The focus of this proposal is to characterize DAergic modulation of coarse and fine locomotor control using a multi-level integrative approach, from behavior to receptor signaling, that employs a powerful array of approaches. To gain a fundamental understanding of the cellular, network and modulatory properties that underlie the development of vertebrate locomotor activity it is critical to examine the neural mechanisms that drive the activity. This proposal is designed to address three main points: 1) Determine the neural mechanisms underlying a developmental switch in locomotor activity from an immature to a mature pattern by a combination of pharmacological, optogenetic and calcium imaging experiments, 2) Characterize the role of descending dopaminergic drive in fine motor behaviors, such as orienting and advancing maneuvers during hunting, by high-speed kinematic analysis of larvae with targeted inactivation (laser photoablation and/or optogenetic) of dopaminergic neurons in the ventral diencephalon, and 3) Identify spinal neurons modulated by the descending dopaminergic drive by correlating the expression of dopamine receptor mRNA transcripts with identified classes of putative locomotor-related spinal neurons. The broad intellectual scope of this proposal and the use of diverse experimental techniques, from simple behavioral measurements to the optical control of neuronal activity, permit the inclusion of students across various levels of sophistication, including high school (restricted to summer months), undergraduate and graduate students, and postdoctoral associates. The lab currently has one graduate student, one post-doctoral associate (5+ years of experience), a senior research associate (over 20+ years of experience), and several undergraduates. Understanding the cellular, network and modulatory properties that underlie the development of locomotor activity will likely aid in developing therapeutic interventions for DAergic-related diseases of the motor system, such as Restless Leg Syndrome, Periodic Leg Movement Disorder and Parkinson's Disease.

Public Health Relevance

In addition to providing excitatory drive to initiate locomotion, the brain contains descending neurons that modulate spinal locomotor circuitry. Dopamine is an important modulator of spinal locomotor circuitry and dysfunction of the dopaminergic system produces severe locomotor defects. Our goal is to gain a fundamental understanding of the cellular, network and modulatory properties that underlie the development of locomotor activity, which will likely aid in the development of therapeutic interventions for DAergic-related diseases of the motor system, such as Restless Leg Syndrome, Periodic Leg Movement Disorder and Parkinson's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094176-03
Application #
9521903
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Tye, Marc T; Montgomery, Jacob E; Hobbs, Maurine R et al. (2018) An Adult Zebrafish Diet Contaminated with Chromium Reduces the Viability of Progeny. Zebrafish 15:179-187
Montgomery, Jacob E; Wahlstrom-Helgren, Sarah; Wiggin, Timothy D et al. (2018) Intraspinal serotonergic signaling suppresses locomotor activity in larval zebrafish. Dev Neurobiol :