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 basal ganglia dystonia linked loss of D1 DA receptor signaling leads to motor deficits, and how M4 modulates these behaviors.
Acetylcholine (ACh) released from cholinergic interneurons in the striatum acting through muscarinic acetylcholine receptors (mAChRs) is a potent regulator of basal ganglia activity and has multiple actions to oppose dopamine release, signaling, and related behaviors. Recent results have challenged both the anatomical location of ACh capable of regulating the basal ganglia direct pathway and the mAChR, M4, responsible for regulation of dopamine and related motor behaviors. In this proposal we will test both how different sources of ACh regulate motor disability as well as how the imbalance in dopamine and M4 signaling contributes to the expression of motor disability, and these results will lead to a mechanistic understanding of how M4 signaling contributes to motor deficits as well as the pre-clinical rationale for the use of selective M4 antagonists to alleviate motor disabilities in movement disorders.
