Prefrontal Cortex Modulates Desire and Dread
Generated by Nucleus Accumbens
Jocelyn M. Richard and Kent C. Berridge
Background: Corticolimbic circuits, including direct projections from prefrontal cortex to nucleus accumbens (NAc), permit top-down
control of intense motivations generated by subcortical circuits. In rats, localized disruptions of glutamate signaling within medial shell
of NAc generate desire or dread, anatomically organized along a rostrocaudal gradient analogous to a limbic keyboard. At rostral
locations in shell, these disruptions generate appetitive eating, but at caudal locations the disruptions generate progressively fearful
behaviors (distress vocalizations, escape attempts, and antipredator reactions). Here, we asked whether medial prefrontal cortex can
modulate intense motivations generated by subcortical NAc disruptions.
Methods: We used simultaneous microinjections in medial prefrontal cortex regions and in NAc shell to examine whether the desire or
dread generated by NAc shell disruptions is modulated by activation/inhibition of three specific regions of prefrontal cortex: medial
orbitofrontal cortex, infralimbic cortex (homologous to area 25 or subgenual anterior cingulate in the human), or prelimbic cortex
(midventral anterior cingulate).
Results: We found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by
amplifying generation of eating behavior by middle to caudal NAc disruptions, without altering fear. In contrast, activation of infralimbic
prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by NAc shell disruptions.
Conclusions: These results suggest that corticolimbic projections from discrete prefrontal regions can either bias motivational valence
or generally suppress subcortically generated intense motivations of desire or fear.
Key Words: Accumbens, eating, fear, infralimbic, medial orbito-
from prefrontal cortex (1,2). In humans, successful voluntary
suppression of subjective cravings or emotional responses is
accompanied by activation of prefrontal cortical areas and
simultaneous reduction of subcortical activity in NAc, amygdala,
and ventral tegmentum (1,3–6).
Here, we sought to probe corticolimbic modulation of intense
unconditioned appetitive and defensive behaviors generated by
disruptions in medial shell of NAc in the rat. The medial shell of NAc
is an important node in the generation of both positive desire and
aversive dread (7–13). Localized disruptions of glutamate transmis-
sion in medial shell, via microinjections of the a-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid (AMPA) antagonist 6,7-dinotroqui-
noxaline-2,3(1H,4H)-dione (DNQX), generate intense unconditioned
appetitive and/or fearful behaviors organized along a rostrocaudal
gradient (probably involving disinhibition of ventral pallidum,
hypothalamus, and related targets from gamma-aminobutyric acid
[GABA]ergic suppression, thus releasing motivation-generating cir-
cuits) (14–18). Rostral disruptions in NAc shell evoke purely appetitive
behaviors like voracious eating (19,20). Caudal disruptions instead
evoke increasingly fearful behaviors, including audible distress
otivations or emotions generated by subcortical circuits
involving the nucleus accumbens (NAc) may be power-
fully modulated by top-down corticolimbic controls
vocalizations, escape attempts, and spontaneous defensive treading,
an innate antipredator reaction in which rodents toss debris at a
threatening stimulus (e.g., rattlesnake) (21–26). Intermediate disrup-
tions produce ambivalent mixtures of appetitive and fearful beha-
The valence of motivation produced by glutamate disruption at
many shell sites can be retuned by changes in external ambience,
which might reflect top-down influences from cortex and related
structures that send glutamate inputs to NAc (27,28). This study
probed three regions of prefrontal cortex that send direct glutamate
projections to the medial shell. First, the medial orbitofrontal cortex
(Brodmann area 10) ([29,30], but see ) is implicated in pleasure
and emotion (32,33). Second, the infralimbic cortex (34) is homo-
logous to human subgenual or deeply ventral anterior cingulate
cortex (Brodmann area 25) (35–37) and has been suggested to
suppress motivated behaviors, such as reinstatement of cocaine and
food seeking (38,39) and conditioned fear (40). Third, the prelimbic
cortex (potentially homologous to Brodmann areas 24 and 32 of
anterior cingulate cortex) (35–37) projects to NAc shell and core and
has been suggested to participate in appetitive and fearful motiva-
tions (41–43) and in some forms of inhibitory control (44,45). Here,
we tested the effects of reversible activation versus inhibition of
medial orbitofrontal, infralimbic, and prelimbic cortex on the ability
of glutamate disruptions within NAc shell to produce unconditioned
appetitive and fearful motivated behaviors.
Methods and Materials
To investigate whether activity in infralimbic, prelimbic, and
orbitofrontal regions of medial prefrontal cortex modulates the
generation of strong unconditioned motivations by NAc shell
glutamate disruptions, we simultaneously generated eating or
fearful defensive behaviors via microinjections in medial shell of a
From the Department of Psychology, University of Michigan, Ann Arbor,
Address correspondence to Jocelyn M. Richard, M.S., University of
Michigan, Department of Psychology, 530 Church Street, 4027 East
Hall, Ann Arbor, MI 48109-1043; E-mail: firstname.lastname@example.org.
Received Apr 27, 2012; revised Aug 1, 2012; accepted Aug 8, 2012.
BIOL PSYCHIATRY 2013;73:360–370
& 2013 Society of Biological Psychiatry
low dose of the AMPA antagonist DNQX (250 ng/.2 mL per side in
50% saline/50% dimethyl sulfoxide), while temporarily either
activating or inhibiting each prefrontal region (Figure 1A). Tem-
porary activation of prefrontal cortex was produced by micro-
injections of the GABA type A antagonist bicuculline (.1 mg/.2 mL
per side in artificial cerebrospinal fluid), which by preventing local
inhibition induces relative activation of neurons (46). Using
bicuculline allowed receptor-based comparison with the oppo-
site polarity effects of GABA agonist microinjections at the same
prefrontal sites (muscimol/baclofen microinjections). We con-
ducted a careful slow motion video analysis of behavior to
ensure that no seizure indicators were ever produced by bicucul-
line in prefrontal cortex, which is consistent with previous reports
of no seizure manifestations after bicuculline injected into cortex
at doses similar to ours or even higher (47–52). Temporary
inhibition of cortex was produced by a mixture of GABA type A
and GABA type B agonists, muscimol (5 ng per side) and baclofen
(65 ng per side in .2 mL artificial cerebrospinal fluid) (38). Micro-
injection spread was assessed by Fos plumes surrounding drug
microinjections. We have previously found that the diameter of
drug-induced Fos plumes shrinks after several microinjections
(28), and therefore we used a dedicated Fos group measured
after a single microinjection to capture maximal diameter.
Male Sprague-Dawley rats (n ¼ 124; prefrontal activation,
n ¼ 68; prefrontal inhibition, n ¼ 30; Fos analysis, n ¼ 26; 300
Figure 1. Microinjection conditions and DNQX effects. Rats received the following microinjections (A): rats in the activation group (top, n ¼ 68) received
either DNQX or vehicle in nucleus accumbens (NAc) shell and bicuculline or vehicle into prefrontal cortex, and rats in the inactivation group (bottom,
n ¼ 30) received either DNQX or vehicle in NAc shell and a baclofen plus muscimol combination or vehicle in prefrontal cortex. Fos plume maps show
the effects of DNQX alone (vehicle in prefrontal cortex) on eating (B) (green) or defensive treading behavior (C) (red). Histogram bars above the maps
show mean behaviors as a percent of vehicle at each rostrocaudal level (errors bars ¼ SEM; the n at each level is listed in the bar). Summary bar graphs
show the DNQX induced eating (B) and treading (C) as change from vehicle at rostral (n ¼ 26), middle (n ¼ 30), and caudal (n ¼ 22) locations in NAc
shell; data are given as seconds per hour,nnp o .01,np o .05 vs. vehicle,##p o .01,#p o .05 subregion difference, with Sidak corrections for multiple
J.M. Richard and K.C. Berridge
BIOL PSYCHIATRY 2013;73:360–370 361
to 400 g before surgery) were housed at ?211C on a reverse
12:12 light:dark cycle, with ad libitum access to both food and
water. All experiments were approved by the University Commit-
tee on the Use and Care of Animals at the University of Michigan.
Surgery and Drug Microinjections
Rats received bilateral implantation of cranial cannulae aimed
at points throughout the rostrocaudal extent of medial shell of
NAc and a separate pair aimed at either the infralimbic, prelimbic,
or medial orbitofrontal regions of prefrontal cortex. Following 1
week of recovery, each rat (n ¼ 68; infralimbic, n ¼ 26; prelimbic,
n ¼ 11; orbitofrontal, n ¼ 29) in the prefrontal activation group
was tested after the following four drug conditions for sponta-
neous motivated behavior (see Supplement 1 for more detail): 1)
vehicle in prefrontal cortex and vehicle in NAc; 2) bicuculline in
prefrontal cortex and vehicle in NAc; 3) vehicle in prefrontal cortex
and DNQX in NAc; and 4) bicuculline in prefrontal cortex and
DNQX in NAc. Each rat in the prefrontal inhibition group (n ¼ 30;
infralimbic, n ¼ 9; prelimbic, n ¼ 5; orbitofrontal, n ¼ 16) received
the following four drug conditions: 1) vehicle in prefrontal cortex
and vehicle in NAc; 2) baclofen plus muscimol in prefrontal cortex
and vehicle in NAc; 3) vehicle in prefrontal cortex and DNQX in
NAc; and 4) baclofen plus muscimol in prefrontal cortex and
DNQX in NAc (Figure 1A). Each rat in the Fos group received
comparable single microinjections of one above condition.
Observers blind to drug treatment scored each 60-minute
session for the total time (seconds) spent in each of the following
behaviors: appetitive behaviors such as eating (mouth on the
food or engaged in chewing action) and drinking (licking the
spout of the water bottle), fearful behavior consisting of
defensive treading (spraying or pushing of bedding by rapid
alternating thrusts of the forepaws), and grooming (a stereo-
typed sequence described in ). Observers scored the total
number for behaviors that tended to occur as discrete events,
including appetitive behaviors such as food carrying (transporta-
tion of food pellets in the mouth) and food sniffs (sniffing near
the food for at least 1 s), and two general motor activities: rearing
(forepaws at least 1 in. off the floor) and cage crosses (forepaws
and head cross the halfway point of the cage). Observers also
looked for any indicators of seizure, including behavioral arrest or
akinesia (freezing) and stereotyped behaviors including repetitive
blinking or rhythmic jaw opening, head nodding, head shaking,
wet dog shakes (repetitive shaking of the entire trunk), tonic
seizures (sudden-onset tonic extension or flexion of the head,
trunk, and/or extremities for several seconds), sudden loss of
posture (falling over), and myoclonic or clonic twitches (brief
arrhythmic or rhythmic jerking of a muscle group).
Fos-like Protein Immunohistochemistry
Rats used for Fos analysis (n ¼ 26) were anesthetized with an
overdose of sodium pentobarbital and transcardially perfused 90 min
after bilateral microinjection of either 1) vehicle in prefrontal cortex
and vehicle in NAc (n ¼ 6), 2) bicuculline in prefrontal cortex and
vehicle in NAc (n ¼ 2), 3) vehicle in prefrontal cortex and DNQX in
NAc (n ¼ 8), or 4) bicuculline in prefrontal cortex and DNQX in NAc
(n ¼ 4) for Fos plumes analysis, and 5) vehicle in prefrontal cortex
and no injection in NAc (n ¼ 3), or 6) bicuculline in prefrontal cortex
and no injection in NAc (n ¼ 3) for analysis of the effect of prefrontal
activation on baseline NAc Fos (see Supplement 1 for more detail).
Local Glutamate Disruptions in Medial Shell of NAc Induce
Appetitive and Defensive Behavior Organized Along a
When prefrontal cortex received no drug manipulation (vehi-
cle microinjection), localized glutamate disruptions in medial
shell generated intense appetitive eating and/or fearful behaviors
as expected, organized by valence along the usual rostrocaudal
gradient (Figure 1B). Medial shell microinjections of a moderate
dose of DNQX produced robust stimulation of eating and food
consumption to above five times vehicle control levels, with the
most intense eating (of up to 10 g) occurring from the most
rostral sites [Figure 1B; average of 611 s ? 65 SEM eating after
rostral DNQX vs. 154 s on vehicle control; eating time: drug ? -
placement, F(1,74) ¼ 5.415, p ¼ .006; average of 5.5 g ? .4 SEM
grams consumed after rostral DNQX vs. 1.1 g on vehicle control;
food intake: drug ? placement, F(1,74) ¼ 7.557, p ¼ .001]. At
caudal sites, the same microinjections produced active fearful
behaviors, including audible distress vocalizations and escape
attempts to touch (vocalizations: 59% of rats on DNQX vs. 0%
on vehicle, McNemar’s test, p o .001; escape: 27% of rats on
DNQX vs. 0% on vehicle, p ¼ .031) and spontaneous defensive
treading at 60 times vehicle control levels [Figure 1C; average
of 31.3 s ? 6.13 SEM after caudal DNQX vs. .49 s on vehicle
control; drug ? placement, F(1,74) ¼ 9.550, p r .001].
Medial Orbitofrontal Activation Specifically Enhances
Appetitive Motivation Produced by NAc Shell
Co-activation of medial orbitofrontal cortex (immediately
rostral to infralimbic cortex) selectively enhanced eating induced
by NAc DNQX at middle and caudal sites that otherwise
produced only fear (Figures 2A and 3A). Orbitofrontal activation
made caudal DNQX generate levels of eating that were 250% of
levels without orbitofrontal activation and as high as any eating
generated at rostral DNQX sites [up to 9.5 g; eating time:
DNQX ? bicuculline,
DNQX ? bicuculline, F(1,21) ¼ 4.376, p ¼ .049; Figure 3A]. At
more rostral NAc sites for DNQX, which generated high levels
of food intake to begin with (45 times control), robust eating
remained unchanged by orbitofrontal co-activation (Figure 3A).
Orbitofrontal activation never altered DNQX generation of fearful
behaviors [Figures 2B and 3B; medial orbitofrontal cortex:
defensive treading, DNQX ? bicuculline, F o 1; DNQX ? bicucul-
line ? NAc placement, F(2,19) ¼ 1.764, p ¼ .198; vocalizations
and escape attempts, p ¼ .375 to 1.00]. Likewise, medial orbito-
frontal activation had no effect on nonvalenced motor behaviors
such as grooming (Fs o 1), cage crosses [F(1,14) ¼ 2.788,
p ¼ .117], or rears [F(1,14) ¼ 1.424, p ¼ .253].
F(1,20) ¼ 4.483,p ¼ .047;foodintake:
Infralimbic Activation Suppressed Eating and Fear Generated
by NAc Shell Glutamate Disruption
Infralimbic activation nonspecifically suppressed all intense
motivated behaviors generated by NAc disruptions, appetitive
and fearful. Bicuculline-induced activation roughly cut in half the
high level of eating behavior and food intake otherwise induced
by DNQX in rostral sites of NAc shell [Figures 2A and 3C; eating
time: DNQX ? bicuculline, F(1,20) ¼ 4.563, p ¼ .045; food intake:
DNQX ? bicuculline, F(1,23) ¼ 10.903, p ¼ .003; DNQX ? bicu-
culline ? NAc placement, F(2,23) ¼ 3.522, p ¼ .046]. Activation
of infralimbic cortex similarly nearly abolished fearful distress
vocalizations, escape attempts, and defensive treading behavior
362 BIOL PSYCHIATRY 2013;73:360–370
J.M. Richard and K.C. Berridge
otherwise produced by DNQX at caudal shell sites [at least 96%
reduction; Figures 2B and 3D; defensive treading: DNQX ? bicu-
culline, F(1,23) ¼ 37.906, p o .001; DNQX ? bicuculline ? NAc
placement, F(2,23) ¼ 31.177, p o .001; vocalizations, McNemar’s
test, DNQX alone vs. DNQX plus bicuculline, p ¼ .021].
Infralimbic Suppression Is Specific to DNQX-Induced Levels of
Infralimbic cortex activation did not interfere with baseline levels
of spontaneous appetitive and defensive behaviors after vehicle
microinjection in NAc. Infralimbic microinjections of bicuculline did
not suppress moderate baseline levels of eating or drinking (Fs o 1;
Figure 3C), nor change baseline defensive behaviors, which remained
near zero (Figure 3D; defensive treading, F o 1, vocalizations and
escape attempts, McNemar’s tests, p ¼ 1.00). It also did not prevent
NAc DNQX microinjections from stimulating nonvalenced activities
such as grooming (F o 1) and even slightly enhanced locomotion
[cage crosses, main effect of bicuculline, F(1,16) ¼ 5.125, p ¼ .038;
rears, main effect of bicuculline, F(1,16) ¼ 7.981, p ¼ .012].
Prelimbic Activation Has No Effect on Motivated Behaviors
Generated by NAc Shell DNQX
By contrast to co-activation of infralimbic cortex, which
suppressed DNQX appetitive and fearful behaviors, co-activation
of the immediately dorsal region of prelimbic cortex failed to alter
NAc DNQX-induced eating or food intake [Figure 2A; eating time:
DNQX ? bicuculline, F o 1; DNQX ? bicuculline ? NAc place-
ment, F o 1; food intake: DNQX ? bicuculline, F(1,5) ¼ 2.330,
p ¼ .187; DNQX ? bicuculline ? NAc placement, F o 1]. Prelim-
bic cortex co-activation also failed to alter defensive treading
behavior, distress calls, or escape attempts induced by glutamate
disruptions in NAc caudal shell (Figure 2B; prelimbic cortex:
defensive treading, Fs o 1). Finally, co-activation of prefrontal
cortex had no impact on baseline defensive behaviors in the
absence of NAc DNQX, which remained near zero (defensive
treading, F o 1, McNemar’s Test, vocalizations and escape
attempts, p ¼ 1.00).
No behavioral indicators of seizure were observed after
microinjections of bicuculline in either prelimbic, infralimbic, or
Figure 2. Maps of prefrontal activation effects on nucleus accumbens shell DNQX generated eating and defensive treading. Maps show the effects of
prefrontal activation (n ¼ 68) on DNQX-induced eating (A) (left) or defensive treading (B) (right) at sites mapped on the sagittal plane of prefrontal
cortex, color-coded for changes in behavior as a percent of DNQX. Histogram bars show mean behavior as percent of DNQX at each rostrocaudal level,
split by dorsal (prelimbic, top; n ¼ 11) and ventral (medial orbitofrontal, n ¼ 29, and infralimbic, n ¼ 26; bottom) areas of prefrontal cortex (error
bars ¼ SEM; the n for each level is listed in or above the bar).
J.M. Richard and K.C. Berridge
BIOL PSYCHIATRY 2013;73:360–370 363
medial orbitofrontal regions. Thus, we conclude that seizures
were not induced by prefrontal activations.
Inhibition of All Prefrontal Cortex Regions Leaves Unchanged
Levels of Unconditioned Appetitive or Defensive Behaviors
Produced by NAc Shell Glutamate Disruption
Inhibition of infralimbic, prelimbic, or medial orbitofrontal
regions of prefrontal cortex, via combined microinjection of
GABA agonists baclofen and muscimol, all failed to alter the
DNQX NAc shell generation of intense levels of appetitive or
[Figure 4A, B; eating time: Fs o 1; food intake: DNQX ? baclo-
fen-muscimol, F(1,14) ¼ 2.580, p ¼ .131; DNQX ? baclofen-mus-
cimol ? prefrontal
DNQX ? baclofen-muscimol,
mol ? prefrontal placement, F(2,14) ¼ 2.536, p ¼ .115; vocaliza-
tions and escape attempts: p ¼ 1.00; Figures 2 and 3]. Inhibition
placement,F o 1;defensive
DNQX ? baclofen-musci-
F o 1;
Figure 3. Motivated behavior graphs. Graphs demonstrating the specific effects of medial orbitofrontal activation (left) and infralimbic activation (right)
on appetitive eating (top) and defensive treading (bottom), depending on particular rostrocaudal location (rostral, middle, or caudal). Simultaneous
microinjections of bicuculline in medial orbitofrontal (n ¼ 29) with DNQX in nucleus accumbens (NAc) shell (black, left) produced enhancement of DNQX
induced eating (A) (green), specifically at more middle (n ¼ 11) and caudal (n ¼ 7) locations but not rostral (n ¼ 11) and had no effect on DNQX-induced
treading (B) (red). Microinjections of bicuculline in infralimbic cortex (n ¼ 26) with simultaneous DNQX in NAc shell (black, right) produced suppression of
both DNQX-induced eating (C) (green) from rostral sites (n ¼ 12) and treading (D) (red) from caudal sites (n ¼ 7; middle sites, n ¼ 7). Data are given as
seconds per hour, errors bars indicate SEM,np o .05 vs. vehicle,nnp o .01 vs. vehicle,#p o .05 vs. DNQX,##p o .01 vs. DNQX, pairwise comparison using
Sidak corrections. PFC, prefrontal cortex.
364 BIOL PSYCHIATRY 2013;73:360–370
J.M. Richard and K.C. Berridge
of prefrontal cortex also had no impact on baseline levels of
eating or defensive behaviors [food intake: Fs o 1; eating:
baclofen-muscimol, F(1,14) ¼ 1.833, p ¼ .197; baclofen plus mus-
cimol ? prefrontal placement, F(2,14) ¼ 1.241, p ¼ .319; defen-
sive treading: Fs o 1].
Fos Plume Analysis: Determining Functional Microinjection
We assessed Fos plumes produced by DNQX microinjections
in NAc and bicuculline microinjections in orbitofrontal and
infralimbic prefrontal cortex and also assessed whether prefrontal
bicuculline modulated distant Fos plumes in NAc induced
by DNQX in medial shell (Figure 5). Microinjections of DNQX
in NAc shell produced plumes containing a small .008 mm3
volume center where Fos expression was more than doubled
(radius ¼ .125 mm), surrounded by a larger .056 mm3sphere of
mildly elevated Fos expression between 1.5 to 2 times vehicle
levels (radius ¼ .24 mm; Figure 5B). Prefrontal bicuculline micro-
injections similarly produced enhancement of Fos expression
surrounding the microinjection. Infralimbic and orbitofrontal
plumes contained a small excitatory .00075 mm3center of tripled
Fos expression (radius ¼ .056 mm), surrounded by a larger
.03 mm3middle zone of more than doubled Fos expression
(radius ¼ .19 mm) and an outer .15 mm3halo of mildly elevated
Fos expression between 1.5 to 2 times vehicle (radius ¼ .33 mm)
(Figure 5A). In addition, bicuculline activation of either infralimbic
or medial orbitofrontal cortex amplified distant Fos expression in
medial shell [main effect of bicuculline, F(1,8) ¼ 7.737, p ¼ .024;
bicuculline ? prefrontal
Figure 5]. Fos expression surrounding NAc shell DNQX micro-
injections was elevated to three times DNQX alone levels in a
radius of .15 mm from microinjection center (volume ¼ .0014
mm3) and two times DNQX levels up to .26 mm away
(volume ¼ .073 mm3) following bicuculline microinjections. Pre-
frontal bicuculline enhanced distant Fos in uninjected NAc shell
to between 550% and 1150% over normal levels [main effect of
drug, F(33,2) ¼ 15.895, p o .001], with greatest effects in dorsal
shell and in particular in the most rostral and dorsal portions of
medialshell[bicuculline ? dorsoventral
8.566, p ¼ .015; bicuculline ? rostrocaudal location ? dorsoven-
tral location, F(2,30) ¼ 4.914, p ¼ .014; Figure 5C].
placement,F(1,8) ¼ 1.484,p ¼ .258;
3.6 3.2 2.8 2.4 5.2 4.8 4.4 4.0
% DNQX Feeding
3.6 3.2 2.8 2.45.2 4.8 4.4 4.0
% DNQX Feeding
3.6 3.2 2.8 2.4
5.2 4.8 4.4 4.0
% DNQX Treading
3.6 3.2 2.8 2.45.2 4.8 4.4 4.0
% DNQX Treading
% DNQX Treading
Baclofen + Muscimol (Inhibition)
Prefrontal inhibition has no effect
on DNQX eating (% DNQX)
Prefrontal inhibition has no effect
on DNQX treading (% DNQX)
Figure 4. Maps of prefrontal inhibition effects on nucleus accumbens shell DNQX generated eating and defensive treading. Maps show the effects of
prefrontal inhibition (n ¼ 30) on DNQX-induced eating (A) (left) or defensive treading (B) (right) at sites mapped on the sagittal plane of prefrontal cortex,
color-coded for changes in behavior as a percent of DNQX. Histogram bars show mean behavior as percent of DNQX at each rostrocaudal level, split by
dorsal (prelimbic, top; n ¼ 5) and ventral (medial orbitofrontal, n ¼ 16, and infralimbic, n ¼ 9; bottom) areas of prefrontal cortex (error bars ¼ SEM; the n
for each level is listed in or above the bar).
J.M. Richard and K.C. Berridge
BIOL PSYCHIATRY 2013;73:360–370365
Bicuculline-Induced Fos By Distance
From Microinjection Center (% Vehicle)
Distance from Microinjection Center (mm)
PFC Activation Enhances Fos Around
DNQX Microinjection (% Vehicle)
Distance from Microinjection Center (mm)
DNQX + PFC Bicuculline
NAc DNQX + PFC Bicuculline
Fos Plume Analysis
NAc Shell Fos
After PFC Vehicle
NAc Shell Fos
After PFC Bicuculline
PFC Bicuculline Increases NAc Shell Fos in the absence of NAc microinjection
Figure 5. Fos plume analysis and nucleus accumbens (NAc)-prefrontal interactions. Fos plumes were analyzed for functional drug spread of bicuculline
in prefrontal cortex (PFC) (A) and DNQX in NAc shell (B). Fos labeled cells were individually counted within successive blocks (50 mm ? 50 mm), along
eight radial arms emanating from the center of the site, with 10 ? magnification (A). Colors indicate levels of Fos expression of 3 ? (red), 2 ? (orange), and
1.5 ? (yellow) vehicle level Fos expression. Line graphs show levels of Fos expression following bicuculline (A) (blue) and DNQX (B) (red), as well as the impact
of prefrontal bicuculline on levels of Fos expression in NAc shell following either DNQX (B) (blue) or vehicle (Veh) (B) (green) microinjections in NAc shell.
Analysis of Fos expression in uninjected NAc shell (C) showed that bicuculline elevated NAc shell Fos even in the absence of NAc shell microinjections at levels
more than 500% (yellow), 650% (orange), and 800% (red) of vehicle. Bar graphs indicate levels of elevated Fos at three rostrocaudal and two dorsoventral levels.
np o .05,nnp o .01 vs. vehicle,#p o .05,##p o .01 vs. DNQX. Bic, bicuculline.
366 BIOL PSYCHIATRY 2013;73:360–370
J.M. Richard and K.C. Berridge
Medial Orbitofrontal Amplification of Subcortically
We found that activation of medial orbitofrontal cortex biased
the valence of motivation generated by NAc DNQX in an
appetitive direction. Activation of medial orbitofrontal neurons
by bicuculline microinjection specifically enhanced the eating
generated by microinjections in caudal NAc shell, which other-
wise produced mostly fearful behaviors. The intensity of eating
generated at caudal NAc sites rose to levels equaling those
normally produced by DNQX microinjections at more rostral sites,
which produced almost purely appetitive valence. However,
orbitofrontal activation never generated behavior on its own,
nor further enhanced the already intense eating generated by
DNQX in rostral NAc. That pattern suggests that orbitofrontal
cortex specifically modulates intense eating generated by NAc,
up to the level of a response ceiling. Alternatively, it is possible
that orbitofrontal co-activation can enhance positive valence only
in the presence of a pre-existing state of negatively valenced fear
In human studies of sensory rewards, neuroimaging activation
of a specific mid-anterior region of orbitofrontal cortex (32) is
specifically associated with subjective pleasure for food, as well
as drugs, music, etc. (32,54–58). A special role for orbitofrontal
cortex in coding human pleasure seems consistent with our
finding that orbitofrontal activation specifically enhanced positive
incentive motivation generated by some sites of NAc (32,59).
Infralimbic Cortex Suppresses Subcortically Generated Fear
We found that activation of infralimbic cortex (corresponding
in humans to deeply ventral or subgenual anterior cingulate
cortex; area 25) generally inhibited the intensity of both positive
and negative motivations produced by glutamate disruptions
in NAc shell. Thus, infralimbic activation acted primarily as a
nonspecific brake, suppressing appetitive behavior elicited by
disruption at rostral shell sites and suppressing fearful behaviors
elicited at caudal shell sites. Our findings therefore support the
hypothesis that infralimbic cortex activation might generally
regulate or inhibit the subcortical generation of intense motiva-
tions of either positive or negative valence.
This hypothesis may fit with neuroimaging evidence from
humans. For instance, anterior cingulate cortex is activated when
people successfully engage in voluntary efforts to suppress their
Figure 6. Potential mechanisms of prefrontal modula-
tion of DNQX generated motivated behaviors. Proposed
direct prefrontal to nucleus accumbens (NAc) shell
mechanism (A) mediating opposite infralimbic vs. orbi-
tofrontal effects on DNQX-induced eating. Bicuculline
infusions excite glutamate inputs (green) from infralim-
bic or medial orbitofrontal cortex. DNQX alone inhibits
rostral NAc shell projection neurons (red), resulting in
disinhibition of downstream targets and intense eating.
Infralimbic activation may overcome DNQX inhibition of
these same neurons, suppressing eating. Medial orbito-
frontal activation may instead activate gamma-amino-
butyric acid (GABA)ergic interneurons, which further
inhibit neurons already inhibited by DNQX, potentiating
eating. A circuit diagram (B) shows prefrontal and NAc
shell projections to relevant third-party structures that
may mediate larger circuit interactions. DNQX micro-
injections likely inhibit neurons in NAc shell, disinhibit-
ing downstream structures such as ventral pallidum,
lateral hypothalamus, and ventral tegmental area (yel-
low) via GABAergic projections neurons (red). Medial
orbitofrontal and infralimbic activation may act to
modulate DNQX-induced behaviors via direct glutamate
(green) projections to NAc shell or parallel projections to
structures such as medial dorsal hypothalamus, lateral
hypothalamus, and basolateral amygdala.
J.M. Richard and K.C. Berridge
BIOL PSYCHIATRY 2013;73:360–370 367
aversive emotional reactions to distressing photos or to suppress
their appetitive cravings to images of palatable foods, and those
anterior cingulate activations are accompanied by reductions of
activity in NAc, ventral tegmental area, and extended amygdala
otherwise triggered by viewing the same images (4,5). Infralimbic
suppression of subcortically generated motivation is also con-
sistent with findings in rodent studies that infralimbic cortex
suppresses reinstated seeking of cocaine and food rewards
(38,39,60–62) and similarly suppresses reinstatement of condi-
tioned fear responses (41,43,63). Our findings extend infralimbic
suppression to include intense unconditioned appetitive and
fearful behaviors, which do not depend on learning or explicitly
require top-down control to be generated.
Prefrontal Cortical Excitation Modulates but Is Not Necessary
for Enhanced Motivation
Our results also showed an asymmetrical role of cortical
excitation versus inhibition in modulating motivations generated
by inhibition of NAc shell. Excitation of medial orbitofrontal and
infralimbic cortex modulated motivations released by NAc shell
DNQX microinjections as described above, but inhibition of the
same orbitofrontal or infralimbic cortex regions failed to alter NAc
shell desire or dread in any detectable way. This asymmetrical
pattern suggests that unconditioned motivations elicited by NAc
shell disruptions may not need input from prefrontal cortex but
that supranormal levels of prefrontal activation are nonetheless
able to modulate these motivations. Additionally, our finding that
neither prefrontal excitation nor inhibition affected normal levels
of baseline eating and fearful behavior may indicate that normal
levels of unconditioned eating and fear do not require prefrontal
Overall, our results are consistent with the notion that
infralimbic cortex and orbitofrontal cortex hierarchically control
NAc production of intense desire and dread (64). Prefrontal
cortex acted here as hierarchically superior in the functional
sense of being able to suppress and/or modulate the valence of
robust motivations triggered by disruptions of NAc. At the
same time, while subordinate, the NAc still possessed a degree
of autonomy that is characteristic of a hierarchical element.
That is, only manipulations of NAc and not prefrontal cortex
were capable of producing intense levels of motivated behaviors.
Such features of suppression/modulation by a hierarchically
superior unit, combined with semiautonomy of a subordinate
unit, have been suggested to characterize functional hierarchies
Neurobiological Bases of Infralimbic Versus Orbitofrontal
Local AMPA blockade by DNQX likely produces relative hyperpo-
larizations in NAc neurons by reducing glutamatergic depolarizations
(65). This likely reduces firing and GABA release by NAc projection
neurons and thus disinhibits downstream target neurons in ventral
pallidum, lateral hypothalamus, and ventral tegmentum to generate
intense levels of motivated behaviors (14–18).
How does prefrontal cortex activation interact with NAc
release of intense motivations? There may be a relatively
straightforward explanation for the effects of infralimbic cortex
activation, which directly opposed or suppressed NAc DNQX-
induced motivation. If infralimbic activation increases glutamate
release on NAc neurons that are hyperpolarized by DNQX, that
elevated glutamate level may compete with and perhaps partially
overcome the local hyperpolarization, thus reducing the intensity
of DNQX-elicited motivations. The explanation of orbitofrontal
modulation of NAc DNQX-generated eating is probably more
complex. One possibility is that orbitofrontal activation may
inhibit some NAc shell neurons by activation of inhibitory
GABAergic interneurons. Nucleus accumbens shell neurons are
reported to be excited by either orbitofrontal activation or
infralimbic activation, but not both (66). That is, if a particular
NAc neuron is excited by infralimbic cortex, it may be inhibited
by medial orbitofrontal cortex (66). Conversely, if a NAc neuron is
excited by orbitofrontal cortex, it is inhibited by infralimbic
cortex. This mutual exclusivity suggests two parallel corticolimbic
channels, with mutual inhibition between them. Thus, orbito-
frontal activation may inhibit some NAc shell neurons (specifically
those excited by infralimbic activation). If inhibition of these NAc
shell neurons contributes to intense appetitive behaviors, then
orbitofrontal activation may increase the intensity of eating by
augmenting their hyperpolarization (Figure 6A). If this hypothesis
is correct, then future pharmacologic or optogenetic inactivation
of local interneurons might modulate orbitofrontal-NAc interac-
tions in producing intense motivated behaviors.
A second category of explanation for infralimbic or medial
orbitofrontal effects goes beyond direct projections to involve
indirect modulations via wider mesocorticolimbic networks,
whereby prefrontal activations could recruit third-party structures
to modulate the valence or intensity of intense motivations
produced by NAc inhibition (including brain structures such as
basolateral amygdala, lateral and medial dorsal hypothalamus, or
brainstem) (Figure 6B) (30,67–70). Combined manipulations of
these other subcortical structures could be used in the future to
test their roles in modulating prefrontal-NAc shell interactions.
Improved top-down control could help deal with maladap-
tively intense emotions in a variety of psychopathologies invol-
ving corticolimbic circuitry, including addiction, schizophrenia,
and posttraumatic stress disorder (71–74). Speculatively, treat-
ments aimed at enhancing medial orbitofrontal function might
conceivably help increase positively valenced emotion or shift
the balance away from negatively valenced emotions. Reduced
orbitofrontal volume is found in patients with schizophrenia,
panic disorders, posttraumatic stress disorder, and obsessive-
compulsive disorder (75–79). Extrapolation of our results to such
conditions would suggest that enhancing orbitofrontal activity
might help add to positive appetitive motivation in cases where
intense but negative valenced emotion already exists, such as in
pathological anxiety or fearful paranoia.
In contrast, reduced activity in subgenual anterior cingulate
cortex (homologous to infralimbic cortex in our study) has been
reported to leave some patients with reduced ability to regulate
certain unwanted emotions, such as in posttraumatic stress
disorder (80). Additionally, abnormalities in area 25 in cocaine
addicts are associated with reduced top-down control and poor
decision making (81). Again, speculatively applying our findings,
these results support the view that activation of deep anterior
cingulate area 25, homologous to infralimbic cortex here, might
suppress the levels of unwanted intense emotions, regardless of
whether the valence of the pathological emotion was appetitive
In conclusion, our results suggest orbitofrontal cortex may
play an important role in enhancing the positive valence of
intense emotional states that might otherwise be purely fearful
or anxious. Additionally, deep anterior cingulate or infralimbic
368 BIOL PSYCHIATRY 2013;73:360–370
J.M. Richard and K.C. Berridge
cortex may be important in suppressing intense emotional states
involving either desire or dread. These demonstrations of top-
down hierarchical control over intense motivations generated by
subcortical neural events in nucleus accumbens illustrate corti-
colimbic mechanisms that may contribute to regulating normal
This research was supported by National Institutes of Health
grants (DA015188 and MH63649 to KCB) and by a National
Research Service Award fellowship to JMR (MH090602). We thank
Aaron Garcia and Stephen Burwell for assistance with immunohis-
tochemistry and Alexandra DiFeliceantonio and Benjamin Saunders
for comments on an earlier version of the manuscript.
All authors report no biomedical financial interests or potential
conflicts of interest.
Supplementary material cited in this article is available online.
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