# Roles for dopamine signaling modes in striatal circuit modulation and behavior

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2024 · $680,195

## Abstract

Summary
Dopamine controls movement, learning, motivation and reward, and changes in its signaling are associated with
drug addiction and Parkinson’s disease (PD). Dopamine operates through multiple modes, including tonic and
phasic signaling, and mechanisms of dopamine in the regulation of behavior continue to be debated. Recent
studies on movement, for example, have suggested that rapid, phasic dopamine triggers movement and
instructed models on the moment-to-moment roles of dopamine in striatal regulation. These models are
contrasted by clinical work that aims at providing stable dopamine levels for PD treatment.
The long-term goal of this project is to determine mechanisms of dopamine in the control of behavior. We
hypothesize that distinct dopamine signaling modes employ activity-dependent and -independent release
mechanisms for producing two-component control of behavioral output. Select roles of dopamine require firing
activity, while many permissive roles can be fulfilled by a release mechanism that does not rely on action
potential-firing. We have developed mouse mutants and acute manipulations to abolish action potential-
induced dopamine release and rapid in vivo dopamine dynamics. In these mutants, movement initiation is
unperturbed, and the mice can learn to make easy, binary decisions. In contrast, motivation, invigoration of
reward-oriented behavior, and prediction error-based learning are impaired. These data indicate the need for a
departure from the model that phasic dopamine triggers movement and justify in-depth analyses of dopamine in
reinforcement learning with the new approaches we established.
We will study striatal dopamine modulation in movement and reinforcement learning. Using the newly generated
tools, we will pursue a range of behavioral assays and simultaneously assess in vivo dopamine dynamics with
fluorescent dopamine sensors and neural activity with calcium indicators. In aim 1, we propose to establish
relationships between dopamine and striatal output during movement. We measure dopamine dynamics,
dopamine axon activity and medium spiny neuron activity during movement initiation and test for the roles of
dopamine release in movement and striatal regulation. In aim 2, we dissect mechanisms of dopamine in
reinforcement learning. We propose a step-wise, systematic approach to assess the necessity for action
potential-induced dopamine release in prediction error-based learning, motivation, motor skill learning, cocaine
self-administration and drug seeking.
This multiple PI project builds on the expertise of Pascal Kaeser, an expert in the biology of dopamine
transmission, and Naoshige Uchida, an expert in behavioral dopamine research. Our work will solve central
discrepancies in models of dopamine action in movement control and will likely establish roles for precise
dopamine signaling in reinforcement learning. The knowledge we generate may ultimately help revise strategies
for treating diseases with altered dopamin...

## Key facts

- **NIH application ID:** 10878352
- **Project number:** 1R01DA058777-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Pascal Simon Kaeser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $680,195
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878352

## Citation

> US National Institutes of Health, RePORTER application 10878352, Roles for dopamine signaling modes in striatal circuit modulation and behavior (1R01DA058777-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10878352. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*