# Molecular and circuit mechanisms of learning supported by heterogeneous dopaminergic neurons

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $324,715

## Abstract

Project Summary/Abstract
Dopaminergic neurons (DANs) are a molecularly, anatomically and functionally heterogeneous neuron group
that is essential for learning across animal phyla. In the midbrain, distinct populations of DANs are responsible
for memories with different valence or stability. Thus, the dopamine system comprises parallel subsystems,
each of which operates as a qualitatively distinct learning system. This raises two important questions: 1. How
does the heterogeneity of DANs impact synaptic plasticity to form distinct types of memories in each
subsystem? 2. How are the signals from parallel subsystems integrated to ultimately trigger a unified behavior?
Answers to these questions are required to understand the logic that governs the parallel memory systems.
The mushroom body (MB), the major associative learning center in the Drosophila brain, is an excellent model
to tackle these questions because it comprises dopamine subsystems, each of which is clearly defined by a
unique set of DANs and MB output neurons (MBONs). These individual MB compartments support distinct
types of memories that vary in valence and stability, properties shared with mammalian dopamine subsystems.
However, in both invertebrate and vertebrate brains, it remains an open question whether the diversity of
memory properties is derived from intrinsic characteristics of DANs or from an extrinsic circuit architecture. Aim
1 will test the hypothesis that combinations of DAN cotransmitters define compartment-specific rules of
synaptic plasticity and thereby determine the memory properties. By identifying novel DAN cotransmitters and
their physiological and behavioral roles, the causal relationship between plasticity rules and memory properties
will be tested. In Aim 2, integration mechanisms of different types of memories will be determined by identifying
neurons that pool input from multiple MBONs. Synaptic integration, behavioral roles and activity changes after
learning will be determined in these integrator neurons. In this project, cell-type-specific transcriptome and the
comprehensive connectome data available in the field will guide our molecular and circuit interrogation by in
vivo electrophysiology, calcium imaging and behavioral assays. Collectively, this project will address
fundamental questions regarding the heterogeneous organization of the dopamine systems and pioneer the
circuit motif that is currently inaccessible in vertebrates.

## Key facts

- **NIH application ID:** 10358623
- **Project number:** 5R01DC018874-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** TOSHIHIDE HIGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $324,715
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358623

## Citation

> US National Institutes of Health, RePORTER application 10358623, Molecular and circuit mechanisms of learning supported by heterogeneous dopaminergic neurons (5R01DC018874-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10358623. Licensed CC0.

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