For last several years, the Downes lab has investigated how the brainstem, spinal cord, and axial muscles develop and function to produce locomotor behavior. In one current project in the lab, we’re continuing to explore this issue, by focusing on the brainstem. Recently, we’ve also become very interested in using the zebrafish system to provide new insight and therapeutics for epilepsy.
Neural Control of Locomotor Behavior
Locomotive behavior relies upon the precise timing and coordination of muscle contractions on the left and right sides of the animal. These muscle contractions are coordinated by neural networks in the spinal cord. In previous studies we analyzed various zebrafish mutants that demonstrate a specific abnormal behavior, however when we began our studies the identity of the mutated gene was not known. These fish can be useful tools to better understand how genetic networks enable locomotion. Normal fish perform alternate muscle contractions on the left and right sides of the body to produce the alternating body bends that allow the animal to swim through the water. However, some mutant fish perform simultaneous muscle contractions on the left and right sides of the animal, that results in compression like an accordion. We and others have determined the molecular identity of the genes mutated in several lines of these fish, which encode proteins required for muscle relaxation, regulating neuromuscular synapses, and inhibition within the spinal cord. Surprisingly, one of these mutant fish contained disruptions in a gene required for the metabolism of certain amino acids (the building blocks of protein), which disrupted spinal cord function and swimming behavior. Humans that have mutations in the human version of this gene demonstrate a very similar inability to a degrade amino acids, which results Maple Syrup Urine Disease, a serious and poorly understood metabolic disorder. Our work established a zebrafish model of Maple Syrup Urine Disease.
Another line of mutant fish line demonstrate abnormal, hyperactive behavior caused by abnormal brainstem function. We found that this mutant, named ‘Techno Trousers’, has a reduced ability to clear the neurotransmitter glutamate from synapses, which causes elevated neuronal activity in the brainstem and spinal cord. We also found that blocking receptors for a different neurotransmitter, GABA, results in similar abnormal, hyperactive behavior. In current studies we are using a diverse array of approaches to further investigate how GABA receptors regulate locomotor networks to balance the activity of glutamate. Given that there are many similarities between the zebrafish and human brainstem, we expect our studies to have broad implications for human brainstem function.
Zebrafish as a Model For Epilepsy
The advantages that zebrafish offer for genetic and cellular analysis have also been used by several groups to study epilepsy. Epilepsy, the fourth most common neurological disease, consists of recurrent, spontaneous seizures. 70% of epilepsy cases can be treated, but not cured, with current medications. About 30% are uncontrollable with current drugs, which underscores the need to find new therapies. Interestingly, mutations in the human version of the gene mutated in the Techno Trousers fish described above cause a severe epilepsy syndrome. This finding, along with many other studies, show that abnormal zebrafish behavior can model seizures and epilepsy. A current project in the lab is focused on using genome editing to mutate the zebrafish versions of human genes that can cause genetic epilepsies. These zebrafish are being used to better understand how certain genes cause epilepsy and search for new genes that can suppress seizures. Given that larval zebrafish are tiny and aquatic, they are a great system for drug discovery. Eventually, we want to use zebrafish models of epilepsy as a high-throughput platform to identify novel anticonvulsant drugs.
A high-speed video clip of wild-type zebrafish at 4 post post-fertilization. Wild-type larvae quickly swim away in response to gentle touch to the head with a probe. Compare to sibling Quetschkommode larvae. Click here for more information.
A high-speed video clip of Quetschkommode zebrafish mutants at 4 post post-fertilization. Quetschkommode mutants perform abnormal behavior due to mutation in the dbt gene. In people, mutations in DBT cause Maple Syrup Urine Disease, therefore Quetschkommode serves as a model for this disorder. Click here for more information.
Tiny zebrafish larvae exhibit spontaneous swimming behavior in a multi-well plate. The size, ease of obtaining large numbers of larvae, and the fact that they are aquatic make this a great system for high-throughput screening strategies.
Our expertise with zebrafish genetics and behavior have led to a variety of fruitful collaborations with other labs to investigate a variety of topics, such as examining how drugs or environmental toxicants effect zebrafish nervous system function. We’ve also enjoyed multiple collaborations to use electrophysiology to analyze neuronal activity in mutant lines.
We gratefully acknowledge funding for past and current projects in the lab from the National Science Foundation (NSF), the National Institutes of Health (NIH), the American Epilepsy Society, the Maple Syrup Urine Disease Family Support Group, the Pioneer Valley Life Science Institute, and the UMass/Healey Endowment Grant program.
Within both of our current research areas, a variety of projects is available for highly motivated undergraduate students, graduate students, and post-doctoral fellows.
Please contact me if you are interested in performing a postdoc with us.
I accept graduate students through the Neuroscience and Behavior and Molecular and Cellular Biology graduate programs. If you are not currently a UMass student but are interested in joining us, apply to one or both of the following graduate programs:
If you are an undergraduate student interested in joining us, you should contact me no later than halfway through your junior year. To apply, please download the application form, fill it out, and send it to me by e-mail (download application form).