# Molecular, anatomic, and functional characterization of midbrain dopamine neuron subtypes

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $681,044

## Abstract

The neurotransmitter dopamine (DA), produced by midbrain DA neurons, influences a spectrum of
behaviors including motor, reward, motivation, and cognition. In accordance with these functions, DA
dysfunction is prominently implicated in a wide gamut of disorders affecting tens of millions of people, including
Parkinson's disease, schizophrenia, ADHD, addiction and depression. Understanding how DA neurons control
all of these distinct behaviors is important for understanding and treating these neuropsychiatric diseases.
 The literature is dominated by anatomical classification of DA neurons based on location within the
Ventral Tegmental Area (VTA) or Substantia Nigra pars compacta (SNc). Guided by an emerging literature on
DA neuron heterogeneity, we hypothesize that there must exist several molecularly and functionally distinct DA
types, perhaps intermingled, that could underpin the myriad functions of DA. As a first step in classifying DA
neurons, the Awatramani lab developed an approach to profile single midbrain DA neurons, each for the
expression of 96 key genes, using a microfluidic dynamic RT-qPCR array. Hierarchical clustering indicated that
DA neurons exhibited roughly six distinct molecular barcodes, presumably indicative of at least six molecularly
and functionally distinct DA subtypes.
 The Dombeck laboratory has developed a robust data set demonstrating functional heterogeneity of DA
neurons in behaving mice. Previous models postulated that slow variations in tonic firing rates bias the system
toward or away from movement, whereas phasic signaling was linked to unpredicted rewards. Using imaging in
behaving mice, we showed heterogeneous expression of phasic locomotion and reward signaling in DA axons
projecting to the striatum. In the dorsal striatum we found that most DA fibers displayed a phasic signal locked
to the animal's cyclic accelerations during locomotion. In the ventral striatum, axonal signaling to unpredicted
rewards was more prevalent. These results indicate that striatum DA release is not simply homogenous and
movement permissive, but is richly heterogeneous with respect to reward and locomotion signaling.
 Based on these complementary data sets- molecular heterogeneity and functional heterogeneity, our
goal is to correlate molecular identity with anatomy and function. In Specific Aim 1, we will define the diversity,
transcriptomes, and projections of DA neuron subtypes, developing intersectional genetic tools to access DA
neuron subtypes. In Specific Aim 2, we will establish the behavioral signaling properties of the genetically
identified DA subtypes that project to the striatum. Thus, using a collaborative approach between two
laboratories each with distinct expertise, we aim to characterize DA neuron subtypes based on their molecular,
anatomic and functional properties. These studies will be vital for designing targeted therapies for the DA
system. Moreover these studies will provide genetic platforms for manipulatio...

## Key facts

- **NIH application ID:** 9873991
- **Project number:** 5R01MH110556-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Rajeshwar B Awatramani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $681,044
- **Award type:** 5
- **Project period:** 2017-03-22 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873991

## Citation

> US National Institutes of Health, RePORTER application 9873991, Molecular, anatomic, and functional characterization of midbrain dopamine neuron subtypes (5R01MH110556-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873991. Licensed CC0.

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