The most debilitating problems in Parkinson's disease block the ability to switch between distinct motor patterns including those required for locomotion. This is caused by loss of dopaminergic signaling due to the degeneration of dopamine neurons in the substantia nigra. The long-term objective of the proposed research is to investigate how changes in dopaminergic function contribute to motor pattern switching. We have recently demonstrated that the powerful genetic model Caenorhabditis elegans resembles humans in that dopamine signaling is an absolute requirement for switching between distinct forms of locomotory behavior. Specifically, C. elegans crawls in a dry environment but swims when suspended in water. By combining behavioral analysis, optogenetics, and neuronal ablation, we have found that dopamine release is both necessary and sufficient to transition from swimming to crawling. We have also found that loss of dopamine neurons results in immobility precisely at the moment of switching between motor patterns in C. elegans - a striking parallel with Parkinson's disease patients. The correspondence between the effects of disruption of dopamine signaling in humans and C. elegans establishes this model organism as an attractive system in which to identify the neuromolecular basis for these switching difficulties. Moreover, the existence of an essentially complete wiring diagram of the C. elegans nervous system together with the fact that it contains exactly eight dopaminergic neurons means that we can study dopamine signaling in unprecedented detail. The proposed research addresses two central questions: First, how does dopamine signaling facilitate a switch to an appropriate motor program, and second, how does switching of motor programs become dysfunctional when dopamine signaling is disrupted? These two questions are addressed in three specific aims that capitalize on our unique expertise in quantitative behavioral analysis and optogenetics as well as electrophysiology and calcium imaging from identified C. elegans neurons in vivo: (1) We will determine which neurons have essential roles in the switch between crawling and swimming with cell ablation and through activation and inhibition of neurons with light-activated ion channels. (2) We will identify the roles of these neurons in intact animals as they switch between crawling and swimming in a microfluidic chamber with functional calcium imaging. (3) We will investigate how dopamine influences the membrane currents and activity of these neurons by performing patch-clamp electrophysiology. The principles uncovered from these studies have the potential to improve understanding of how dopamine is used to switch between motor patterns in humans and how motor pattern initiation and switching becomes dysfunctional in Parkinson's disease.
The ability to initiate movement (e.g. sitting up and swallowing) and switch between motor patterns (e.g. walking and reaching) is essential for everyday life. These behaviors are severely compromised in Parkinson's disease. In the United States, the estimated costs for Parkinson's disease amount to well over $25 billion each year. Here we present the first example of analogous motor dysfunction in a C. elegans model of Parkinson's disease. Our proposal seeks to leverage the power and ease of molecular manipulation of C. elegans to resolve conserved dopaminergic mechanisms for motor pattern switching as well as how switching is perturbed after elimination of dopamine neurons.
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