# M4 muscarinic acetylcholine receptor signaling as a potent regulator of motor deficits

> **NIH NIH R00** · UNIVERSITY OF FLORIDA · 2021 · $249,000

## Abstract

Candidate: My long term goal is to become an independent investigator running an interdisciplinary and
collaborative research team to understand the mechanisms and novel treatments of neurological disorders.
Specifically, my interests surround understanding how different sources of acetylcholine (ACh, i.e. cholinergic
interneurons verse pedunculopontine nucleus) regulate motor dysfunction, as well as how imbalanced
dopamine (DA) and M4 muscarinic acetylcholine receptor (mAChR) signaling exacerbates motor dysfunction. I
have a strong background in biochemistry and electrophysiology. I propose to learn behavioral and voltammetry
techniques to round out my training, and have the necessary skills to produce high impact publications and
successful R01 submissions. I received my Ph.D. in April 2015, this is my last year of eligibility for the K99/R00.
Training: In addition to Dr. Conn, I have an advisory committee of experts in behavioral pharmacology, Dr.
Jones, dystonia and dopaminergic signaling, Dr. Ehrlich, and in using molecular probes to understand GPCR
signaling, Dr. Lindsley. This committee will provide the necessary training and guidance to accomplish this
proposal. Outside of the committee, we have identified, both at Vanderbilt and externally, courses, seminars,
and meetings to provide further technical training, presentation experience, responsible conduct in research,
and the necessary skills (offer negotiations, tenure, lab management, etc.) to transition to independence.
Research: Anti-mAChR therapy is efficacious at reducing motor symptoms of some movement disorders, but
severe side effects limit their utility. Our lab has made breakthroughs elucidating the roles of mAChRs, and
found the M4 mAChR subtype diminishes DA release, signaling, and related motor behaviors. Additionally, M4
inhibition of DA signaling occurs tonically outside the striatum. This has led us to the model that when DA
release or signaling is low, this allows M4 signaling to predominate, leading to motor dysfunction, and has led to
our broad hypothesis that M4 antagonists will reduce motor deficits in movement disorders. While M4
activity may be a critical modulator of DA and basal ganglia activity, providing similar efficacy to non-selective
mAChRs without side effects, this has not been tested. In preliminary data, we report the discovery of novel tool
compounds to directly test our hypothesis, demonstrate losing D1 DA receptor signaling diminishes basal
ganglia activity and produces motor deficits, and M4 activity bi-directionally modulates motor deficits. In aim 1,
using animal models predictive of anti-parkinsonian efficacy, we will test how, and through what ACh sources,
M4 activity modulates motor deficits. In aim 2, we will use a model of loss of D1 DA receptor signaling linked to
dystonia to test how diminished DA signaling, possibly allowing M4 signaling to predominate, effects basal
ganglia output and signaling. In aim 3, we will test how and where in the...

## Key facts

- **NIH application ID:** 10336602
- **Project number:** 4R00NS110878-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Mark S Moehle
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336602

## Citation

> US National Institutes of Health, RePORTER application 10336602, M4 muscarinic acetylcholine receptor signaling as a potent regulator of motor deficits (4R00NS110878-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10336602. Licensed CC0.

---

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