Creation of whole-brain functional connectomes will facilitate a holistic understanding of memory formation, which is a major goal of modern neuroscience. Information gained from understanding the functional connections between neurons and the underlying plasticity between connections can be used to understand and treat neurological and mental disorders. In vivo whole-brain mapping with current technologies requires advantageous biological attributes in combination with a substantial molecular toolbox. Two invertebrate model organisms have these properties: D. melanogaster and C. elegans. However, zebrafish (Danio rerio) is the only vertebrate species with this capacity. The ability to form a functional connectome with larval zebrafish affords distinct advantages to understanding memory formation or pinpointing aberrant neural circuits in animal models of human disorders. Further, rapid development, small size, and high fecundity of zebrafish makes them an ideal organism for high- throughput screening, a useful mechanism to discover novel therapeutics for these disorders. The project will attempt to create a new tool to rapidly form in vivo whole-brain connectomes in freely moving fish with the long-term goal of understanding brain function and dysfunction at a circuit-level. Towards this goal, we will create transgenic fish that express a photoconvertible protein under the control of activity- dependent promoters. We will then determine the experimental procedures for each line of transgenic fish that most efficiently and accurately reflect the neural activity under investigation and minimize signals related to nonspecific neural activity. After we have defined the experimental potential and constraints of our transgenic lines of fish, we will seek to determine if the recorded neural activity is physiologically valid. To do so, we will form functional maps of neural activity in response to stimulation of sensory systems with previously defined neural connections. These experiments should provide the pilot data necessary to begin investigating changes in functional connectomes due to memory formation in zebrafish models of neurodevelopmental disorders. Data from the proposed studies are expected to facilitate the development of effective treatments for brain diseases and disorders, including Alzheimer's disease, PTSD, schizophrenia and autism.
Neurological and mental disorders that involve dysfunction in neural connectivity, including Alzheimer's disease, posttraumatic stress disorder (PTSD), schizophrenia, and autism, affect an increasingly larger proportion of the U.S. population. By developing new tools to form in vivo whole-brain functional connectomes and understand memory formation in a simple vertebrate model system the proposed project will seek to begin to understand these disorders and help develop effective treatments for them.
