendritic spine formation that appears to
drive this behavior (Christoffel et al, 2011a). However, it is
still unknown whether IkK more generally regulates emotional
behaviors, and whether increased IkK activity in mice is
sufficient to promote the synaptic and behavioral changes
associated with repeated stress exposure.
To evaluate the role of IkK in regulating emotional
behavior, we utilized viral-mediate gene transfer of herpes
simplex viruses (HSVs) expressing either green fluorescent
protein (GFP), a constitutively active IkK (IkKca) or IkKdn
into the NAc of C57BL/6J mice and performed a battery
of behavioral tests (open field, forced swim, and sucrose
preference). To assess whether IkK promotes susceptibility
to acute stress, we exposed mice either to an acute swim
stress or acute social defeat and examined sucrose pre-
ference (anhedonia), social interaction (avoidance), and
synaptic adaptations. We found that elevation of IkK activity
in the NAc increases baseline anxiety- and depression-like
behaviors, as well as susceptibility to acute stress-induced
anhedonia and social avoidance. Importantly, we found that
IkKca is sufficient to promote immature spine synapse
formation in mice vulnerable to acute social defeat stress.
These findings, in conjunction with our previous work,
highlight the critical nature of de novo synaptic formation
in guiding emotional behavior.
Eight-week-old C57BL/6J mice (Charles River Laboratories,
Wilmington, Massachusetts) were used for all experiments.
For acute social defeat studies, 4-month-old retired CD-1
breeders (Jackson Laboratories, Bar Harbor, Maine) were used
as aggressors. One-week before the start of all experiments,
mice were group housed and maintained on a 12h light/
dark cycle with ad libitum access to food and water.
Behavioral assessments and tissue collection were per-
formed during the animals’ light phase (0700–1900hours).
Mouse procedures were performed in accordance with the
Institutional Animal Care and Use Committee guidelines of
the Mount Sinai School of Medicine.
Stereotaxic Surgery and Viral Gene Transfer
Eight-week old C57BL/6J mice (n¼53 mice, 4–8mice/group)
were anesthetized with a mixture of ketamine (100mg/kg)
and xylazine (10mg/kg) and positioned in a small-animal
stereotaxic instrument (David Kopf Instruments, Tujunga,
California), and the skull surface was exposed. Thirty-three-
gauge syringe needles (Hamilton , Reno, Nevada) were used
to bilaterally infuse 0.5ml of HSV (1.5?108infectious
units/ml) expressing GFP, or IkKca and IkKdn mutants
to activate or inhibit NFkB signaling, respectively, into
the NAc (bregma coordinates: anteroposterior, 1.5mm;
mediolateral, 1.6mm; dorsoventral, 4.4mm; angle 101; see
Figure 1a for degree of infection just before behavior
and after behavioral testing) at a rate of 0.1ml/min. All of
these viral vectors have been tested and validated in vivo
and in vitro (Christoffel et al, 2011a; LaPlant et al, 2009;
Russo et al, 2009).
Construction of Viral Vectors
Viral vectors were constructed as previously described
(Russo et al, 2009). Briefly, for the IkKdn, using the coding
sequence of the b form, lysine 44 was substituted with
methionine (Mercurio et al, 1997) and subcloned into the
bicistronic p1005+ HSV plasmid. For the IkKca mutant,
serine 177 and 181 of the b form were mutated to glutamic
acid (Mercurio et al, 1999), we designed primers with KpnI
restriction sites (forward primer, CAAGGTACCARGAGC
TGGTCACCTTCCC; and reverse primer, CAAGGTACCTC
ATGAGGCCTGCTCCA) and amplified fragments were
subcloned into the bicistronic p1005+ HSV plasmid at
Kpn1. As previously reported, both mutant vectors express
IkK at similar levels to wildtype IkK in PC12 cells. IkKca
expression increases levels of phospho-p65 and in vivo
overexpression in the NAc of NFkB-LacZ reporter mice
increases b-gal expression. Additionally, overexpression of
HSV-IkKdn in NAc of the NFkB-LacZ reporter mice results
in a 50% reduction in b-gal expression (Russo et al, 2009).
120 hrs72 hrs
Day 2Day 3 Day 4
Day 0Day 2
and 120h, just before and following behavioral testing, respectively.
(b) Experimental timelines for each behavioral study.
(a) Representative images of viral expression in NAc at 72
IjK regulates emotional behavior
DJ Christoffel et al
Mice underwent stereotaxic surgery to deliver the virus and
then were given 1 day to recover. During the recovery day,
mice were habituated to two bottles for sucrose preference
testing. Ninety-six hours after surgery, depressive behavior
was assessed with the forced swim test. The last sucrose
measurement was taken the morning after forced swim.
This behavioral test constituted the acute swim stressor. In
a separate cohort, 72h after surgery, anxiety-like behavior
was assessed with the open field test. All animals were
perfused on day 5 for histological viral placement assess-
ment (Figure 1b). Any mouse without viral expression or
poor targeting outside of the NAc was removed from the
analysis. Behavioral tests were timed to take place during
peak HSV expression on day 2–4 post-surgery (Carlezon
and Neve, 2003).
Open field. Open field test was performed as previously
described (Monteggia et al, 2007). Videotracking-based
methods (Ethovision, Noldus Systems, Leesburg, Virginia)
were used during 10-min trials to record the distance moved
and time spent in the arena (72cm in diameter) under dim
lighting, along with a delineated ‘periphery zone’, a delineated
‘non-periphery zone’, and a delineated ‘center zone’
(34cm?34cm) (Figure 2a).
Forced swim test. Forced swim test was performed as
previously described (Monteggia et al, 2007). Mice were
videotaped while in a 4l Pyrex glass beaker containing 3l
of water at 24±11C for 6min. Water in each beaker was
changed after each trial. Two trained and blinded observers
scored the videotape manually. Total immobility was mea-
sured as the time spent without any motion except for single
limb paddling to maintain flotation. Latency to immobility
was assessed as the time until the mouse first became
Sucrose preference. Sucrose preference was performed as
previously described (Monteggia et al, 2007). For sucrose-
preference testing, a solution of 1% sucrose or diluent alone
(drinking water) was placed into 50ml tubes with ball-point
sipper tubes (Ancare, Bellmore, NY). All animals were
acclimatized to two-bottle choice conditions before testing
conditions. Daily, the weight of each bottle was measured,
and the positions of the tubes were interchanged to prevent
preferential drinking based on location in the cage. Sucrose
preference was calculated as a percentage (amount of
sucrose consumed (in bottle A)/total amount consumed
(bottles A and B)) across 3 days of testing.
Social defeat stress and social interaction. To measure
increased susceptibility to stress, we adapted a subthreshold
‘microdefeat’ as previously described (Krishnan et al, 2007).
Under these conditions, C57BL/6J mice were exposed to a
novel CD1 aggressor for 5min, followed by 5min rest in the
home cage. Exposure to the CD1 aggressor occurred three
times with 5-min intervals between each exposure. Twenty-
four hours later mice were assessed using the social
interaction test. Under control conditions, this subthreshold
microdefeat protocol does not induce social avoidance.
Social interaction was performed as previously described
(Berton et al, 2006; Golden et al, 2011). Briefly, mice were
placed into a novel arena with a small animal cage at one
end. Their movement was monitored for 2.5min in the
absence of an aggressive CD1 mouse (used to determine
baseline exploratory behavior), followed by 2.5min in the
presence of the caged aggressor. We measured the distance
traveled (in centimeters), and the duration spent in the
interaction zone and corner zones (in seconds) using
Ethovision 3.0 software (Noldus Information Technology,
Attleboro, Maine). We calculated social interaction as a
ratio of the time spent in the interaction zone with an
aggressive mouse present over the time spent with the
aggressive mouse absent. All mice with a ratio 41 were
classified as resilient and all mice with a ratio o1 were
classified as susceptible.
Time spent in zone (s)
Latency to enter (s)
Distance traveled (cm)
field test. (b) Mice expressing IkKca spend significantly less time in the non-periphery and significantly more time in the periphery of the arena. There was also
a trend for a decrease in time spent in the center. (c) IkKca-expressing mice also showed an increased latency to enter the center zone. (d) There were no
differences in total distance traveled across all groups. Data are represented as group means. Error bars represent SEM (*po0.05,tp¼0.10, one-way
IkKca expression in NAc is axiogenic. (a) Schematic of zones in open field arena and representative traces of mouse movement during an open
IjK regulates emotional behavior
DJ Christoffel et al
Perfusion and Tissue Processing
On day 5 after viral expression, all mice were given a
euthanizing dose of 15% chloral hydrate and transcardially
perfused with cold 1% paraformaldehyde in phosphate-
buffered saline (pH 7.4), followed by fixation with cold 4%
paraformaldehyde in phosphate-buffered saline. Brains
were dissected and postfixed for 18h in the same fixative.
The brain was cut into 50mm coronal slices to assess viral
placement or 150mm for spine analysis.
Imaging and Spine Analysis
For spine analysis, dendritic segments 50–150mm away
from the soma were randomly chosen from HSV-infected
cells that express GFP (Figure 5a). Images were acquired on
a confocal LSM 710 (Zeiss, Oberkochen, Germany) for
morphological analysis as described previously (Radley
et al, 2006). Neurons were selected from the NAc shell. To
qualify for spine analysis, dendritic segments had to satisfy
the following requirements: (1) the segment had to be com-
pletely filled (all endings were excluded) and (2) segment
must be at least 50mm from the soma (Radley et al, 2006).
Dendritic segments were imaged using a ?100 lens (NA
1.4, Zeiss) and a zoom of 2.5. Pixel size was 0.03mm in the
x–y plane and 0.01mm in the z plane. Images were taken
with a resolution of 1024?B300 (the y dimension was
adjusted to the particular dendritic segment to expedite
imaging), pixel dwell time was 1.27mm/s, and the line
average was set to 4. An average of 2 dendrites per neuron
on 5 neurons per animal (n¼13 mice, n¼4–5mice/group)
totaling approximately 1000 dendritic spines per experi-
mental group were analyzed. For quantitative analysis of
spine size, shape, and volume, NeuronStudio was used
employing the rayburst algorithm previously described
(Rodriguez et al, 2008). NeuronStudio classifies spines as
thin, mushroom, or stubby based on the following values:
(1) aspect ratio, (2) head to neck ratio, and (3) head
diameter. Spines with a neck can be classified as either thin
or mushroom; those without a significant neck are classified
as stubby. Spines with a neck are labeled as thin or
mushroom based upon head diameter. These parameters
have been verified by comparison with trained human
All data are expressed as the mean±SEM. Mean differences
between groups were determined using either a one- or two-
way analysis of variance (ANOVA) followed by Newman
Keuls post-hoc tests when the main effect was significant at
po0.05. Statistical analyses were performed using Prism 5.0
(GraphPad Software, La Jolla, California).
To assess anxiety and measure basal activity, we performed
an open field test in mice following expression of IkKca,
IkKdn, or GFP in NAc (Figure 2a). We found a main effect
of viral expression for time spent in the non-periphery
(one-way ANOVA: F(2,23)¼7.308, po0.01) and periphery
zones (one-way ANOVA: F(2,23)¼7.308, po0.01; Figure 2b).
Post-hoc analysis revealed that the IkKca group spent less
time in the non-periphery zone and increased time spent in
the periphery compared with GFP controls (po0.01). We
also observed a trend towards decreased time spent in
center for the IkKca group (one-way ANOVA: F(2,23)¼1.918,
p¼0.10). ANOVA revealed a main effect of virus on latency
to enter the center (one-way ANOVA: F(2,23)¼5.209, p¼0.01),
with mice expressing IkKca taking significantly longer to
enter the center zone compared with mice expressing GFP
or IkKdn (Figure 2c). We observed no differences in total
distance traveled for any group, suggesting that any changes
observed were not due to altered locomotor activity
(Figure 2d). Together, these data suggest that IkKca expres-
sion in the NAc increases basal anxiety behavior as mea-
sured in this exploratory-based behavioral assay.
To inspect how manipulation of IkK activity alters baseline
depression-like behaviors, we performed the forced swim
test, an established measure of behavioral ‘despair’ (Porsolt
et al, 1978). We found a main effect of virus on time spent
immobile (one-way ANOVA: F(2,17)¼5.21, po0.01), with
post-hoc analysis revealing a significant increase in time
spent immobile in the IkKca group compared with the
GFP control group (Figure 3a). However, there were no
significant differences in latency to immobility (p40.05;
Next, to assess consummatory reward behavior, we mea-
sured sucrose preference, a standard assay of anhedonia
(Papp et al, 1991). We found no effect of either IkK mutant
on basal sucrose consumption or total liquid consumed
(Figure 4a and b, respectively). However, 24h after an acute
swim stress, we found a main effect of virus on sucrose pre-
ference (one-way ANOVA: F(2,20)¼5.098, po0.05). Post-hoc
analysis revealed a significant reduction in sucrose pre-
ference in the IkKca group compared with both the GFP and
IkKdn groups. In addition, no change in total liquid con-
sumed was observed, indicating that viral expression did
not affect normal drinking behavior (po0.05; Figure 4c
and d, respectively). In mice undergoing an acute social
defeat stress paradigm, we confirmed our previous results,
finding a significant interaction between stress and virus
revealing that IkKca decreased time spent in the interaction
zone. Likewise, there was an interaction effect observed in
time spent in corner zones, with increased time only for the
IkKca group (two-way ANOVA: F(2,16)¼9.94, po0.001;
Figure 5b). As would be expected, we found a significant
difference in social interaction ratio, with post-hoc analysis
revealing a significant decrease in the IkKca group
Time immobile (s)
Latency to immobility (s)
mice expressing IkKca spend significantly more time (a) immobile. (b) No
differences were observed in latency to immobility. Data are represented
as group means. Error bars represent SEM (*po0.05, one-way ANOVA,
IkKca expression is pro-depressant. During a forced swim test,
IjK regulates emotional behavior
DJ Christoffel et al
(one-way ANOVA: F(2,13)¼11.23, po0.01; post-hoc analy-
sis po0.01; Figure 5c). Previously, we reported that IkKdn
reversed social avoidance and immature spine formation in
NAc only in mice susceptible, but not resilient, to chronic
social defeat stress. (Christoffel et al, 2011a). However,
IkKdn expression did not have any significant effect after
acute social defeat (two-way ANOVA: F(2,12)¼6.26, po0.01;
post-hoc analysis po0.001; Figure 5a).
To further examine the interaction between IkK activity
and stress-induced plasticity, we analyzed spine density and
morphology in NAc MSNs in mice expressing HSV-GFP,
HSV-IkKca, or HSV-IkKdn after an acute stressor. Expand-
ing upon our previous finding, we observed that IkKca
is sufficient to induce new immature spine formation,
whereas IkKdn did not alter the spine morphology profile.
Specifically, we found a significant increase in total spine
density (one-way ANOVA: F(2,13)¼5.03, po0.05: post-hoc
analysis po0.05; Figure 6a and b), driven predominantly by
an increase in thin spine density (one-way ANOVA:
F(2,13)¼8.79, po0.01: post-hoc analysis po0.01; Figure 6c)
in mice expressing IkKca compared with GFP alone. We did
not find significant differences in stubby or mushroom
spine density (Figure 6d and e). Additionally, we see a trend
in the correlation between spine density and social inter-
action, suggesting that these neuroadaptations may indeed
drive social avoidance (r2¼0.2967, p¼0.06; Figure 6f). We
observed a similar correlation between thin spin density
and social interaction (r2¼0.2848, p¼0.07; Figure 6g). We
further examined other parameters of spine size finding a
significant decrease (one-way ANOVA: F(2,13)¼5.14, po0.05:
post-hoc analysis po0.05) in average spine head volume
only in mice expressing IkKca as compared with GFP
controls (Figure 7a). This average decrease is due to a shift
towards more spines with smaller head volume (Figure 7b).
Consistent with the change in volume, there was a trend
observed for a decrease in average spine head diameter
only in mice expressing IkKca as compared with GFP con-
trols (one-way ANOVA: F(2,13)¼3.42, p¼0.07; Figure 7c)
There was no change in average spine length for any group
Our results demonstrate that increasing basal levels of IkK
activity is sufficient to induce anxiety and depression-like
behavior in stress-naive mice, and increase susceptibility to
acute stressors. We also found that following acute social
defeat stress, which normally is insufficient for induction
of depression-like behavior, overexpression of IkKca is
sufficient to drive synaptic structural adaptations and
promote social avoidance behavior. These findings high-
light the critical regulatory role of IkK in controlling NAc
MSN dendritic spine structural plasticity to promote anxiety
and depression-like behavior. Previously, we demonstrated
the capability of IkK inhibition to reverse chronic stress-
induced neuroadaptations and behavior, yet our current
findings suggest inhibition of IkK activity via IkKdn does
not affect baseline behavior or response to a minor acute
stressor. These results also show that under both stress naive
and acute stress conditions, IkKdn has minimal effects on
spine morphology, complementing our current behavioral
findings (Christoffel et al, 2011a and current data set).
Though further studies are needed, perhaps this indicates
low basal levels of IkK activity in MSNs, contrasting what is
found in pyramidal neurons. Collectively, our results do
suggest that stress promotes depression and anxiety-like
% Sucrose preference
% Sucrose preference
Total liquid consumed (mL)
Total liquid consumed (mL)
stress. There was no effect of either IkK mutant on (a) basal sucrose
consumption or (b) basal levels of liquid consumption. (c) There was a
significant decrease in the IkKca group 24h after undergoing an acute swim
stress. (d) Swim stress did not result in any significant difference in total
liquid consumed. Data are represented as group means. Error bars
represent SEM (*po0.05, one-way ANOVA, n¼6–7mice/group).
IkKca expression promotes anhedonia following acute swim
Time in interaction zone (s)
Time in corner zone (s)
Social interaction ratio
interaction zone with a target mouse present 24h after acute social defeat. (b) IkKca-expressing mice spend more time in the corner zones. (c) IkKca mice
have a significantly lower social interaction ratio. Data are represented as group means. Error bars represent SEM (*po0.05, two-way ANOVA, one-way
IkKca expression promotes social avoidance after acute social defeat stress. (a) Mice expressing IkKca show a decrease in time spent in the
IjK regulates emotional behavior
DJ Christoffel et al
mechanism requiring IkK activation leading to synaptic
The presented results also support the hypothesis that
hyperactivity of the IkK/NFkB pathway may serve as a risk
factor for mood and anxiety disorders, and detection of
increased basal activity could serve as a biomarker for
diagnosis. Indeed, it has been shown that patients with
major depressive disorder have increased blood levels of
cytokines, an established upstream regulator of this path-
way (Liu et al, 2011). Further evidence of the important
role of cytokine signaling is the ability of celecoxib, a
cyclooxygenase-2 inhibitor, to reduce serum levels of IL-6
in patients with major depressive disorder and concurrently
reduce depressive symptoms (Abbasi et al, 2012). From a
more basic perspective, transgenic mice lacking the p50
subunit of the NFkB transcriptional complex exhibit
increased basal levels of anxiety as measured by both open
field and the light/dark box test (Lehmann et al, 2010).
The authors suggest that p50 in neurons serves to dampen
the intracellular activity of NFkB and thus in the knock-
out, the activity of this pathway is heightened. Together
with the current findings, this demonstrates that over-
activity of this pathway, either throughout development
or only discrete periods during adulthood, produces
exaggerated anxiety behaviors.
The observed increase in spine density suggests that
restructuring of synaptic connectivity is crucial for the
observed maladaptive behavior. Similar results have been
observed in the amygdala, where prolonged restraint stress
leads to increased dendritic spine density accompanied by
an increase in anxious behavior (Vyas et al, 2006). Similarly,
we recently reported that chronic social defeat stress results
in an increase in immature dendritic spines that have
smaller postsynaptic densities, which strongly correlated
with the social interaction scores of both defeated and
control mice. Additionally, overexpression of IkKdn ap-
pears only to prevent the maintenance of the stress-induced
increases in stubby spines, while not significantly changing
the type or density otherwise. These results are consistent
with the idea that under control conditions inhibition
of IkK does not lead to significant synaptic remodeling
(Christoffel et al, 2011a). Conversely, increased IkK activity
is sufficient to induce thin spine formation and promote
susceptibility to maladaptive behavioral responses following
an acute social defeat stress. Thin dendritic spines are
immature synaptic structures that are highly plastic in
nature, and possess smaller spine heads, consistent with our
finding of an overall decrease in the average spine head
volume. These spines readily stabilize or retract in response
to increased or weakened synaptic input (Bourne and
Harris, 2007), making them prime candidates for synaptic
reorganization. Interestingly, immature synaptic structures
are known to predominately express the GluN2B receptor
(Sheng et al, 1994), and ketamine, a potent NMDA receptor
antagonist, along with GluN2B-specific antagonists have
rapid antidepressant effects in multiple models of depres-
sion (Autry et al, 2011; Li et al, 2010). Collectively, this
suggests that the formation of new immature glutamatergic
synaptic structures on NAc MSNs is a critical step in the
development and expression of maladaptive behavioral stress
IkK exerts many of its downstream effects through NFkB,
and expression of the IkK mutant constructs alters levels of
phospho-p65. Yet, there are other effectors that may be
involved in regulating synaptic plasticity mechanisms.
Recent evidence suggests that IkK acts directly on other
pathways, such as insulin and neurotrophic signaling cascades,
to alter dendritic spines and neuronal function (Lee
et al, 2007; Nakamori et al, 2006; Schmeisser et al, 2012).
Schmeisser et al (2012) demonstrate that inhibition of IkK,
via conditional expression of an IkKdn allele or knockout of
IkK specifically in excitatory neurons, prevents synapse
p = 0.06
p = 0.07
Social interaction ratio
Social interaction ratio
r2 = 0.30
r2 = 0.28
NAc MSNs after acute social defeat. There was a significant increase (b) in
total, and (c) thin spine density in the IkKca group only. No changes in (d)
stubby or (e) mushroom spine density was observed for either IkKca or
IkKdn. (f) There is a trend for a correlation between social interaction ratio
and total spine density. (g) A similar trend was observed between thin
spine density and social interaction ratio. Data are represented as group
means. Error bars represent SEM (*po0.05, one-way ANOVA, n¼4
(a) IkKca expression alters spine density and morphology on
IjK regulates emotional behavior
DJ Christoffel et al
formation and maintenance in a manner that is dependent
upon Igf2 signaling. Along similar lines, phosphorylation of
TSC1 by IkK activates the mTOR pathway, which is known
to be involved in spine plasticity, and mediates the rapid
antidepressants effects of ketamine. Taken as a whole, these
findings implicate IkK as a broadly acting kinase, capable of
modulating multiple signaling cascades to exert its effects
on neuronal function.
The IkK-dependent synaptic adaptations mentioned
above suggest that IkK affects not only anxiety and depressive
behaviors, but more broadly can serve as a molecular
mechanism for experience-dependent synaptic plasticity.
For example, the IkK signaling pathway is recruited
following cocaine administration, and is necessary for
psychostimulant-induced structural plasticity in NAc MSNs
(For review, see Russo et al, 2010). Similar to our findings,
overexpression of the NFkB transcriptional complex sub-
unit p65 in cultured hippocampal pyramidal neurons
results in increased spine density. Conversely, knockout of
the p65 gene in a transgenic line leads to decreased spine
density in vivo (Boersma et al, 2011). IkK activity in the
hippocampus has also been found to affect histone actey-
lation, and this action was shown to be a critical regulator of
reconsolidation of conditioned fear memories (Lubin and
Sweatt, 2007). Interestingly, activation of NFkB in the
hippocampus by IL-1b has been shown to inhibit neurogen-
esis and is important in the pro-depressant effects of
chronic unpredictable stress (Koo and Duman, 2008; Koo
et al, 2010). Complementary to our findings, Koo et al
(2010) found that inhibition of NFkB in hippocampus
blocked the anhedonic effects of CUS as measured by sucrose
consumption. However, stress-induced IkK or NFkB activity
has not been observed in other brain regions that show
decreased spine density in response to stress, such as in
prefrontal cortical neurons (Radley et al, 2008). It is
tempting to speculate whether IkK activity is increased or
decreased in these regions and correlates with the observed
spine adaptations. Future studies characterizing brain-wide
alterations in IkK activity in response to stress will provide
important information regarding the global regulation of
IkK signaling in psychiatric disorders.
In addition to brain region–specific regulation of IkK
activity, there is also likely to be cell-type specificity. Studies
of cocaine’s effects in the NAc have shown dopamine
receptor 1 (D1R)-expressing cells to be the primary long-
term locus of spine change (Lee et al, 2006; Lobo et al,
2010), and as mentioned above, IkK is a potent regulator of
spine density in this region. IkK activity in response to
stress or stimulant administration may similarly be regulated
in a cell-type–specific manner. In fact, a transgenic line
expressing the super-repressor, IkBa-SR, predominately in
interneurons, leads to a hyperexcitable state characterized
by increased long-term potentiation, spatial learning, and
seizures (O’Mahony et al, 2006). Perhaps not surprising,
a transgenic line expressing the Tet-O inducible super-
repressor under the CamKII-a promoter, shows opposite
behavioral changes, namely deficits in spatial learning
(Kaltschmidt et al, 2006). These behavioral deficits were
accompanied by impaired long-term potentiation and
reduced forskolin-induced CREB phosphorylation. Simi-
larly, transgenic mice lacking the p65 subunit are impaired
in spatial learning tasks (Meffert et al, 2003). Interestingly,
in the p50 knockout, there is a paradoxical increase in NFkB
activity, and better performance in the Morris water maze,
but not in the less anxiety-provoking Barnes maze. This
suggests that developmental effects of p50 knockout may
lead to a compensatory increase in NFkB activity and sub-
sequent anxiety profile consistent with our results. We
are able to avoid the difficulties of these subunit specific
developmental effects of IkK on behavior by controlling the
activity of the pathway at a higher regulatory level. Using
viral-mediated gene transfer to provide greater spatiotem-
poral precision (Carlezon and Neve, 2003, we manipulated
IkK specifically within the adult NAc. Together, our
findings provide strong evidence for a critical role of IkK
in the NAc in synaptic plasticity and behavior.
Ultimately, it appears that elevation of the activity of the
IkK pathway regulates biochemical or transcriptional events
to induce a highly plastic state. This permissive state is
essential to the formation of novel behavioral responses,
whether in response to normal experience or noxious
stimuli, such as stress or drugs of abuse. Repeated induction
of this state by either type of stimuli appears to enhance the
behavioral response through restructuring of synaptic con-
tacts. Increased IkK activity and immature spine formation
occur in response to chronic social defeat in susceptible
mice, and increasing IkK activity during an acute social
stress is sufficient to promote immature thin spines and
social avoidance behavior. Although only speculative at this
point, stabilization of these new contacts is potentially the
root problem in reversing maladaptive behaviors. There has
been much discussion in the literature concerning the slow
onset of efficacy of traditional antidepressants, and whether
this is due to a slow onset of plasticity mechanisms has
yet to be shown definitively. The rapid relief of depres-
sive symptoms via ketamine, acting on glutamate transmis-
sion and inducing plasticity of spines, suggests that
0.00.2 0.40.60.8 1.0
Spine head volume (?m3)
Spine head diameter (?m)
Spine length (?m)
the average spine head volume only in the IkKca group. (b) Cumulative
frequency plot shows a greater frequency of small spines across a range of
sizes for the IkKca group. A strong trend was observed for (c) spine head
diameter. No changes were observed in (d) length for either IkKca or
IkKdn. Data are represented as group means. Error bars represent SEM
(*po0.05,tp¼0.07, one-way ANOVA, n¼4mice/group).
IkKca affects spine size. (a) There was a significant decrease in
IjK regulates emotional behavior
DJ Christoffel et al
dysregulation of plasticity mechanisms is a primary cause of
In conclusion, we found that IkK activity affects
emotional behaviors and regulates vulnerability to acute
stress, likely through modulation of synaptic plasticity
mechanisms. These findings point to the induction of
immature synaptic structures in the NAc as a key neuro-
adaptation-regulating vulnerability to stress. Furthermore,
the common effect of multiple molecules on depressive
behaviors, suggest many signaling cascades might interact
to alter the state of plasticity in the brain. Gaining a further
understanding of these interactions will further elucidate
the most effective means to modulate neuronal function in
We thank Kevin Guise for his assistance in performing the
cumulative frequency plots of average spine head volume.
This work was supported by funding from the US National
Institute of Mental Health (R01MH090264-01) and the
National Alliance for Research on Schizophrenia and
The authors declare no conflict of interest.
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