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Imbalanced Activity in the
Orbitofrontal Cortex andNucleus Accumbens Impairs Behavioral InhibitionHighlights
d DREADDs were used to simultaneously alter neural activity in
OFC and NAC
d A functional imbalance between OFC and NAC disrupted
inhibitory control
d The data causally support current models of behavioral
control during adolescence
d The data provide new insight into the neurobiology of
negative occasion setting
Meyer & Bucci, 2016, Current Biology 26, 2834–2839October 24, 2016 ª 2016 Elsevier Ltd.http://dx.doi.org/10.1016/j.cub.2016.08.034
Authors
Heidi C. Meyer, David J. Bucci
In Brief
Meyer and Bucci demonstrate that
simultaneously increasing neural activity
in the nucleus accumbens and
decreasing activity in the orbitofrontal
cortex using chemogenetics impairs
inhibitory learning and behavioral control.
The findings inform the functional
consequences of imbalanced activity in
these areas as observed during
adolescence.
Current Biology
Report
Imbalanced Activity in the Orbitofrontal Cortexand Nucleus AccumbensImpairs Behavioral InhibitionHeidi C. Meyer1 and David J. Bucci1,2,*1Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03755, USA2Lead Contact
*Correspondence: [email protected]://dx.doi.org/10.1016/j.cub.2016.08.034
SUMMARY
Contemporary models of behavioral regulationmaintain that balanced activity between cognitivecontrol areas (prefrontal cortex, PFC) and subcorticalreward-related regions (nucleus accumbens, NAC)mediates the selection of appropriate behavioral re-sponses, whereas imbalanced activity (PFC < NAC)results in maladaptive behavior [1–6]. Imbalance canarise from reduced engagement of PFC (via fatigueor stress [7]) or from excessive activity in NAC [8].Additionally, a concept far less researched is that animbalance can result from simultaneously low PFCactivity and high NAC activity. This occurs duringadolescence,when thematuration ofPFC lagsbehindthat of NAC and NAC is more functionally activecompared to adulthood or pre-adolescence [2, 5, 9,10]. Accordingly, activity is disproportionately higherin NAC than in PFC, which may contribute to impul-sivity and risk-taking exhibited by adolescents [5, 6,10–12]. Despite having explanatory value, supportfor this notion has been solely correlational. Here,we causally tested this using chemogenetics to simul-taneously decrease neural activity in the orbitofrontalcortex (OFC) and increase activity inNAC in adult rats,mimicking the imbalance during adolescence. Wetested the effects on negative occasion setting, animportant yet understudied form of inhibitory learningthat may be particularly relevant during adolescence.Rats with combined manipulation of OFC and NACwere impaired in learning to use environmental cuesto withhold a response, an effect that was greaterthan that of either manipulation alone. These findingsprovide direct evidence that simultaneous underac-tivity in OFC and overactivity in NAC can negativelyimpact behavioral control and provide insight intothe neural systems that underlie inhibitory learning.
RESULTS
Many stimuli that humans and other animals encounter can have
multiple meanings that depend on the environmental setting, or
2834 Current Biology 26, 2834–2839, October 24, 2016 ª 2016 Elsev
context, in which they occur. Thus, an essential aspect of behav-
ioral control is the ability to use environmental cues to guide
appropriate responses [13, 14]. Accordingly, while it is necessary
to learn the conditions in which emitting a response to a stimulus
will result in a desired outcome, it is also imperative to learn the
conditions in which responding will not be associated with a
desired outcome and should therefore be withheld. To use a
common example, a crosswalk (stimulus) can indicate a safe
place to cross the street (response). However, the response
should be withheld if a car (environmental cue) is about to pass
through the crosswalk.
Despite the importance of this form of learning (referred to as
‘‘negative occasion setting’’ or ‘‘context monitoring’’) for adap-
tive behavioral control [13], very little is known about the neural
systems that support it. This is particularly important to address
because emerging evidence suggests that adolescent humans
and other animals experience difficulty using environmental
cues to withhold behavior [2, 15–18], which might contribute
significantly to the impulsive tendencies and heightened risk-
taking that characterize adolescence compared to other age
groups [6]. Consistent with this, we have shown that adolescent
rats require twice asmuch training as either adults or pre-adoles-
cents to learn to inhibit behavior in a negative occasion setting
procedure [19, 20]. During this procedure (Figure 1A), rats
receive daily training sessions consisting of reinforced trials in
which a ‘‘target’’ stimulus (tone) is presented by itself and fol-
lowed immediately by delivery of food reinforcement. On inter-
mixed non-reinforced trials, a ‘‘feature’’ cue (light) is presented
just before the tone and no reinforcement occurs on those trials.
In this way, the feature acts to ‘‘set the occasion’’ to disambig-
uate the meaning of the target stimulus and indicate when a
response should be emitted or withheld [21]. Furthermore, like
the relationship between the car and the crosswalk, the relation-
ship between the feature and the target is very specific in that the
feature cue does not gain general inhibitory properties that trans-
fer to other stimuli [22].
Additionally, it remains unclear whether and how the combina-
tion of excessive activity in NAC and hypoactivity in PFC that ex-
ists during adolescence (Figure 1B) [2, 5, 6, 9–12] causally con-
tributes to difficulties in behavioral control, largely because of
the lack of viable means to simultaneously manipulate neural ac-
tivity in two brain regions in different directions over an extended
period of training. We addressed both of these issues by using a
novel variant of the chemogenetic approach Designer Receptors
Exclusively Activated by Designer Drugs (DREADDs [23, 24]),
to simultaneously decrease neural activity in PFC and increase
ier Ltd.
Reinforced Trials
Non-reinforced Trials 5sec 5sec
5secFood (US)
Light(feature)
Tone(target)
A
B
NAC OFC NAC
OFC
NAC
OFC
NAC
OFC
Figure 1. Configuration of Stimuli in the
Negative Occasion Setting Procedure and
Schematic of the Balance Model of Behav-
ioral Control
(A) Red and green lines indicate inhibitory and
excitatory relationships in the behavioral proced-
ure, respectively (US, unconditioned stimulus).
The feature stimulus acts to gate or set the occa-
sion for the meaning of the target stimulus and
indicates that a response should be withheld dur-
ing the subsequent presentation of the target [21].
(B) Balanced activity (left side of panel, and indi-
cated by dashed line) is necessary for appropriate
behavioral control and is present in preadoles-
cence and adulthood. An imbalance can result
from impairing the function of OFC (middle left [7]),
increasing the influence of NAC (middle right [8]),
or by simultaneously disrupting and potentiating
activity in OFC and NAC, respectively [2, 5, 9, 10].
activity in NAC while rats were trained in negative occasion
setting (Supplemental Experimental Procedures). Briefly, the
DREADDs approach involves infusing a virus containing the
DNA for a synthetic G protein-coupled receptor (GPCR) into
target neurons. The ‘‘designer receptor’’ is expressed in the
neuronal membrane and is insensitive to any endogenous li-
gands. It can be activated for about 2 hr [25] only by systemic
administration of the designer drug (clozapine-N-oxide; CNO),
which is an otherwise inert molecule that does not interact with
any endogenous receptors [23, 24].
In experiment 1, we infused a virus (AAV8-HA-hM4Di-IRES-
mCitrine, abbreviated hM4Di) containing the DNA for a synthetic
inhibitory GPCR into OFC neurons, and a virus (AAV5-HA-
hM3Dq-IRES-mCitrine, abbreviated hM3Dq) containing the
DNA for an excitatoryGPCR intoNACof adult rats (Supplemental
Experimental Procedures). Injection of CNO attenuates the ac-
tivity of neurons expressing hM4Di as shown previously [24,
26–28] and, conversely, lowers the threshold for firing action
potentials in neurons expressing hM3Dq [23–25]. Thus, concur-
rent activation of both receptors results in a simultaneous and
counter-directional manipulation of neural activity in OFC and
NAC that mimics the imbalance observed in adolescence [5,
10–12]. We targeted the OFC because of its role in representing
contingencies between predictive stimuli and reward outcomes
[29–31] and updating response patterns after a change in
outcome value [32]. Importantly, representations of outcome ex-
pectancies in OFC manifest in the regulation of reward-related
impulses [33, 34]. In addition, hypoactivity particularly in the
OFC is thought to negatively impact behavioral control in adoles-
cents [9]. NAC, on the other hand, mediates motivational im-
pulses triggered by reward-related cues and is integral in repre-
senting the value of potential reward [35–37].
An example of conditioned responding over the course of
training in the negative occasion setting procedure is illustrated
in Figure 2A. Comparable to intact adult rats in our prior studies
[19, 20], the vehicle-treated control group in experiment 1
required 13 training sessions to consistently exhibit a significant
difference in responding to the tone on reinforced versus non-re-
inforced trials (Figure 2B; Z = 2.60, p < 0.005, see Supplemental
Experimental Procedures for data analysis). This is also illus-
trated in the summary graph in Figure 3. In contrast, rats that
were infused with both viruses and treated with CNO required
22 training sessions (Z = 3.60, p < 0.001, Figure 3) to exhibit dif-
ferential responding to the tone. In line with these data, CNO-
treated rats required significantly more training sessions than
vehicle-treated rats to reach the criterion of three consecutive
sessions with a discrimination ratio >0.5 (Supplemental Experi-
mental Procedures) [t(22) = 1.7, p < 0.05]. Thus, the simultaneous
increase in NAC activity and decrease in OFC activity resulted in
a substantial delay in learning to inhibit responding to the tone
when it was preceded by the light. This effect was not due to
changes in baseline activity or effects on motivation to consume
the food pellets (see caption for Figure 3). However, it was
possible that the impairment resulted not from the combination
of hypoactivity in OFC and hyperactivity in NAC per se, but
from one of the manipulations alone.
To test this possibility, rats in experiment 2 received only infu-
sions of hM4Di into OFC. Half of these rats were injected with
CNO, and half were injected with vehicle prior to each training
session. We also included another set of control rats that
received infusions of a virus that is identical to hM4Di but does
not contain the gene for the designer receptor (AAV8-hSyn-
eGFP, abbreviated GFP) to control for non-specific effects of
viral infusion. Half of these rats received CNO, while half received
vehicle to also test for non-specific effects of CNO. As shown in
Figure 3, rats in the hM4Di-CNO group required 14 sessions to
exhibit differential responding to the tone (Z = 2.46, p < 0.01).
In contrast, rats in each of three control groups required only
ten to 11 sessions (hM4Di-Veh group, Z = 3.41, p < 0.001;
GFP-CNO group, Z = 5.05, p < 0.001; GFP-Veh group,
Z = 2.54, p < 0.01). In addition, rats in the hM4Di-CNO group
required significantly more sessions than controls to consistently
exhibit a discrimination ratio >0.5 [t(24) = 1.9, p < 0.04]. Thus,
dampening the activity of OFC neurons alone did not affect
negative occasion setting to the same extent as when it is co-
occurred with hyperactivation of NAC. In addition, the compara-
ble performance among the three control groups indicates that
the behavioral effects cannot be attributed merely to viral infec-
tion itself or to CNO. Further, infusion of hM4Di into other regions
of PFC, such as prelimbic cortex, were without effect (data not
Current Biology 26, 2834–2839, October 24, 2016 2835
Figure 2. Example of Conditioned Food Cup Behavior during
Training in the Negative Occasion Setting Procedure
(A) Conditioned responding during presentation of the tone on reinforced (R)
and non-reinforced trials (NR) and (B) the difference in responding between
trial types, exhibited by the vehicle-treated control group in experiment 1.
Asterisk refers to the first of three consecutive sessions during which the
group’s difference score between R and NR trials was significantly different
from zero, defined as a Z score R 2.325 (i.e., p < 0.01; see Supplemental
Experimental Procedures). Data are means ± SEM.
0
5
10
15
20
25
Sess
ions
to c
riter
ion
Figure 3. Summary Data Indicating the Number of Sessions until
Each Group in the Study Consistently Exhibited a Significant Differ-
ence in Responding to the Tone on Reinforced and Non-reinforced
Trials
Significant difference is defined as Z score R 2.325, p < 0.01 for three
consecutive sessions; see Supplemental Experimental Procedures. Data in
black are from experiment 1 (combined manipulations of OFC and NAC), data
in blue are from experiment 2 (manipulation of OFC alone), and data in red are
from experiment 3 (manipulation of NAC alone). Rats with combined manip-
ulation of OFC and NAC required more training to consistently exhibit a sig-
nificant difference in responding to the tone on reinforced versus non-re-
inforced trials compared to either manipulation alone (see Results). Dotted line
indicates the mean number of sessions for all control groups in the study (the
individual control groups in each experiment exhibited comparable learning
(see Results); thus, only the controls that received the DREADDs virus and
vehicle treatment are shown). All groups in experiments 1 and 2 exhibited low
levels of baseline responding during the Pre-CS epoch (Ps > 0.3; see Sup-
plemental Experimental Procedures). In experiment 3 there was a significant
group difference [F(3,40) = 4.74, p < 0.01] in that the NAC-hM3Dq-CNO group
had higher levels of baseline responding than rats in the NAC-GFP-CNO
group, but there were no differences compared to either NAC-hM3Dq-vehicle
or NAC-GFP-vehicle rats. Similarly high levels of feeding behavior during the
Post-CS epochwere observed each experiment (Ps > 0.1). Therewas no effect
of group on time spent rearing during the light in any experiment (Ps > 0.1). In
addition, food cup behavior during the light was low (on average �0.75 s) and
did not differ between groups in experiments 1 or 2 (P’s > 0.7). In experiment 3,
a main effect of group was observed [F(3,40) = 4.24, p < 0.05], which was
driven by lower levels of responding by rats in the NAC-GFP-CNO group
relative to rats in the NAC-hM3Dq-CNO and NAC-hM3Dq-VEH groups and
thus cannot explain the primary impairment observed in the NAC-hM3Dq-
CNO group. Furthermore, although all groups showed a slight increase in re-
sponding during the first few sessions (likely attributable to a decrease in
rearing during these same sessions), we did not observe any other changes in
food cup responding during the light across training. OFC, orbitofrontal cortex;
NAC, nucleus accumbens; CNO, treatment with clozapine-N-oxide; VEH,
vehicle-treated control group.
shown) suggesting that negative occasion setting is sensitive to
decreases in activity in OFC in particular.
Similarly, experiment 3 tested whether hyperactivation of NAC
alone would impact negative occasion setting. Rats received in-
fusions of either hM3Dq or the GFP control construct into NAC
and half of the rats in each group received CNO, while the other
half received vehicle injections. As shown in Figure 3, rats in the
hM3Dq-CNO group required 18 sessions (Z = 2.76, p < 0.005) to
exhibit differential responding to the tone. In comparison, rats in
the three control groups required 11–12 sessions to discriminate
the dual meaning of the tone (hM3Dq-Veh group, Z = 2.66,
p < 0.005; GFP-CNO group, Z = 2.34, p < 0.01; GFP-Veh group,
Z = 5.28, p < 0.001). Rats in the hM3Dq-CNO group also required
significantly more sessions than controls to consistently exhibit a
discrimination ratio >0.5 [t(20) = 2.6, p < 0.01]. Thus, like attenu-
ating activity in OFC, overexcitation of NAC alone also increased
the number of sessions that were required to exhibit significant
discrimination between the trial types, but the effect did not
reach the magnitude produced by the combined manipulation
of OFC and NAC. This suggests that combined alteration of ac-
tivity in OFC and NAC may have an additive effect on behavior.
Importantly, attenuating activity in NAC by infusing hM4Di
2836 Current Biology 26, 2834–2839, October 24, 2016
instead of hM3Dq only mildly impacted behavior (data not
shown), indicating that it is specifically hyperactivity in NAC
that adversely affects negative occasion setting.
In each of the three experiments, expression of the DREADDs
receptor in OFC and/or NAC was comparable and evident along
the rostro-caudal extent of each region (Figure 4). Few fluores-
cent neurons were observed outside of the target region. In addi-
tion, for eachexperiment, themanipulations did not substantively
impact baseline responding, overall conditioned responding to
DLOLO VO
MO
LOVO
LOVO
NAC-cNAC-sh NAC-c NAC-sh NAC-c NAC-sh
AP +4.7mm AP +3.8mm AP +3.0mm
AP +2.3mm AP +1.6mm AP +0.9mm
A
C
B
D
Figure 4. Expression of the DREADDs Re-
porter in OFC and NAC
(A and C) Fluorescent labeling of OFC neurons ex-
pressing hM4Di (A) and NAC neurons expressing
hM3Dq (C) (203 magnification).
(B and D) Schematic diagram of representative
minimum (dark gray) and maximum (light gray)
expression of hM4Di in OFC (B) and hM3Dq in NAC
(D). Expression of the reporter was comparable and
evident along the rostrocaudal extent of each re-
gion. Few fluorescent neurons were observed
outside of the target region. Expression of the re-
porter in theGFP control groups was comparable to
that observed in the hM4Di groups (data not
shown). Expression of the reporters for the viruses
was very similar across experiments.
either the feature or target cue, or themotivation to consume food
pellets.
DISCUSSION
The findings presented here provide the first direct evidence
that an imbalance in PFC-NAC activity resulting from concur-
rent hypoactivity in PFC and hyperactivity in NAC, like that
observed during normal adolescence, impacts behavioral con-
trol. Indeed, in experiment 1, simultaneously attenuating the ac-
tivity of OFC neurons and exciting NAC neurons produced a
delay in learning to use environmental information to success-
fully withhold behavior that mimicked the delay exhibited
by adolescent rats compared to either adults or pre-adoles-
cents [19, 20]. Difficulty using negative occasion setters may
contribute to the propensity of adolescents to be more impul-
sive and to engage in more risk-taking behavior compared to
other age groups [5, 6, 10–12, 38]. Insofar as abnormal activity
in PFC and/or NAC is also associated with addiction and other
forms of mental illness, these findings also have bearing on
understanding the basis of dysfunctional behavioral control in
a variety of populations [3, 4].
The present data also inform our understanding of the neural
systems that support negative occasion setting. Indeed, despite
the importance of negative occasion setting for appropriate
behavioral control, very little is known about the neural sub-
strates that mediate this form of inhibitory learning. Instead,
most prior research on inhibitory control has focused on the neu-
ral systems that underlie stopping a response that is already in
progress (e.g., Stop-Signal Reaction Time task) [39] rather than
withholding a response in the first place. Studies of inhibition us-
ing ‘‘go/no-go’’ procedures also do not tap the same processes
as negative occasion setting since the go and no-go stimuli are
distinct cues and there is no ambiguity to resolve [2, 15, 40].
Moreover, most prior work on inhibition has considered the ef-
fects of neural manipulations on performance of a previously
learned task, rather than on acquisition of inhibitory behavior.
Here, we demonstrate that the ability to learn to use environ-
Current Bio
mental cues to withhold behavior involves
both OFC and NAC, in addition to a bal-
ance in activity between them.
The effect of dampening activity in OFC is consistent with the
notion that OFC is necessary for updating response patterns and
also indicates that OFC may have a more general role in medi-
ating cue representations under conditions of ambiguity. Specif-
ically, OFC is involved in encoding the reward predictive value of
cues relative to the environment [32, 41, 42], which is integral to
establishing the contingencies under which a cue may lead to a
reinforcing outcome. Furthermore, information about the reward
contingencies of a cue can be used to resolve the appropriate
course of action when that cue is encountered [43]. Thus, atten-
uating activity in OFC may affect negative occasion setting by
impairing the ability to use the feature to disambiguate whether
or not the target will be reinforced.
The effect of NAC overexcitation may reflect the role of NAC in
attributing incentive-salience to reward-related cues, which has
been shown to invigorate approach behavior [44]. Thus, one
explanation for the impairment following overexcitation of NAC
is that the excitatory properties of the target stimulus are en-
coded with a disproportionately high value. In other words,
NAC-mediated approach behaviors may outweigh the inhibitory
control processes that normally predominate when the feature is
present. Additionally, NAC is involved in the integration of cues
processed by frontal lobe regions into reward representations,
particularly when the appropriate course of action is uncertain
[45]. As a result, negative occasion setting may be impaired
because responding appropriately to the target depends on
the incorporation of information about the feature, which likely
requires communication with frontal lobe regions [46]. Indeed,
OFC and NAC may work in concert to encode and represent
information about the target, the feature, and the contingency
between them, a process that may be impacted during adoles-
cence [9]. Commensurate with this, juveniles may need to
engage PFC to a higher degree in tasks requiring inhibition in
order to compensate for existing inefficiencies.
Finally, the findings reflect utility of the DREADDs approach
to simultaneously and counter-directionally alter neural activity
in separate brain areas. This has significant potential for study-
ing the circuit dynamics underlying behavior, particularly in
logy 26, 2834–2839, October 24, 2016 2837
circumstances in which specific brain systems act either in con-
cert or in competition to regulate behavior. Additionally, the ma-
nipulations and results described here set the stage for additional
studies to identify in more detail the specific cell types and path-
ways involved in negative occasion setting.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures
and can be found with this article online at http://dx.doi.org/10.1016/j.cub.
2016.08.034.
AUTHOR CONTRIBUTIONS
H.C.M. and D.J.B. conceived the study design. H.C.M. carried out the exper-
iments and data analysis. H.C.M. and D.J.B. co-wrote the manuscript.
ACKNOWLEDGMENTS
All experiments were carried out in accordancewith the NIHGuide for the Care
and Use of Laboratory Animals, and all protocols were approved by the Dart-
mouth College Animal Care and Use Committee. This research was funded by
NIH grants R01DA027688 to D.J.B. and F31MH107138 to H.C.M. The authors
thank Dr. George Wolford for assistance with data analysis and Dr. Kyle Smith
for commenting on prior versions of the manuscript.
Received: May 19, 2016
Revised: July 14, 2016
Accepted: August 12, 2016
Published: September 29, 2016
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