Understanding how the brain transforms sensory input into complex behavior is a fundamental question in systems neuroscience. Using larval zebrafish, we study the temporal component of phototaxis, which is defined as orientation decisions based on comparisons of light intensity at successive moments in time. We developed a novel "Virtual Circle" assay where whole-field illumination is abruptly turned off when the fish swims out of a virtually defined circular border, and turned on again when it returns into the circle. The animal receives no direct spatial cues and experiences only whole-field temporal light changes. Remarkably, the fish spends most of its time within the invisible virtual border. Behavioral analyses of swim bouts in relation to light transitions were used to develop four discrete temporal algorithms that transform the binary visual input (uniform light/uniform darkness) into the observed spatial behavior. In these algorithms, the turning angle is dependent on the behavioral history immediately preceding individual turning events. Computer simulations show that the algorithms recapture most of the swim statistics of real fish. We discovered that turning properties in larval zebrafish are distinctly modulated by temporal step functions in light intensity in combination with the specific motor history preceding these turns. Several aspects of the behavior suggest memory usage of up to 10 swim bouts (~10 sec). Thus, we show that a complex behavior like spatial navigation can emerge from a small number of relatively simple behavioral algorithms.
The hereditary hearing-vision loss disease, Usher syndrome I (USH1), is caused by defects in several proteins that can interact with each other in vitro. Defects in USH1 proteins are thought to be responsible for the developmental and functional impairments of sensory cells in the retina and inner ear. Harmonin/USH1C and Sans/USH1G are two of the USH1 proteins that interact with each other. Harmonin also binds to other USH1 proteins such as cadherin 23 (CDH23) and protocadherin 15 (PCDH15). However, the molecular basis governing the harmonin and Sans interaction is largely unknown. Here, we report an unexpected assembly mode between harmonin and Sans. We demonstrate that the N-terminal domain and the first PDZ domain of harmonin are tethered by a small-domain C-terminal to PDZ1 to form a structural and functional supramodule responsible for binding to Sans. We discover that the SAM domain of Sans, specifically, binds to the PDZ domain of harmonin, revealing previously unknown interaction modes for both PDZ and SAM domains. We further show that the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex. Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins.