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Adolescent rats engage the orbitofrontal-striatal pathway differently than adults during impulsive actions

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Adolescence is characterized by increased impulsive and risk-taking behaviors. To better understand the neural networks that subserves impulsivity in adolescents, we used a reward-guided behavioral model that quantifies age differences in impulsive actions in adult and adolescent rats of both sexes. Using chemogenetics, we identified orbitofrontal cortex (OFC) projections to the dorsomedial striatum (DMS) as a critical pathway for age-related execution of impulsive actions. Simultaneous recording of single units and local field potentials in the OFC and DMS during task performance revealed an overall muted response in adolescents during impulsive actions as well as age-specific differences in theta power and OFC–DMS functional connectivity. Collectively, these data reveal that the OFC–DMS pathway is critical for age-differences in reward-guided impulsive actions and provide a network mechanism to enhance our understanding of how adolescent and adult brains coordinate behavioral inhibition.
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Adolescent rats engage
the orbitofrontal‑striatal
pathway dierently than adults
during impulsive actions
Aqilah M. McCane , Lo Kronheim , Alejandro Torrado Pacheco & Bita Moghaddam
*
Adolescence is characterized by increased impulsive and risk‑taking behaviors. To better understand
the neural networks that subserves impulsivity in adolescents, we used a reward‑guided behavioral
model that quanties age dierences in impulsive actions in adult and adolescent rats of both sexes.
Using chemogenetics, we identied orbitofrontal cortex (OFC) projections to the dorsomedial
striatum (DMS) as a critical pathway for age‑related execution of impulsive actions. Simultaneous
recording of single units and local eld potentials in the OFC and DMS during task performance
revealed an overall muted response in adolescents during impulsive actions as well as age‑specic
dierences in theta power and OFC–DMS functional connectivity. Collectively, these data reveal that
the OFC–DMS pathway is critical for age‑dierences in reward‑guided impulsive actions and provide
a network mechanism to enhance our understanding of how adolescent and adult brains coordinate
behavioral inhibition.
Adolescence is a developmental period associated with risky behaviors and increased sensation seeking. While
these phenotypes may be adaptive and help adolescents acquire new skills and facilitate independence, they may
lead to impulsivity and poor decision making. Our knowledge of neural networks that subserve impulsivity in
adolescent models remains limited1,2. Impulsive actions may directly aect the ability to withhold a response that
was previously rewarding, a behavior known as response inhibition. Response inhibition decits are greater in
adolescents than adults3,4. Understanding the neural mechanisms of response inhibition in adolescents is critical
for identifying those most at risk for reckless and impulsive decision making5.
e developmental period of adolescence to early adulthood is associated with considerable neuronal matura-
tion in frontal cortical regions such as the orbitofrontal cortex (OFC) and in striatal regions6,7. In adults, these
regions have been implicated in response inhibition and impulsive actions. For example, response inhibition
is associated with activation of the OFC in healthy adults8, and a dysfunctional OFC activity is observed in
patients with disorders characterized by decits in response inhibition such as obsessive compulsive disorder,
Tourette’s syndrome and attention decit hyperactivity disorder912. In preclinical rodent models, OFC lesions
impair response inhibition13,14, whereas optogenetic stimulation of the OFC reduces spontaneous compulsive
behaviors15. While OFC projects to most striatal subregions, its projections to the dorsomedial striatum (DMS)16
are hypothesized to mediate response inhibition17. is notion is supported by optogenetic stimulation of this
pathway reversing decits in response inhibition in a rodent model of compulsive behavior15 and DMS lesions
impairing behavioral inhibition similar to prefrontal cortex damage18. Finally, in adolescents, OFC and DMS
neurons encode the same rewarded actions dierently than adults19,20.
Here we asked if OFC–DMS projections process impulsive actions dierently in adolescents and adults.
Sparsity of preclinical data related to neural processing of behavioral inhibition in adolescents is primarily due
to limitations caused by the brief period of adolescence in rodents where behavioral and invivo measures have
to be completed in less than two weeks. We overcame these limitations by developing the cued response inhibi-
tion task (CRIT), an operant task which measures response inhibition in both adolescents and adults21 using the
same training duration. Here we combined this behavioral model with chemogenetics or electrophysiological
recording of units and local eld potentials (LFPs) and observe age-dependent roles for OFC–DMS projections
to support impulsive actions.
OPEN
Oregon Health and Science University, Portland, OR, USA. *email: bita@ohsu.edu
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Results
OFC to DMS projection is critical for expression of response inhibition in an age‑specic
manner
To assess the role of OFC–DMS projections in response inhibition, we quantied premature responses during
CRIT training (Fig.1A) while inhibiting OFC cells that project to DMS using chemogenetics. We infused a Cre
virus (Cav2Cre) into the DMS and an inhibitory DREADD (designer receptors exclusively activated by designer
drugs;AAV5-hSyn-DIO-hM4D(Gi)-mCherry) into the OFC (Fig.1B,C). To validate the eectiveness of this
approach to inuence OFC neuronal activity, we performed invivo electrophysiology recordings and observed
signicant modulation of OFC ring rate following clozapine-N-oxide (CNO) administration (t = 2.31, p = 0.03:
Fig.1D, E) compared to saline. Moreover, to control for nonspecic eects of virus or CNO injections, we per-
formed control experiments using a control virus (AAV-hSyn-DIO-mCherry) injected into the OFC and Cav2Cre
into the DMS as well as treated surgery naïve animals with CNO (Supplemental Figure1).
We next measured the eect of inhibition of DMS projecting OFC cells in adults and adolescents during CRIT
by injecting animals with CNO (10mg/kg) or saline for 10 consecutive days 30min before behavioral testing. All
animals were injected with saline during xed ratio 1 (FR1) training to become habituated to injections (Fig.2A).
Dierences were observed in premature actions (Fig.2B). As CRIT training progressed, premature actions ini-
tially increased [main eect of session: F(9,221) = 11.29, p = 1.70 × 10–14] as correct actions also increased [main
eect of session: F(9,221) = 46.63, p < 2 × 10–16]. CNO injection, as compared to saline, signicantly increased
Figure1. Experimental methods. (A) Experimental design of the cued response inhibition task (CRIT).
Sessions begin with simultaneous presentation of an inhibit action cue (variable time 5–30s), and an action
cue which remained lit for 10s following cessation of the inhibit action cue. Created with Biorender.com. (B)
Schematic of chemogenetic methods. DREADDs receptors were expressed in DMS projecting OFC neurons
by injecting CAV/2 Cre (green) bilaterally in the DMS and inhibitory DREADDs receptors (red) in the OFC.
(C) Robust expression of both viruses in their respective brain regions is observed. (D) Administration of CNO
(10mg/kg) suppresses ring rate (Z-scored) in a spontaneously active population of OFC neurons (not limited
to DREADDs expressing units) under isourane anesthesia. (E) Compared to saline control (light grey), CNO
injection (dark grey) produced a signicant and sustained modulation of OFC ring rate.
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premature actions [main eect of group: F(1,24) = 10.52, p = 0.003; Fig.2B] suggesting that OFC projections to
DMS play a key role in behavioral inhibition. Critically, an age-related dierence emerged when we compared
the eect of CNO and saline in adolescents vs adults. Whereas the number of premature actions in the saline
control group were inuenced by both age and session [age by session interaction: F(9,108) = 3.36, p = 0.001], with
adolescents performing more premature actions than adults, the CNO adult group became more adolescent-like
in that inhibition of DMS projecting OFC cells resulted in a statistically similar amount of premature actions
in adolescents and adults [main eect of age: F(1,7) = 0.22, p = 0.66; Fig.2C]. e number of correct trials was
similarly reduced in both age groups aer CNO administration [main eect of group: F(1,24) = 5.40, p = 0.03;
Fig.2D—main eect of session: F(9,108) = 31.004, p < 2 × 10–16; Fig.2E]. Collectively these data indicate that
while OFC cells that project to the DMS are critical for CRIT performance in both groups, silencing this pathway
ablates age dierences in response inhibition.
Adolescent OFC and DMS exhibit dierent electrophysiological correlates to response
inhibition
Given the critical role of OFC and DMS in response inhibition and observed age-related behavioral dierences,
we investigated the neural correlates of relevant behavioral events in CRIT while recording units in adults and
adolescents (Fig.3A). We classied cells as putative pyramidal cells or medium spiny neurons based on their r-
ing rates and spike widths. Baseline ring rate in the OFC and DMS was statistically similar between adolescents
and adults (independent samples t-test: p values > 0.05, Fig.3B,C). Consistent with untethered animals (Fig.2),
adolescents made more premature responses than adults during CRIT [main eect of age: F(1,21) = 6.27, p = 0.02;
Fig.3D] while the number of correct trials completed was comparable between age groups [main eect of age:
F(1,16) = 0.38, p = 0.55; Fig.3E]. Adolescents also executed more total actions compared to adults [main eect
of age: F(1,20) = 5.43, p = 0.03; supplemental Figure2].
We next investigated the physiological correlates of behavior in both age groups by isolating the ring activity
of single units in the OFC and DMS. Data presented are aggregated from the last three days of recording (PND
44–46 and 69–71). While some age-related small dierences were observed during tone exposure in either region,
the more robust phasic response dierences were observed during action (premature or correct) execution. In
response to premature actions, while dierent populations of OFC putative pyramidal cells in both age groups
were inhibited or excited (Fig.4A), the global ring rate was signicantly decreased only in adults (Fig.4C). In
contrast, no dierencesbetween adolescent and adult OFC ring rates were observed aer correct responses
(Fig.4F). In the DMS, while both adolescents and adults show a suppression of MSN ring rates aer premature
responding, this eect was more persistent in adults (Fig.4G–I). Compared to adults, adolescents exhibited a
dierent response to correct actions and the resulting reward in DMS MSNs (Fig.4L). While neurons in both
groups displayed a phasic response, the temporal prole of this response was dierentin each age group.
Figure2. Chemogenetic manipulation of corticostriatal circuits. (A) Timeline of CRIT showing animals’
age at each stage for adolescents (top) and adults (bottom). Arrows represent days animals were injected with
either saline or CNO. Created with Biorender.com. (B) CNO (10mg/kg) treatment resulted in increased
premature actions in both age groups during later sessions. (C) Number of premature actions is similar between
adults and adolescents treated with CNO, but adolescent premature actions dier from adults across sessions
following saline treatment. (D) CNO treatment resulted in reduced correct actions in both age groups. (E) Both
adolescents and adults increase the number of correct actions across session. Data are presented as mean + SEM.
*p < 0.05 main eect.
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Local eld potential recordings reveal age‑specic alterations in the theta oscillations
To further understand the neural correlates of CRIT, we also analyzed LFP activity in the OFC and DMS of the
same animals depicted in Figs.3 and 4. Power spectral densities were parametrized using the FOOOF toolkit22.
We focused our analysis on the theta frequency band (5–11Hz) because this frequency is associated with cog-
nitive control23,24, response inhibition2527, and reward processing28,29. LFP analyses included power, aperiodic
exponent and phase synchrony.
Mean theta power was extracted from putative oscillatory activity (Fig.5A). OFC theta power was signi-
cantly inuenced by event [main eect of event: F(2,560) = 5.11, p = 0.006], where power during correct actions
was reduced, relative to baseline [Tukey Post hoc, p = 0.007; Fig.5B]. ere was no eect of age on OFC theta
power across events [main eect of age: F(1,560) = 0.27, p = 0.61]. In the DMS, theta power was signicantly
inuenced by both event and age [event by age interaction: F(2,767) = 3.15, p = 0.04; Fig.5C]. Compared to adults,
adolescents exhibited stronger DMS theta power at baseline (p = 2.12 × 10–6, Bonferroni post hoc) and following
premature actions (p = 1.04 × 10–10, Bonferroni post hoc; Fig.5C).
e aperiodic exponent or power spectrum density slope was extracted and used as an index of excitation-
inhibition balance30. Steeper slopes or larger exponents are hypothesized to reect greater inhibition, while atter
slopes or smaller exponents occur when excitation is greater than inhibition30. ere was a signicant event by age
interaction for aperiodic exponents in the OFC [F(2,506) = 9.01, p = 0.0001], followed with Bonferroni corrected
post hoc tests. Adolescents had smaller exponents in the OFC during premature actions (p = 0.001, B onferroni
post hoc; Fig.5D). In the DMS, adolescent aperiodic exponents were lower than adults across all events [main
eect of age: F(1,767) = 47.81, p = 9.89 × 10–12; Fig.5E]. Aperiodic exponents were also signicantly inuenced by
event [main eect of event: F(2,767) = 104.64, p < 2 × 10–16], where both ages exhibited larger aperiodic exponents
following correct actions (p < 0.001, Tukey post hoc).
Finally, we assessed functional connectivity between the OFC and DMS in the theta frequency band by com-
puting the phase locking index γ as reported previously31 (Fig.5F). Adolescents exhibited stronger OFC–DMS
synchrony during baseline [t(2591.6) = 28.50, p < 2.2 × 10–16] and aer premature responding [t(1979.8) = 24.62,
p < 2.2 × 10–16; Fig.5G]. Higher theta synchrony was positively correlated with total premature actions r(85) = 0.23,
p = 0.03 (Fig.5H).
Figure3. Simultaneous recording from OFC and DMS in adults and adolescents as they perform CRIT (A)
Schematic of the operant chamber where simultaneous recordings in the OFC and DMS were performed.
Created with Biorender.com. (B) Baseline ring rate in adolescent (orange) and adult (blue) putative pyramidal
cells (C), and medium spiny neurons (MSNs;2). Numbers reect total number of cells recorded across
all sessions. ere were no age dierences baseline ring rate. (D, E) Behavioral data for both age groups
performing CRIT. (D) Adolescents make more premature responses during CRIT. (E) Adolescents and adults
made similar number of correct responses. Data are presented as mean + SEM. *p < 0.05, main eect of age.
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Figure4. Single unit electrophysiology recordings in OFC and DMS during cue presentation, premature
action and correct actions in adults and adolescents. (AF) OFC heatmaps for unit ring and corresponding
mean ring rate (GL). DMS heatmaps for unit ring and corresponding mean ring rate. e bars on the
heatmaps in the le column depict the 500ms change in ring rate following the task event (cue on, or action).
Age dierences in line graphs on the right (Z-score responses) are depicted as adults in blue and adolescents
in orange. e panel events (tone on, premature or correct action) occurred at time 0s. Adults (blue) but not
adolescents (orange) show a suppression of OFC cell ring rate aer premature responding (A). In the DMS,
MSNs show age dierences in response to premature responding (B). OFC cell ring rate was not dierent
between adults and adolescents following correct responses (C). Adolescent DMS MSNs show a larger response
to reward compared to adults (D). Numbers at the top of y-axis reect cell counts for each group. Data are
presented as mean + SEM. Black signicant bars reect permutation testing between age groups, p < 0.05.
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Figure5. Simultaneous local eld potential recordings in OFC and DMS in adults and adolescents during CRIT
performance. (A) Schematic of LFP methods for determining age dierences in LFP measures. eta power, aperiodic
exponent (power spectral density slope) and theta phase synchrony during task performance in the OFC and DMS were
isolated from the power spectrum density in adults and adolescents (please see methods for detail). (B, C) Compared to
baseline, OFC theta power is reduced following correct actions. Adolescents exhibit greater DMS theta power than adults at
baseline and following premature actions. (D, E) e aperiodic exponent in OFC and DMS. e exponentwas larger in adults
than adolescents in the OFC during premature actions. In the DMS, the aperiodic exponent was increased following correct
actions and was larger in adults compared to adolescents for all events. (F, H) Schematic and results of phase synchrony
between the OFC and DMS. Phase synchrony between the OFC and DMS was stronger in adolescents compared to adults
at baseline and during premature actions (G). Synchrony during premature actions in both age groups was also correlated
with the total number of premature responses (H). Data are presented as mean + SEM. #p < 0.05, Tukey Post hoc, *p < 0.05
Bonferroni post hoc,
p < 0.05, main eect of age, $p < 0.05, Welch’s two sample t-test.
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Discussion
A wealth of adult-focused literature implicates cortico-striatal circuits in mediating response inhibition17,32,33. e
nature of the contribution of these cortico-striatal networks and circuits to adolescent impulsivity and response
inhibition is poorly understood. We have previously observed age-related dierences in reward processing in
the OFC and DMS19,20. We therefore hypothesized that the immaturity of adolescent cortical-striatal circuits
may underlie these age dierences in impulsivity. To test this hypothesis, we used a response inhibition task,
where adolescents learn similarly to adults to withhold an action to receive a reward21, but make more premature
actions than adults. We nd that while chemogenetic inhibition of OFC–DMS pathway increases impulsive
actions in both ages, it has a more robust inuence in adults making them more adolescent-like. e analyses
of unit recording form OFC and DMS further supported our hypothesis by demonstrating a dierent pattern of
neural engagement and coordination in these regions in adults and adolescents.
OFC–DMS projection is critical for expression of impulsive actions
e OFC is strongly implicated in response inhibition. Metabolic activity in the OFC is related to compulsivity
and impulsivity in Tourette’s syndrome9. Increased activation of OFC is observed when healthy adults are engaged
in response inhibition8 whereas reduced OFC activation is observed when response inhibition is impaired in
individuals with OCD10,12 or ADHD11. In rodent models, OFC lesions are associated with increased impul-
sive choices34, impaired response inhibition13,14 and impaired reversal learning35,36. Additionally, optogenetic
stimulation of the OFC reduces spontaneous compulsive behaviors15. Collectively this literature demonstrates
that aberrant activity in the OFC across a spectrum of disorders, and in both clinical and preclinical models, is
associated with compulsive and impulsive responding.
e OFC projects to the DMS16, and this pathway is hypothesized to play a role in compulsive behaviors37.
Similar to the OFC, the DMS plays a role in response inhibition17,3840 and goal-directed actions4143. e OFC
inuences actions via direct modulation of the DMS44. Lesions of DMS impaired behavioral inhibition similar
to prefrontal cortex damage18, suggesting that activity in both of these regions is necessary for expression of
response inhibition. Consistent with this notion, optogenetic stimulation of the OFC-striatum pathway reverses
decits in response inhibition in a rodent model of compulsive behavior15.
Our ndings here complement the above adult-focused literature by demonstrating that the OFC projections
to DMS are necessary for appropriate expression of response inhibition. Our results further demonstrate that
the OFC–DMS projection has a more robust inuence in controlling response inhibition in adults. Specically,
the observation that chemogenetic inhibition of OFC–DMS makes adults’ response inhibition more adolescent-
like provides strong evidence that maturation of this pathway is critical for better response inhibition in adults.
Adolescents OFC and DMS neurons are engaged dierently during CRIT
OFC population activity signicantly decreased aer premature actions in adults but not adolescents. Previ-
ous work in adult models has shown that OFC activity before an action execution is modulated by previous
actions and predicts subsequent response duration, suggesting that the OFC may use previous action-related
information to inuence current actions45. Consistent with this function of the OFC, we observed that OFC
activity was signicantly altered aer premature actions in adults but not in adolescents. ese age dierences
further suggest that actions informed by action-history develop with maturity. Adolescents may, therefore, have
reduced capacity to utilize prior events to inform current events, likely due to functionally immature cortical
networks. Alternatively, age dierences in behavioral performance and corresponding cortical-striatal dynamics
may reect impaired acquisition of the CRIT. e OFC is hypothesized to guide decision making via state repre-
sentation or the formation of a cognitive map4648. As such, inactivation of the OFC disrupts learned behavioral
performance48,49, possibly via disruption of cognitive map formation. erefore, inhibition of OFC–DMS cells
in an immature OFC network may result in a dierent pattern of cognitive mapping during task performance
in adolescence.
DMS neurons are inuenced by the OFC and inactivation of the OFC impairs DMS state representation44
and decision-making50. In our single unit data, strong age dierences were observed in the DMS aer premature
actions where both adult and adolescent ring rates decreased. e temporal prole of this phasic response
was dierent in that adult neurons remained inhibited longer whereas adolescent neurons return to baseline
quickly, possibly reecting weaker cortical inhibition in adolescents. Consistent with previous ndings20, we
observe age dierences in the DMS aer correct actions with adolescents showing a stronger phasic response
to reward compared to adults. Post-action striatal responses may reect encoding of action outcome values45,51.
ese values may be updated from trial to trial, and in this way inuence future responding. In adolescents,
impaired encoding of outcomes may result in a failure to utilize feedback to guide future behaviors resulting in
persistent premature actions. e DMS is hypothesized to encode reward value51,52, which can also inuence
future actions. Moreover, DMS-projecting OFC neurons play a role in encoding reward value50. erefore, a
larger DMS response in adolescents to reward may suggest that they assign greater value to reward than adults.
Adolescent OFC and DMS network dynamics are dierent during CRIT
Coordinated changes in neuronal activity give rise to changes in net current ux and LFP oscillations53. ese
oscillations may provide information about event-driven or state-level global activity in the brain. Importantly,
LFPs cannot disambiguate the contributions of individual neurons but their activity may be an indirect measure
of network level dynamics54. We recorded LFPs in adults and adolescents during CRIT and utilized the tting
oscillations and one over f (FOOOF) algorithm22.is algorithm extracts the aperiodic component which is
hypothesized to reect the balance between excitation and inhibition. Specically, when excitation is greater than
inhibition, the exponent is lower30,55. e OFC aperiodic exponent in adolescents was lower than adults during
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premature actions, indicating less cortical inhibition. Reduced inhibition may be associated with impulsivity in
clinical populations. For example, adolescents with ADHD, a disorder characterized by increased impulsivity
and reduced response inhibition, have smaller exponents than control adolescents56,57. Moreover, an increased
exponent is observed during response inhibition58,59. Increased cortical inhibition in adolescents observed here
may, therefore, be associated with decits in response inhibition caused by immature OFC-mediated outcome
encoding.
In our analyses we focused on the theta frequency range because theta oscillations are hypothesized to
modulate neural activity by coordinating activity across networks60 and may be important for organizing activity
during active behavior61. Moreover, theta oscillations are hypothesized to reect active learning62 and are associ-
ated with reward outcome expectancy29 and anticipation63. In our LFP data we found that adolescents exhibit
stronger theta power in the DMS during premature actions. Stronger theta in adolescents following premature
responding may therefore be associated with aberrant reward-expectation. Collectively, our electrophysiology
data during CRIT demonstrate robust age dierences in DMS activity aer premature actions. ese age-specic
dierences may reect diminished capacity of the DMS to process action-outcome relationships in adolescents
and premature actions in CRIT.
Because the adolescent frontal cortex and striatum are immature relative to adults, we tested whether that
OFC–DMS synchrony would be reduced in adolescents. Unexpectedly, we observed stronger connectivity in
adolescents and a signicant positive relationship between neural synchrony and the number of premature
actions. Recent ndings in clinical populations suggest a positive relationship between impulsive behaviors and
cortico-striatal connectivity strength. Patients with obsessive compulsive disorder, a condition characterized
by increased compulsive actions, exhibit increased striatal-OFC connectivity and impulsivity when compared
to healthy controls64. Furthermore, Sanefuji etal.65 classied children with ADHD as impulsive and inattentive
subtypes and observed that impulsive but not inattentive children exhibit increased cortico-striatal connectiv-
ity. ese data suggest that interactions between the OFC and DMS may play a causal role in age dierences
in impulsive actions. is notion is consistent with our chemogenetic experiments, where inhibition of OFC
neurons that project to the DMS abolished age dierences in premature actions. Collectively, these data suggest
OFC–DMS connectivity plays a critical role in age associated dierences in premature actions and that ine-
cient processing of task state in the OFC may inuence the DMS’s ability to encode outcome-value information
in adolescents. Given the increased premature actions of adolescents in CRIT, our OFC–DMS synchrony data
may indicate that adolescents receive weaker feedback from their actions compared adults. In this way, their
performance may be more habitual and less goal-directed, as others have hypothesized66.
Limitations
Our current experimental design was guided by the hypothesis that adolescent and adult neurons are engaged dif-
ferently during response inhibition. Given the short period of rodent adolescence, we were limited to employing
a task that could be learned and completed in less than two weeks. We chose CRIT for this study, having exten-
sively characterized it in adults and adolescents21,67. We, however, acknowledge that CRIT may not dierentiate
between learning and performance. Premature actions may result from an inability to learn the task contingency
or a failure to inhibit a response, despite knowledge that inappropriate responding will not be rewarded. us,
while our previous work had not shown any associative learning decits in adolescents68, we cannot rule out
that learning decits in adolescents may have contributed to some of the observed behavioral age dierences.
Conclusions
We investigated the role of OFC–DMS in response inhibition in adolescent and adult rats. We observed a causal
and age-dependent relationship in OFC projections to DMS, and pronounced age-dependent neuronal dier-
ences in the OFC and DMS. We hypothesize that these data reect impaired state representation, likely due to
reduced inhibition in adolescent OFC.
Methods
Subjects subjects were male and female adolescent (PND 28–46; N = 19) and adult (PND 60+; N = 15) Long Evans
rats bred in-house. Rats were pair housed until surgery under temperature and humidity-controlled conditions
using a 12-h reverse light/dark cycle. Adolescents (PND 28) and adults (PND 60) were surgically implanted with
custom-made 8-channel electrode arrays (50-µm-diameter tungsten wire insulated with polymide, California
Fine Wire) in the lateral OFC (AP 3.2, ML 3.0, DV-4.0) and DMS (AP 0.7, ML 1.6,DV -4.0) under isourane
anesthesia as described previously19,20. All animals had one week to recover before behavioral testing. All experi-
ments were performed during the dark phase, in accordance with the National Institute of Health’s Guide to the
Care and Use of Laboratory Animals, were approved by the Oregon Health and Science University Institutional
Animal Care and Use Committee and were in compliance with the ARRIVE guidelines69. Aer the end of
each experiment, animals were anesthetized, perfused with paraformaldehyde, and histology was performed to
conrm probe placements (Supplementary Figure3). Animals with probes outside of the target regions were
excluded from analyses.
Statistical analyses all analyses were performed in MATLAB (MathWorks) and R (https:// www.r- proje ct.
org/). Unless otherwise specied, all comparisons were rst tested using analyses of variance (ANOVA) testing,
followed by post hoc tests for multiple comparisons procedures.
Behavior all recordings took place in an operant chamber (Coulbourne, Instruments) equipped with a food
trough and reward magazine opposite a nose-poke port with a cue light, infrared photo-detector unit, and a
tone-generating speaker. Adolescents (PND 35–36) and adults (PND 67–68) were food restricted, habituated to
the operant box and trained to nose poke in response to a light cue for a sucrose pellet (45mg, Bio-Serv) on a
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xed ratio one schedule over two days. Aer successful acquisition of cue-action responding, all animals begin
CRIT training as described previously21. All CRIT sessions last 60min. In each trial, in addition to the light cue
that signaled that an action would lead to reward, animals were presented with an inhibitory cue (auditory tone).
Responses made during the inhibitory cue were not rewarded and coded as “premature.” Following cessation
of the inhibitory cue (variable time 5–30s), the light cue remained lit for 10s. An action executed during this
time was rewarded and coded as “correct”. Failure to respond within 10s was coded as an omission. Following
either a response or omission, a variable length inter-trial interval of 10–12s preceded the start of a new trial. All
animals experienced ten CRIT sessions. Behavior data were analyzed using mixed design analyses of variance
(ANOVA) testing with between subjects factor age and within subjects factor session.
Electrophysiology recordings single units and local eld potentials (LFPS) were simultaneously recorded during
performance of CRIT over the course of 10 sessions using a Plexon recording system. Spikes were amplied at
1000× gain, digitalized at 40kHz, and single-unit data were band pass ltered at 300Hz. Single units were isolated
in Kilosort70. OFC neurons with baseline ring rates less than or equal to 10Hz and spike widths greater than
or equal to 0.30 were classied as putative pyramidal cells71. DMS neurons with baseline ring rates less than or
equal to 5Hz and spike widths greater than or equal to 0.25 were classied as putative medium spiny neurons72.
Firing rate analyses ring rates for all units were averaged across trials and Z-score normalized to each unit’s
baseline (ITI prior to trial) ring rate. Friedman’s ANOVA was computed to determine whether ring rate
changed during events of interest. Signicant ANOVA results were followed up using Bonferroni corrected
multiple comparisons. Age dierences were assessed using permutation tests73.
Spectral analyses spectral analysis were performed on LFP recordings using the Matlab wrapper for the
FOOOF toolkit22. A power spectrum density (psd) was computed using Welchs power spectral density estimate
and putative theta oscillation power was extracted. We did not compute power from datasets which did not
exhibit putative theta oscillations, as indicated by a frequency specic peak. e aperiodic exponent or slope of
the power spectral density was measured for all subjects. We used a broad frequency range (1–50Hz) to assess the
aperiodic t and exponents as recommended22,57. e impact of age and event on the psd slope was rst assessed
using ANOVA testing. Signicant main eects were followed up using Tukey HSD post doc testing. Signicant
interactions were followed up with Bonferroni corrected planned comparisons.
Phase synchrony data were ltered in the theta band (5–11Hz) and segregated by behavioral epoch. To meas-
ure strength of OFC–DMS synchrony, the phase locking index γ was computed by taking the complex value of
the average of all points (1/N) where
ϕ1(t)
and
ϕ2(t)
are two phases from the ltered signals, the phase dierence
θ
t
j
=ϕ1
t
j
ϕ2
t
j
,
tj
are the times of data points, and N is the number of all data points during the given
time interval31,7476. Age-group dierences were assed using Welch’s two sample t-test. Person’s correlation was
used to compare premature actions and synchrony across both groups.
Chemogenetics DREADD receptors were expressed in DMS projecting OFC neurons by injecting 0.5µL of
CAV/2 Cre (Montpellier Vector Platform) bilaterally in the DMS and 0.5µL of the DREADD receptor AAV5-
EF1a-DIO-hM4D(Gi)-mCherry (Addgene) in the OFC under isourane anesthesia on PND 20 as reported
elsewhere33. Animals were divided into groups of either saline or CNO treatment and tested in either adolescence
or adulthood. Aer two days of nose-poke training (PNDs 35–36, PND 58–59) animals experienced 10days of
CRIT with either CNO (10mg/kg; Hello Bio) or saline treatments, 30min prior to behavior. Aer the end of
each experiment animals were anesthetized, perfused with paraformaldehyde, and the extent of virus expression
was determined using immunohistochemistry techniques.
Data availability
e datasets generated during and/or analyzed during the current study are available from the corresponding
author on reasonable request. Data is provided within the manuscript or supplementary information les. Codes
will be made available upon request.
Received: 20 December 2023; Accepted: 2 April 2024
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Acknowledgements
is work was supported by Grants R01MH048404 (B.M.), NIAAA F32AA027935 (A.M.), and Brain & Behavior
Research Foundation Young Investigator Grant (A.M.).
Author contributions
Conceptualization, A.M., B.M.; investigation, A.M., L.K., A.T.P.; formal analysis, A.M.; writing-original dra,
A.M., B.M., writing-review and editing, A.M., L.K., A.T.P., B.M.; visualization, A.M.; funding acquisition, A.M.,
B.M.
Competing interests
e authors declare no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at https:// doi. org/
10. 1038/ s41598- 024- 58648-w.
Correspondence and requests for materials should be addressed to B.M.
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... Optogenetic stimulation of the OFC-striatum pathway was able to reverse deficits in response inhibition in a rodent model of compulsive behavior (Burguière et al., 2013). Lastly, inhibition of OFC neurons that project to the DMS results in increased premature actions during CRIT performance (McCane et al., 2024). ...
... Adolescents and adults were food restricted, habituated to the operant box and trained to nose poke in response to a light cue for a sucrose pellet (45 mg, Bio-Serv) on a fixed ratio one schedule over two days. After successful acquisition of cue-action responding, all animals begin CRIT training as described previously (Simon et al., 2013;McCane et al., 2024). Each CRIT session lasted 60 minutes. ...
... Here we used a voluntary (Holgate et al., 2017) and relatively brief drinking paradigm in adolescents. We focused on the OFC and DMS because these regions undergo pronounced development during adolescence and are reported to mediate response inhibition and impulsive choice (Chudasama et al., 2003;Rieger et al., 2003;Eagle et al., 2007;Mar et al., 2011;McCane et al., 2024). Cortical-striatal circuitry is also implicated in in AUD pathology in clinical populations (Cservenka and Nagel, 2012;Courtney et al., 2013;Cservenka et al., 2014). ...
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Alcohol use disorder (AUD) is strongly associated with initiation of drinking during adolescence. Little is known about neural mechanisms that produce the long-term detrimental effects of adolescent drinking. A critical feature of AUD is deficits in response inhibition, or the ability to withhold a reward-seeking response. Here we sought to determine if adolescent drinking affects response inhibition and encoding of neural events by the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), two regions critical for expression of response inhibition. Adolescent male and female rats were given access to alcohol for four hours a day for five consecutive days. Then, rats were tested in a cued response inhibition task as adolescents or adults while we recorded concomitantly from the OFC and DMS. Adolescent voluntary alcohol drinking impaired response inhibition and increased alcohol drinking in adult male but not female rats. Adolescent alcohol drinking also resulted in sex-specific effects on both unit firing and local field potential measures in the OFC and DMS during premature and correct actions. Collectively, these data suggest sex-specific effects of adolescent alcohol drinking on response inhibition and corresponding alterations in cortical-striatal circuitry. Highlights Moderate adolescent alcohol drinking disrupts adult response inhibition Action encoding in the OFC and DMS changes after adolescent alcohol drinking OFC-DMS connectivity is altered in males after adolescent alcohol drinking Adolescent alcohol drinking promotes increased alcohol intake in adult males
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Animals must continually evaluate stimuli in their environment to decide which opportunities to pursue, and in many cases these decisions can be understood in fundamentally economic terms. Although several brain regions have been individually implicated in these processes, the brain-wide mechanisms relating these regions in decision-making are unclear. Using an economic decision-making task adapted for rats, we find that neural activity in both of two connected brain regions, the ventrolateral orbitofrontal cortex (OFC) and the dorsomedial striatum (DMS), was required for economic decision-making. Relevant neural activity in both brain regions was strikingly similar, dominated by the spatial features of the decision-making process. However, the neural encoding of choice direction in OFC preceded that of DMS, and this temporal relationship was strongly correlated with choice accuracy. Furthermore, activity specifically in the OFC projection to the DMS was required for appropriate economic decision-making. These results demonstrate that choice information in the OFC is relayed to the DMS to lead accurate economic decision-making.
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We use mental models of the world—cognitive maps—to guide behavior. The lateral orbitofrontal cortex (lOFC) is typically thought to support behavior by deploying these maps to simulate outcomes, but recent evidence suggests that it may instead support behavior by underlying map creation. We tested between these two alternatives using outcome-specific devaluation and a high-potency chemogenetic approach. Selectively inactivating lOFC principal neurons when male rats learned distinct cue–outcome associations, but before outcome devaluation, disrupted subsequent inference, confirming a role for the lOFC in creating new maps. However, lOFC inactivation surprisingly led to generalized devaluation, a result that is inconsistent with a complete mapping failure. Using a reinforcement learning framework, we show that this effect is best explained by a circumscribed deficit in credit assignment precision during map construction, suggesting that the lOFC has a selective role in defining the specificity of associations that comprise cognitive maps. Animals form cognitive maps of the world to guide behavior. This study shows that the lateral orbitofrontal cortex is essential for creating precise, outcome-specific cognitive maps during initial learning, but not for general map creation in itself.
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The ability to use information from one’s prior actions is necessary for decision-making. While orbitofrontal cortex (OFC) has been hypothesized as key for inferences made using cue and value-related information, whether OFC populations contribute to the use of information from volitional actions to guide behavior is not clear. Here, we used a self-paced lever-press hold-down task in which mice infer prior lever-press durations to guide subsequent action performance. We show that the activity of genetically identified lateral OFC (lOFC) subpopulations differentially instantiate current and prior action information during ongoing action execution. Transient state-dependent lOFC circuit disruptions of specified subpopulations reduced the encoding of ongoing press durations but did not disrupt the use of prior action information to guide future action performance. In contrast, a chronic functional loss of lOFC circuit activity resulted in increased reliance on recently executed lever-press durations and impaired contingency reversal, suggesting the recruitment of compensatory mechanisms that resulted in repetitive action control. Our results identify a novel role for lOFC in the integration of action information to guide adaptive behavior.
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A hallmark of electrophysiological brain activity is its 1/f-like spectrum - power decreases with increasing frequency. The steepness of this 'roll-off' is approximated by the spectral exponent, which in invasively recorded neural populations reflects the balance of excitatory to inhibitory neural activity (E:I balance). Here, we first establish that the spectral exponent of non-invasive electroencephalography (EEG) recordings is highly sensitive to general (i.e., anaesthesia-driven) changes in E:I balance. Building on the EEG spectral exponent as a viable marker of E:I, we then demonstrate its sensitivity to the focus of selective attention in an EEG experiment during which participants detected targets in simultaneous audio-visual noise. In addition to these endogenous changes in E:I balance, EEG spectral exponents over auditory and visual sensory cortices also tracked auditory and visual stimulus spectral exponents, respectively. Individuals' degree of this selective stimulus-brain coupling in spectral exponents predicted behavioural performance. Our results highlight the rich information contained in 1/f-like neural activity, providing a window into diverse neural processes previously thought to be inaccessible in non-invasive human recordings.
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Neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the VTA and substantia nigra (SN). We find that, in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning. These results suggest that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar, supporting the notion that differences in reward response in each paradigm may be because of differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons, such as dopamine cell number and size, were similar in the VTA and SN of both ages, but there were age-related differences in stimulated dopamine release and correlated spike activity, suggesting that differences in reward responsiveness by adolescent dopamine neurons are not because of differences in intrinsic properties of these neurons but engagement of different dopaminergic networks.Significance Statement:Reckless behavior and impulsive decision-making by adolescents suggest that motivated behavioral states are encoded differently by the adolescent brain. Motivated behavior, which is dependent on the function of the dopamine system, follows learning of cause-and-effect associations in the environment. We find that dopamine neurons in adolescents encode reward differently depending on the cause-and-effect relationship of the means to receive that reward. Compared with adults, reward contingent on action led to a muted response, whereas reward that followed a cue but was not gated by action produced an augmented phasic response. These data demonstrate an age-related difference in dopamine neuron response to reward that is not uniform and is guided by processes that differentiate between state and action values.
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The orbitofrontal cortex (OFC) is a critical structure in the flexible control of value-based behaviors. OFC dysfunction is typically only detected when task or environmental contingencies change, against a backdrop of apparently intact initial acquisition and behavior. While intact acquisition following OFC lesions in simple Pavlovian cue-outcome conditioning is often predicted by models of OFC function, this predicted null effect has not been thoroughly investigated. Here we test the effects of lesions and temporary muscimol inactivation of the rodent lateral OFC on the acquisition of a simple single cue-outcome relationship. Surprisingly, pre-training lesions significantly enhanced acquisition after over-training whereas post-training lesions and inactivation significantly impaired acquisition. This impaired acquisition to the cue reflects a disruption of behavioral control and not learning since the cue could also act as an effective blocking stimulus in an associative blocking procedure. These findings suggest that even simple cue-outcome representations acquired in the absence of OFC function are impoverished. Therefore, while OFC function is often associated with flexible behavioral control in complex environments, it is also involved in very simple Pavlovian acquisition where complex cue-outcome relationships are irrelevant to task performance.
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Efficient information processing facilitates cognition and may be disrupted in a number of neurodevelopmental conditions. And yet, the role of inefficient information processing and its neural underpinnings remains poorly understood. In the current study, we examined the cognitive and behavioral correlates of the aperiodic exponent of the electroencephalogram (EEG) power spectrum, a putative marker of disrupted, inefficient neural communication, in a sample of adolescents with and without ADHD (n = 184 nADHD = 87; Mage = 13.95 years, SD = 1.36). Exponents were calculated via FOOOF (Donoghue et al., 2020a) from EEG data recorded during an 8-minute baseline episode. Reaction time speed and variability, as well as drift diffusion parameters (including the drift rate parameter, a cognitive parameter directly related to inefficient information processing) were calculated. Adolescents with ADHD had smaller aperiodic exponents (a “flattened” EEG power spectrum) relative to their typically-developing peers. After controlling for ADHD, aperiodic exponents were related to reaction time variability and the drift rate parameter, but not in the expected direction. Our findings lend support for the aperiodic exponent as a neural correlate of disrupted information processing, and provide insight into the role of cortical excitation/inhibition imbalance in the pathophysiology of ADHD.
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Significance Chemogenic activation of interneurons can bring about unexpected short-term and long-term changes in circuit dynamics. DREADD activation of all interneuron types suppressed firing of pyramidal cells but, unexpectedly, individual interneurons did not display sustained firing but instead undulated firing rates, interleaved with other interneurons. Despite the tonic suppression of spikes of individual pyramidal neurons, population bursts underlying sharp wave ripples persisted, often with stronger synchrony. Repeated drug application induced progressively weaker changes over days. Such plastic effects of DREADD activation should be taken into account in the interpretation of behavioral consequences.
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The aperiodic exponent of the electroencephalogram (EEG) power spectrum has received growing attention as a physiological marker of neurodevelopmental psychopathology, including attention‐deficit/hyperactivity disorder (ADHD). However, its use as a marker of ADHD risk across development, and particularly in very young children, is limited by unknown reliability, difficulty in aligning canonical band‐based measures across development periods, and unclear effects of treatment in later development. Here, we investigate the internal consistency of the aperiodic EEG power spectrum slope and its association with ADHD risk in both infants (n = 69, 1‐month‐old) and adolescents (n = 262, ages 11–17 years). Results confirm good to excellent internal consistency in infancy and adolescence. In infancy, a larger aperiodic exponent was associated with greater family history of ADHD. In contrast, in adolescence, ADHD diagnosis was associated with a smaller aperiodic exponent, but only in children with ADHD who had not received stimulant medication treatment. Results suggest that disruptions in cortical development associated with ADHD risk may be detectable shortly after birth via this approach. Together, findings imply a dynamic developmental shift in which the developmentally normative flattening of the EEG power spectrum is exaggerated in ADHD, potentially reflecting imbalances in cortical excitation and inhibition that could contribute to long‐lasting differences in brain connectivity.
Article
Objectives Convergent evidence has demonstrated that trait impulsivity, a key feature in obsessive-compulsive disorder (OCD), involves dysregulated frontal-striatal circuits. The present study aims to explore relationships between frontal-striatal circuits, trait impulsivity, and obsessive-compulsive symptoms. Methods Thirty-six unmedicated patients with OCD and 50 healthy controls (HCs) matched for age, sex, and years of education underwent a magnetic resonance imaging (MRI) procedure. Voxel-wise statistical parametric analysis was used to investigate the differences in resting-state functional connectivity between brain regions functionally connected to six pairs of a-priori defined striatal seed regions, between patients with OCD and HCs. Associations between frontal-striatal connectivity and both trait impulsivity and symptom severity of OCD were analyzed. Results The results showed altered striatal functional connectivity in OCD group compared to HCs, including increased connectivity of dorsal caudate (DC)-orbitofrontal cortex (OFC), ventral striatum (VS)-OFC, VS-medial prefrontal cortex, and putamen-sensorimotor area, and decreased functional connectivity of DC-anterior cingulate cortex (ACC), putamen-ACC, and putamen-dorsolateral prefrontal cortex (DLPFC). Furthermore, the putamen-DLPFC connectivity was negatively correlated with attentional impulsivity in the OCD group, but showed a positive correlation in HCs. Conclusions The present findings suggested that dorsal cognitive circuits could reflect the level of inhibitory control, which is balanced with the impulsive drive in healthy controls, but breakdown in OCD. Our findings supported that DLPFC-putamen connectivity underlying trait impulsivity, which were involved in the pathophysiology of OCD. The findings have provided new insights into the neurobiological mechanisms of OCD.