Model organisms have proven invaluable as more tractable systems to study fundamental principles of biology and by yielding breakthroughs that result from studying evolutionary innovations, for example, GFP, from jellyfish, or CRISPR, from bacteria. My goal is to leverage a new model system, developed during my postdoctoral work, that is uniquely positioned to provide insights of both types: Clytia hemisphaerica, a species of Mediterranean jellyfish. This proposal uses Clytia's distinctive features to identify precise mechanisms at the interface of neural development, neural regeneration, and systems neuroscience. First, Clytia are tiny (<1mm-1cm), transparent, and genetically tractable, making it possible to image and manipulate the activity of every neuron in the nervous system simultaneously, in vivo, using genetically encoded optical techniques. Further, Clytia numerically scale their nervous system at least an order of magnitude during their lifespan without disrupting system function, ending with more than ten thousand neurons. It is therefore also possible to observe continuous differentiation, migration, axon targeting, and functional activity simultaneously across the whole organism. Lastly, Clytia have poorly understood and powerful regenerative capabilities. These include the regeneration of large populations of genetically ablated neurons, with rapid recovery of the behaviors that those neurons control. These properties make Clytia an experimentally tractable platform to investigate: Fundamental questions in systems neuroscience, including mechanisms underlying behaviors and behavior states, roles of neuromodulation, and approaches for studying system organization and function across scales. Basic principles of neurodevelopment, particularly at the interface of development and function. Mechanisms enabling regeneration and the seamless integration of new neurons into a functioning network.
In Aim 1, I will characterize the molecular phenotypes of neurons and establish CRISPR-based knock-in to target effectors to specific subpopulations of cells.
In Aim 2, I will use a coordinated behavior as my point of entry and develop and test models of underlying neural mechanisms.
In Aim 3, I will examine how this behavioral system is robust to constant neurogenesis, and the mechanisms that enable its rapid recovery following genetic ablation of neurons. My vision is that, once the key foundational work has been completed and published, Clytia will become a widely used model system. This proposal serves as the first step, laying the foundation for my future independent program and for a Clytia community more broadly, and providing the essential training that I need to fill gaps in my knowledge, focusing on computational and single-cell RNA sequencing approaches.

Public Health Relevance

The goal of this proposed research is to leverage unique features of a new animal model to study fundamental principles of neural systems, the integration of newborn neurons into functioning networks, and regeneration following injury. With this tiny, transparent organism, it is possible to examine cell migration, axon outgrowth and retraction, and the functional activity of the entire network simultaneously across the whole organism, in vivo, using genetically encoded optical techniques. Moving forward, these high-resolution studies will generate new theories and approaches towards understanding how nervous systems generate animal behavior, mechanisms linking neurogenesis to system function, and insights into novel regenerative capabilities.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Career Transition Award (K99)
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Neurological Sciences Training Initial Review Group (NST)
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Bambrick, Linda Louise
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California Institute of Technology
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