Determining the mechanisms by which genes influence behavior is the central goal of my research program. The genome-sequencing revolution has identified thousands of genetic mutations that cause neurological disorders that impact human behavior. For any given disorder, mutations in hundreds of different genes can similarly affect behavior, and yet how these disparate mutations converge on similar behavioral phenotypes is largely unknown. To address this question, my group generates zebrafish models of inherited human behavioral disorders to understand how mutations impact neural circuit development and behavior. By comparing multiple forms of a single disorder, we elucidate shared mechanisms by which different mutations affect behavior. Our long-term goal is to leverage these models to inform treatment strategies for individuals with inherited disorders of the nervous system.
Despite over a hundred years of genetic screens in fruit flies and yeast that identified a core set of genes essential for life, we lack mechanistic understanding of most genes that affect behavior. Unlike mutations in essential genes that cause early death, mutations that affect behavior are compatible with life. Life in the context of these mutations is enabled by compensatory mechanisms (collectively known as resilience), that mask pathologies imparted by the mutation. Therefore, our strategy to elucidate how mutations alter behavior is to study mechanisms of both pathology and resilience. My group’s strategy has been developed by modeling both neurodevelopmental disorders in which symptoms are most severe early in life, e.g. autism spectrum disorders, and neurodegenerative disorders in which symptoms are most severe later in life e.g. axonopathies. Our findings suggest that stage-specific resilience mechanisms can mask chronic pathology to produce changes in the severity of symptoms across life-span. Our dual focus on pathology and resilience also expands possibilities for treatment since boosting endogenous resilience mechanisms is likely to be more generally effective than addressing specific pathologies in treating symptoms.
To decipher how mutations affect behavior, we use the zebrafish Danio rerio. We disrupt zebrafish versions of genes known to affect human behavior to determine the role of those mutations in the development of neuronal circuits that underlie behavior. Using recent advances in genome editing approaches, we are reliably and efficiently making stable mutations that mimic human mutations to better understand the impact of those mutations through lifespan on behavior. The ability to model these disorders using genetic approaches combined with state-of-the-art physiological and molecular analyses positions my lab at the forefront of understanding how genes impact behavior.
Despite over a hundred years of genetic screens in fruit flies and yeast that identified a core set of genes essential for life, we lack mechanistic understanding of most genes that affect behavior. Unlike mutations in essential genes that cause early death, mutations that affect behavior are compatible with life. Life in the context of these mutations is enabled by compensatory mechanisms (collectively known as resilience), that mask pathologies imparted by the mutation. Therefore, our strategy to elucidate how mutations alter behavior is to study mechanisms of both pathology and resilience. My group’s strategy has been developed by modeling both neurodevelopmental disorders in which symptoms are most severe early in life, e.g. autism spectrum disorders, and neurodegenerative disorders in which symptoms are most severe later in life e.g. axonopathies. Our findings suggest that stage-specific resilience mechanisms can mask chronic pathology to produce changes in the severity of symptoms across life-span. Our dual focus on pathology and resilience also expands possibilities for treatment since boosting endogenous resilience mechanisms is likely to be more generally effective than addressing specific pathologies in treating symptoms.
To decipher how mutations affect behavior, we use the zebrafish Danio rerio. We disrupt zebrafish versions of genes known to affect human behavior to determine the role of those mutations in the development of neuronal circuits that underlie behavior. Using recent advances in genome editing approaches, we are reliably and efficiently making stable mutations that mimic human mutations to better understand the impact of those mutations through lifespan on behavior. The ability to model these disorders using genetic approaches combined with state-of-the-art physiological and molecular analyses positions my lab at the forefront of understanding how genes impact behavior.