Control of behavior in the natural environment where sensory stimuli are abundant requires superfluous information to be ignored. In part, this is achieved through selective transmission, or gating of signals to motor systems. A quantitative and clinically important measure of sensorimotor gating is prepulse inhibition (PPI) of the startle response, impairments in which have been demonstrated in several neuropsychiatric disorders, including schizophrenia. Here, we show for the first time that the acoustic startle response in zebrafish larvae is modulated by weak prepulses in a manner similar to mammalian PPI. We demonstrate that, like in mammals, antipsychotic drugs can suppress disruptions in zebrafish PPI induced by dopamine agonists. Because genetic factors underlying PPI are not well understood, we performed a screen and isolated mutant lines with reduced PPI. Analysis of Ophelia mutants demonstrates that they have normal sensory acuity and startle performance, but reduced PPI, suggesting that Ophelia is critical for central processing of sensory information. Thus, our results provide the first evidence for sensorimotor gating in larval zebrafish and report on the first unbiased screen to identify genes regulating this process.

SUMMARY The neural basis of behavioral choice in vertebrates remains largely unknown. Zebrafish larvae have a defined locomotor repertoire as well as a simple nervous system and are therefore an attractive vertebrate system in which to study this process. Here we describe a high-throughput system for quantifying the kinematics of motor events in zebrafish larvae in order to measure the initiation frequency of different maneuvers. We use this system to analyze responses to photic stimuli and find that larvae respond to changes in illumination with both acute responses and extended behavioral programs. Reductions in illumination elicit large angle turns, distinct from startle responses, which orient larvae toward the source of light. In continuing darkness, larvae are transiently hyperactive before adopting a quiescent state. Indeed, locomotor activity is controlled by the state of light or dark adaptation similar to masking phenomena in higher vertebrates where light directly regulates motor activity. We propose that regulation of motor activity by photic stimuli in zebrafish larvae serves a behavioral goal of maximizing exposure to well lit environments optimal for feeding.

The molecular basis of sensory hair cell mechanotransduction is largely unknown. In order to identify genes that are essential for mechanosensory hair cell function, we characterized a group of recently isolated zebrafish motility mutants. These mutants are defective in balance and swim in circles but have no obvious morphological defects. We examined the mutants using calcium imaging of acoustic-vibrational and tactile escape responses, high resolution microscopy of sensory neuroepithelia in live larvae, and recordings of extracellular hair cell potentials (microphonics). Based on the analyses, we have identified several classes of genes. Mutations in sputnik and mariner affect hair bundle integrity. Mutant astronaut and cosmonaut hair cells have relatively normal microphonics and thus appear to affect events downstream of mechanotransduction. Mutant orbiter, mercury, and gemini larvae have normal hair cell morphology and yet do not respond to acoustic-vibrational stimuli. The microphonics of lateral line hair cells of orbiter, mercury, and gemini larvae are absent or strongly reduced. Therefore, these genes may encode components of the transduction apparatus.