Neuronal Circuits Controlling Behavior: Genetic Analysis in Zebrafish

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

This project has three main goals. 1. Understanding central mechanisms that control sensory processing. In zebrafish, as in mammals, auditory startle responses are inhibited when an intense acoustic stimulus is preceded by a weak prepulse. This form of startle modulation, termed prepulse inhibition, is diminished in neurological conditions including schizophrenia. We previously discovered that during prepulse inhibition, sensory drive from auditory afferents is selectively diminished to central neurons that initiate rapid startle responses, while sparing signaling to other auditory centers, including those that initiate delayed auditory responses. We are now studying mechanisms that control how relevant auditory information is relayed to target brain regions, with a focus on the role of glutamate receptors linked to schizophrenia in regulating prepulse inhibition. 2. Functional mapping of neuronal architecture mediating short-term behavioral states. Tonic immobility is a behavioral state where individuals, confronted with extreme threat, lose mobility and responsiveness to external cues. Peritraumatic tonic immobility has been linked to the induction of post-traumatic stress disorder in humans, but little is known about the underlying neurobiology. We used a genetic approach in zebrafish to discover a previously uncharacterized cluster of neurons in the mesopontine tegmentum that are essential for the expression of this state. By tracing input and output pathways to these cells, we outlined a comprehensive circuit that triggers tonic immobility. Single cell sequencing revealed that these neurons express several key stress hormones, with shared expression in a homologous parabrachial area in humans. This study has thus provided key insights into neural mechanisms that subserve an evolutionarily ancient behavioral response to threat. 3. Development of new tools for analysis of neural circuits. We previously developed a zebrafish brain atlas comprising images of several hundred co-registered Gal4 and Cre transgenic lines. We also implemented a computational approach for automated neuroanatomical analysis of the brain. This has enabled us to systematically screen genetic mutant fish for changes in brain microstructure and composition, in an unbiased fashion. In this way we are using zebrafish as an experimental system in which to assess consequences of mutations linked to severe neurodevelopmental disorders.