# Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2024 · $380,968

## Abstract

PROJECT SUMMARY
 Reward-guided decision-making and impulse control are disrupted after chronic cocaine use. These changes
have been attributed to altered functions in brain circuits critical for computation of reward predictions, action
policies, prediction errors and attention. ‘Reward prediction’ signals reflect the reward the animal expects to
receive as a result of behavior or presentation of a stimulus. ‘Action policies’ are rules that govern behavior that
are triggered by external stimuli or context, and are thought to underlie habits. Both reward predictions and action
policies are modified when there are violations in predictions known as ‘reward prediction errors’. ‘Signed’ reward
prediction errors reflect the valence associated with an error, strengthening or weakening the associability
between cues, responses and outcomes. ‘Unsigned’ prediction errors reflect the surprise induced by errors which
lead to increases in ‘attention’ so that learning can occur. We have uncovered neural correlates of these
constructs and the relationship between them by recording from multiple brain areas as rats perform a reward-
guided decision-making task in which we unexpectedly varied the delay to and size of reward across several
trial blocks. We have shown that nucleus accumbens core (NAc) and anterior insula (AI) encode reward
predictions, firing strongly for cues that predict more valued reward, whereas firing in dorsal lateral striatum (DLS)
is highly associative, encoding action policies such as stimulus-response associations and contextual bias
signals. We have also shown that midbrain dopamine (DA) neurons increase firing to unexpected reward and
decrease firing to unexpected reward omission. During learning these signed prediction errors transfer to cues,
with cues predicting more valued reward eliciting stronger firing. Unlike firing of DA neurons in ventral tegmental
area (VTA), our work has shown that firing in basolateral amygdala (ABL) and anterior cingulate cortex (ACC)
better reflects integrated unsigned prediction error signals and attention, increasing during unexpected up- and
down-shifts in value at the time of the error and during cue sampling on subsequent trials.
 Here, we propose that activation of ACC increases attention and engages model-based mechanisms that
govern goal-directed behavior and associated mechanisms in AI, NAc and VTA, and that chronic cocaine
reduces the fidelity of reward prediction and prediction error signals, in part, by disrupting ACC function. Further,
we propose that epigenetic changes in ACC, NAc and DLS after chronic drug use alter cue selectivity in a way
that promotes fast, automatic behavior by altering the start point and rate of signals that drive actions. In this
resubmission of my renewal application we propose to further model the normal circuit and behavior, and its
disruption after cocaine-exposure by bi-directionally manipulating neural signals via optogenetics and epigenetic
(histone deacetyl...

## Key facts

- **NIH application ID:** 10828380
- **Project number:** 5R01DA031695-12
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** MATTHEW R ROESCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,968
- **Award type:** 5
- **Project period:** 2011-07-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828380

## Citation

> US National Institutes of Health, RePORTER application 10828380, Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration (5R01DA031695-12). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10828380. Licensed CC0.

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