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Report Imbalanced Activity in the Orbitofrontal Cortex and Nucleus Accumbens Impairs Behavioral Inhibition Highlights 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 Authors Heidi C. Meyer, David J. Bucci Correspondence [email protected] 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. Meyer & Bucci, 2016, Current Biology 26, 2834–2839 October 24, 2016 ª 2016 Elsevier Ltd. http://dx.doi.org/10.1016/j.cub.2016.08.034

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Report

Imbalanced Activity in the

Orbitofrontal Cortex andNucleus Accumbens Impairs Behavioral Inhibition

Highlights

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

[email protected]

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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