# Dopaminergic mechanisms for motivation and reinforcement learning

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $398,403

## Abstract

PROJECT SUMMARY/ABSTRACT
 Dopamine is a key modulator of motivated behavior. Dopamine is also a key modulator of reinforcement-
driven learning. Yet the relationship between these critical functions is unclear. Based on seminal recordings of
dopamine cells in head-fixed animals, the dominant theory is that dopamine signals reward prediction errors -
i.e. a learning signal. However, the actual release of dopamine has been repeatedly found to escalate as
freely-moving animals approach rewards, in a manner more consistent with reward prediction than reward
prediction errors. Furthermore, optogenetic stimulation of dopamine immediately invigorates behavior, as if
boosting reward predictions.
 This project seeks to resolve this apparent discrepancy, and gain a new understanding of dopamine
signaling and regulation. Prior studies in brain slices have established that dopamine release is strongly
influenced by local mechanisms, especially nicotinic acetylcholine receptors on dopamine terminals. Aim 1 will
directly test whether there is a dissociation between dopamine firing and dopamine release. VTA dopamine cell
body activity will be assessed using both optogenetic identification of single neurons, and fiber photometry, and
dopamine terminal activity in accumbens core and shell will be measured using both fast-scan cyclic
voltammetry and fiber photometry. These measures will be taken as rats perform multiple behavioral tasks,
including a trial-and-error reinforcement learning task and a more passive Pavlovian task for better comparison
to prior studies. Aim 2 will monitor and manipulate accumbens cholinergic interneurons during the same
behavioral tasks, while examining dopamine terminal activity. The hypothesis is that these interneurons can
both shape the motivational message conveyed by dopamine release, and rapidly switch this message to a
reinforcement learning signal. Finally, Aim 3 will use variably-timed local optogenetic manipulations of
dopamine and accumbens spiny neuron subpopulations (direct vs indirect) to investigate the exact timing
requirements for dopamine to serve as a reinforcement learning signal.
 The long-term goal of this research program is to understand circuit mechanisms of adaptive decision-
making, and how drugs such as nicotine perturb these mechanisms to produce addictive behavior. By using
state-of-the-art techniques and carefully-designed behavioral tasks to test novel hypotheses, this project may
transform our understanding of the neurobiology of motivated behavior.

## Key facts

- **NIH application ID:** 10132277
- **Project number:** 5R01DA045783-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JOSHUA D BERKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,403
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132277

## Citation

> US National Institutes of Health, RePORTER application 10132277, Dopaminergic mechanisms for motivation and reinforcement learning (5R01DA045783-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132277. Licensed CC0.

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