To thrive, animals must successfully interact with their environment (i.e. behave). These interactions are often complex and include: 1) detecting relevant stimuli (sensation), 2) processing information and selecting appropriate outputs (integration), and 3) performing selected patterns of activity (execution). Nervous systems, operating under constant genetic regulation, mediate these diverse tasks. Understanding the neuro-molecular basis of behavior is necessary in order to discern the principles governing animal (and human) behavior. This knowledge will further allow us to understand and target disease and other challenges (e.g. aging).
Our lab works to elucidate the neuronal and genetic basis of behavior. We use a three-pronged approach to investigate the components of behavior enumerated above. We tackle each of these processes by focusing on distinct questions selected both for their independent merits, and for their potential to advance our understanding of the principles governing animal behavior. We use invertebrates as our animal models because they have succinct nervous systems, and are experimentally amenable. Techniques in our lab range from behavioral analysis, microscopy, immunohistochemistry, molecular tools (e.g. cloning, transgenesis, RNAi, qPCR), optogenetics, calcium ratiometry, etc. Ongoing areas of inquiry include identifying and investigating:
a) The molecular and neural basis of magnetic field detection and navigation (sensation).
b) Molecular targets capable of preventing degeneration in muscular dystrophy (execution).
c) The molecular basis of neural circuit robustness (integration).
Investigating these distinct questions is possible thanks to: a) the experimental amenability of our animal models, b) ongoing collaborations with labs at ISU and beyond, and c) the untiring labor of many dedicated students. Since opening our doors in January 2015, our lab has mentored over a hundred students (ranging from postdocs to high school volunteers). These students produced over fifty scientific abstracts, eight manuscripts (plus three nearing publication), three honors theses, one MS thesis, and nearly thirty awards and prizes. Their work enabled us to secure over 1.7 million dollars in funding (across six awards). Below we briefly describe our projects, their contributions (at this point in time), and their future potential.
Molecular and neural basis of magnetic field detection and navigation:
While we know much about the common senses (taste, sight, touch, smell, sound), how animals detect and orient to the magnetic field of the earth remains one of the last frontiers in sensory neuroscience. Evidence suggests that most magneto-sensitive animals use intracellular compass needles they assemble from environmental iron. We discovered that soil nematodes engage in vertical migrations guided by the earth’s magnetic field, and identified the first sensory neurons (in any animal) known to respond to magnetic stimuli. Our students work to discern how worms achieve this feat at the behavioral, cellular, and molecular levels. They discovered that sensory endings at the tip of magnetosensory neurons are required for magnetic orientation, and identified magnetic iron accumulating near these structures. Our present hypothesis is that worms accumulate magnetic iron, and couple it to mechanoreceptors at/near the endings of magnetosensory neurons. This would allow them to feel the pull of the magnetic field as they move through their environment. To measure how nervous systems encode magnetic information, our students created animals expressing proteins that glow when neurons are active. By measuring changes in brightness brought about by magnetic stimuli, they can determine which (and how) neurons respond to magnetic fields. We use unbiased computer algorithms (developed by our students) to analyze the behavior of worms navigating magnetic fields. This
permits identification of strategies optimized for orientation to these force fields. Many magnetosensory organisms (e.g. insects, fish, birds, reptiles, mammals) likely use a similar mechanism to C. elegans. Insights into C. elegans magnetosensation will have broad impact on our understanding of animal behavior, and sensory biology in general. To date, this work resulted in four publications (plus two nearing submission), and a NSF award. Our lab is uniquely positioned to investigate how animals detect magnetic fields, process this information, and select behavioral outputs at the molecular, cellular, and behavioral levels.
Molecular targets capable of preventing and reversing degeneration during Duchenne muscular dystrophy: Muscle cells are the ultimate effectors of behavior. Their importance is most evident when disease or accident challenge their function. Duchenne muscular dystrophy (DMD) affects 1 in 3,500 males. It occurs when random mutations maim the gene encoding dystrophin. This protein is essential to shield muscles from the great forces they generate. Loss of dystrophin leads to muscle necrosis, loss of mobility, and death. For decades, researchers sought to study DMD by breaking the dystrophin gene in animals, but struggled to observe the dramatic degree of degeneration common among patients. Our lab devised a novel assay that (for the first time) modelled not only the genetic lesion causing the disease, but also the cellular decay, loss of mobility, and early mortality hallmarks of DMD. By introducing random mutations into our DMD animals, we were able to isolate several strains whose mutations rescued (suppressed) their dystrophic fate. Genes modified by this suppressor screen represent potential therapeutic targets
in the treatment of DMD. They will also inform our understanding of the mechanics of muscle function. Students in our lab study the molecular events accompanying muscular degeneration in DMD; evaluate the potential usefulness of different therapeutic approaches; and test molecular targets that might prevent muscle degeneration. To date, this work produced two publications (plus a manuscript in revision), and an NIH award (R15). Over the coming years, our students will increase our understanding of the molecular events linked to DMD. They will likely identify molecular targets, and chemical agents able to stall or reverse the damage caused by DMD, improving the lives of thousands of patients suffering this terrible disease.
Molecular basis of neural circuit robustness in response to temperature fluctuations: Studying the cellular and molecular basis of behavior is simplest at the sensory and motor levels as these involve the interface between animal and environment. Studying how neurons integrate information and select outputs is more challenging because this occurs deep within nervous systems. Crustaceans are choice organisms for studying neuronal integration, as their nervous systems can be isolated and interrogated for days. However, most of these animals are difficult to grow in the lab. This has hindered the development of molecular tools to study the role of genes in neural integration. Recently, we began a collaboration with the Stein (at ISU) and Lyko Labs (Germany), obtaining sequences of the genome and transcriptome of a new species of crayfish that reproduces asexually (allowing their cultivation and study in the lab). Our students work to adapt modern molecular techniques to the study of neural integration using these Marble crayfish. To investigate how animals select and implement reliable outputs in the face of constant environmental fluctuations, our students expose these ectothermic animals to temperature fluctuations mimicking those their encounter in their environment. By then comparing neural output to changes in gene expression, they will determine the molecular mechanisms responsible for the production of reliable neural integration. The insights generated in this project will advance our understanding of how nervous systems regulate their activity to insure the selection and performance of appropriate behaviors, even in the face of unpredictable external conditions. In addition, the resources developed by our lab (and collaborators) have the potential to revolutionize the field of crustacean neuroscience, facilitating the adoption of this new model system in the study of a wide array of important questions.
Our lab studies the neural and genetic basis of behavior by separating the components of behavior into three complementary but distinct questions. In addition to investigating these questions, our program actively seeks to synergize with the training mission of the College of Arts and Sciences. To date, our lab introduced over a hundred students to research, and many more through our updated Biotechnology and Cell biology laboratory courses.