Our laboratory is broadly interested in how genes control behavior and how these behaviors are regulated by drugs of abuse. Using C. elegans as a model system, we have taken a molecular genetic approach to these questions.
Ethanol Sensitivity and Tolerance.
Ethanol is a widely used and abused drug, yet the molecular mechanisms responsible for the behavioral effects of ethanol remain uncertain. We have pursued forward genetic studies, to identify the molecular targets of ethanol and biochemical pathways mediating ethanol sensitivity and tolerance. Ethanol results in neurodepressive effects on multiple behaviors of C. elegans. Through genetic screens we identified mutants showing a high level of resistance or hypersensitivity to ethanol intoxication. Other mutants show altered adaptation to the drug over time or changes in tolerance. Molecular characterization of selected mutants has led to the identification of novel neuronal targets of ethanol. For instance, mutations in slo-1, encoding a C. elegans BK channel, result in behavioral resistance to ethanol, and our electrophysiological studies suggest a direct activating effect of ethanol on the channel, which depresses neuronal activity. We have begun to extend our findings in C. elegans to mammalian systems. Mammalian BK channels are similarly activated by ethanol in vitro. Disruption of mouse homologues of two of the ethanol response genes identified in C. elegans results in similar changes in the behavioral responses of mice to ethanol.
Neurobehavioral and Neurotoxic Effects of AmphetamineMost of the behavioral responses to amphetamine are thought to occur through modulation of the neuronal dopamine transporter (DAT) responsible for reuptake of dopamine. The C.elegans DAT transporter exhibits similar sensitivity to amphetamine in vitro. High concentrations of amphetamine can also lead to neuronal cell death. We have characterized the behavioral effects of amphetamine and developed selections for amphetamine-resistant mutants. We found that one of the mutants, eg814, exhibits strong resistance to multiple effects of the drug. We then mapped and cloned the eg814 gene, which encodes a multi-pass transmembrane protein. Curiously, eg814 is related to the C. elegans fluoxetine (Prozac) resistant mutants nrf-6 and ndg-4. Our continued molecular analysis of amphetamine-resistant mutants suggests that multiple molecular pathways modulate the behavioral and neurotoxic effects of amphetamine.
Neuromuscular Disease
Many forms of muscular dystrophy result from genetic defects in components of the dystrophin-glycoprotein complex (DGC). Yet, how disruption of the dystrophin complex leads to the muscle degeneration that characterizes the disease has remained unclear. C. elegans has proven to be a useful model system for studies of muscular dystrophy. As in mammalian systems, mutations in genes encoding components of the C. elegans DGC can result in progressive degeneration of body muscles. Our genetic studies have led to the identification of novel proteins that interact with the dystrophin complex and modulate the resulting muscle degeneration that characterizes the disease. One of these proteins, SNF-6, is an acetylcholine transporter that is localized to the neuromuscular junction and regulates the excitation of body muscle by acetylcholine released from motorneurons. We are characterizing additional genes that mediate and regulate muscle degeneration.
The McIntire Lab is a research laboratory that studies the neural basis of behavior, with a focus on understanding how the brain processes sensory information and generates appropriate behaviors. The McIntire Lab is led by Dr. David M. J. S. McIntire, who is a neuroscientist and a Professor of Psychology at the University of Virginia.
The McIntire Lab uses a variety of techniques, including electrophysiology, imaging, and optogenetics, to study the neural mechanisms underlying sensory processing and behavior. The lab’s research has contributed to a better understanding of how the brain processes sensory information and how this information is used to guide behavior and has identified potential targets for the development of treatments for neurological and psychiatric disorders.