# The role of the nigrostriatal circuit in self-timed movements

> **NIH NIH U19** · HARVARD MEDICAL SCHOOL · 2021 · $585,034

## Abstract

Project abstract
Study of movement disorders suggests that dopamine (DA) and the broader nigrostriatal circuit may play a
specialized role in self-timed movements, for which the drive to move must be generated internally rather than
in reaction to external events. However, classic experiments suggested that DA neurons (DANs) encode
reward-prediction errors (RPEs) that occur too late to facilitate movements. In project 1, our collaborators
present an updated temporal difference (TD) model for which, under appropriate conditions, RPE/DA signals
“ramp-up” during ongoing behavior. These signals could be associated with, or facilitate, self-timed
movements. We will address the hypothesis in three ways, using a self-timed movement task in mice. First, we
will record from genetically defined DANs during self-timed movements, to assess the relationship between
DAN activity and movement time. We already have strong preliminary evidence that DANs indeed ramp up
their activity before self-timed movements, with the slope of ramping inversely related to the movement time.
Second, we will test whether DA ramps are causal to self-timed movements, by optogenetically stimulating
genetically defined DANs and examining the effect on the timing of self-timed movements. Third, the TD/RPE
theory explains how DANs can evince ramping activity, but does not address how DA ramping affects
downstream targets. We hypothesize that DANs facilitate self-timed movements by oppositely modulating
striatal spiny projection neurons (SPNs) of the direct and indirect striatal pathways. To test this hypothesis, we
will simultaneously monitor pairwise activity from genetically identified DANs, dSPNs or iSPNs to assess 1) the
relationship of dSPN/iSPN balance and movement time, and 2) the cell types' influence on each other. These
experiments will provide crucial information on the function of the key nigrostriatal circuit, grounded in a novel
theory that makes testable hypotheses.

## Key facts

- **NIH application ID:** 10226987
- **Project number:** 5U19NS113201-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** JOHN ASSAD
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $585,034
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226987

## Citation

> US National Institutes of Health, RePORTER application 10226987, The role of the nigrostriatal circuit in self-timed movements (5U19NS113201-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226987. Licensed CC0.

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