This project has three main goals. 1. Analysis of startle modulation. We previously demonstrated that intense acoustic stimuli elicit two types of startle response in zebrafish larvae: rapid short latency responses and lower performance long latency responses. All fish can generate both types of response, but which response emerges is unpredictable from trial to trial.
We aim to understand how fish select to deploy a short or long latency response. Short latency responses are modulated in a similar fashion to startle responses in 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 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 have identifed an enhancer trap line marking neurons required for PPI and are now performing neuroanatomical and gene expression profiling on these neurons. Together, these approaches will allow us to find neuronal mechanisms for the implementation of behavioral choice in zebrafish larvae. 2. Functional mapping of serotonergic neuronal architecture. We previously demonstrated that water flow induces a transient state of arousal in zebrafish larvae characterized by hyperactivity and increased visual sensitivity to flow. We are now studying the mechanism by which serotonergic activity modulates visual processing, using calcium imaging and neuronal tracing. Ultimately this will allow us to establish a neuronal level functional map of serotonergic anatomy. In parallel we have established a new paradigm for inducing a state of arousal, by activating a light-activated cation channel (channelrhodopsin) in sensory neurons. We are tracing projections of these neurons to determine how activation of different neurons produce either acute behavioral responses or a change in behavioral state. 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 developed a new method for triggering startle responses in larval zebrafish that bypasses sensory processing, allowing the sensitivity of startle command neurons to be directly measured in free swimming larvae. To date, methods for sensitizing neuronal function in freely moving zebrafish larvae remain limited. We have developed novel optogenetic and chemically controlled transgenes enabling neurons to be activated or sensitized, allowing their contribution to behavior to be assessed using our method for activating startle responses.
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