This project has three main goals. 1. Analysis of startle modulation. In zebrafish, startle responses are modulated in a similar fashion to mammals where startle magnitude is inhibited when the startle stimulus is preceded by a weak auditory prepulse. This form of startle modulation, termed prepulse inhibition, is diminished in several neurological conditions including schizophrenia. We previously conducted a circuit breaking screen using a brain selective enhancer trap library of Gal4 lines to ablate defined groups of neurons before testing PPI. Using this approach we determined that the transcription factor Gsx1 defines neurons required for PPI in both zebrafish and mice. More recently, using volumetric calcium imaging and intersectional genetic approaches, we have located the precise cluster of neurons that regulate prepulse inhibition. Selective optogenetic activatation of these neurons suppresses startle responses to an acoustic stimulus, confirming that this group of neurons control prepulse inhibition. As gsx1 neurons only control prepulse inhibition at intervals between prepulse and startle stimulus of greater than 100 ms, we have performed a new circuit breaking screen and identified a transgenic line that labels neurons required for prepulse inhibition at short interstimulus intervals. 2. Functional mapping of neuronal architecture mediating short-term behavioral states. We previously demonstrated that light sensitive neurons in the preoptic area of the hypothalamus induce a state of hyperactivity in response to loss of illumination. Behavioral tests demonstrated that this state is part of a light-search strategy. Upon loss of light, larvae initially perform an area-restricted search for illumination. If no light is detected, larvae then swim in an outwards pattern to locate remote sources of light. By performing CRISPR-mediated gene inactivation, we demonstrated that the transition between these two light-search behavioral states requires somatostatin signaling. 3. Development of new tools for analysis of neural circuits involved in motor behavior. The relatively simple nervous system of zebrafish larvae and restricted range of motor behaviors opens up the possibility of identifying neuronal pathways which underlie the entire behavioral repertoire. We previously developed transgenic tools for genetically targeting neurons in the nervous system using Gal4 lines. Using these transgenic lines, we have developed an atlas of the larval zebrafish brain and software that enables researchers to identify a transgenic line corresponding to any selected region. We are now developing computational approaches to enable automated neuroanatomical analysis of the brain. In addition, this atlas enables us to undertake systematic analysis of brain microstructure and composition in zebrafish mutants of human neurodevelopmental disorders, such as schizophrenia and autism. Finally, we developed methods that enable accurate registration of atlases produced by different laboratories, facilitating community efforts to map the larval zebrafish brain.
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