The long-term goals of this project are to elucidate how neural networks are organized to give rise to behaviors, such as locomotion, and how they are selectively activated by dopamine (DA). By learning how DA is involved in motor control, I hope to gain further insights into human diseases of motor control such as Parkinson's disease, tardive dyskinesia and restless leg syndrome. To study how DA regulates locomotion, I will use the medicinal leech. The leech is an ideal system for studying the role of DA in locomotor control because the CNS is relatively simple, containing only about 200 paired neurons per segmental division. The neurons of the CNS are large in size and uniquely identifiable between individuals. For my studies, I will use electrophysiological, computational and voltage-sensitive dye imaging methods. I will induce fictive crawling in isolated central nervous system (CNS) tissue using DA, which I found reliably activates fictive crawling in as little as a single isolated ganglion. Hypothesis 1: The crawl rhythm generator consists of neurons dedicated to crawling and multifunctional neurons that are part of both the swim and crawl rhythm generators. To test this hypothesis, I propose to identify neurons that can reset the crawl rhythm (i.e. rhythm generator neurons), and when depolarized, will activate the crawl rhythm generator (i.e. gating neurons). I will record from cells that are rhythmically active during both swimming and crawling and cells that are only active during crawling. I will also determine if intersegmental coordination is dependent on the head brain. These studies are inherently valuable for establishing the foundation for understanding the cellular basis of crawling. Hypothesis 2A: Activation of the crawl motor pattern is a consequence of DA influencing the intrinsic membrane properties of the rhythm-generating cells (e.g., cell 208), gating cells (e.g., cell 204), and identified motoneurons that participate in both swimming and crawling. To test this hypothesis, I will determine which changes in the membrane properties of specific cells enable DA to bias locomotor networks to crawl. I will test whether DA causes changes in the membrane properties of cells 208, 204, and motoneurons involved in crawling, and test whether the electrical coupling of motoneurons is altered. Hypothesis 2B: DA is part of a natural route for activating the crawl CPG. I will test whether the endogenous release of DA is sufficient to activate crawling by stimulating the DA cells. Through these studies, I will gain a better understanding of the cellular mechanisms of DA in biasing locomotor neural networks to crawl.
| Puhl, Joshua G; Masino, Mark A; Mesce, Karen A (2012) Necessary, sufficient and permissive: a single locomotor command neuron important for intersegmental coordination. J Neurosci 32:17646-57 |
| Puhl, Joshua G; Mesce, Karen A (2010) Keeping it together: mechanisms of intersegmental coordination for a flexible locomotor behavior. J Neurosci 30:2373-83 |
