# Dopamine Timing-Dependent Plasticity in Reward Learning

> **NIH NIH R21** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $234,750

## Abstract

Project Summary/Abstract
The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) plays a critical role in
reward-based learning. DA neurons in the VTA display phasic burst firing in response to unexpected primary
rewards. The timing of this bursting activity shifts to the onset of reward-predicting cues during repeated cue-
reward pairing, where cue presentation needs to precede reward delivery for effective conditioning. DA neuron
bursting gives rise to phasic DA transients lasting several seconds in the nucleus accumbens (NAc), a key site
for the formation of cue-reward memory. In general, reward-evoked DA transients are thought to promote
Hebbian plasticity induced by coordinated pairing of presynaptic and postsynaptic activities (pre-post pairing)
during conditioning. However, this assumption leads to the following conundrum (known as the distal reward
problem): how can DA, which communicates via slow intracellular signaling cascades, influence the
consequence of preceding neural activities to regulate synaptic plasticity? In addressing this question, it is of
note that DA neuron bursting to the cue develops during the early phase of cue-reward conditioning. This
raises the possibility that DA transients elicited by the cue, not by the reward, may act to drive the learning of
specific cue-reward associations as conditioning progresses. Thus, this project will explore the cellular
mechanisms supporting the idea that DA transients need to precede the pre-post pairing to regulate Hebbian
plasticity in the NAc. Cytosolic Ca2+ signaling dependent on the intracellular messenger inositol 1,4,5-
triphosphate (IP3) can act as a coincidence detector to mediate synaptic plasticity. Medium spiny projection
neurons (MSNs) in the NAc comprise two subpopulations, i.e., D1 receptor-positive and D2 receptor-positive
MSNs, that play opposing roles in reward-driven behavior. Our recent study has reported differential regulation
of IP3-Ca2+ signaling by preceding DA transients in these two MSN subpopulations. We hypothesize that DA
will enhance long-term potentiation (LTP) of glutamatergic transmission in D1-positive MSNs while preventing
LTP, or promoting long-term depression (LTD), in D2-positive MSNs through opposing regulation of IP3-Ca2+
signaling. Temporal rules governing DA action on plasticity will be examined by varying the timing of DA
transients, produced by local pressure ejection of DA or optogenetic stimulation of DA fibers, relative to the
pre-post pairing. The goal of this R21 project is to open a new line of research addressing the role and timing
of phasic DA signals in regulating synaptic plasticity underlying reward learning.

## Key facts

- **NIH application ID:** 9904760
- **Project number:** 5R21MH119253-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** HITOSHI MORIKAWA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,750
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904760

## Citation

> US National Institutes of Health, RePORTER application 9904760, Dopamine Timing-Dependent Plasticity in Reward Learning (5R21MH119253-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904760. Licensed CC0.

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