Learning reflects the ability of animals to modify behavioral responses using new information obtained from the environment. Habituation is learning in its simplest form: animals cease to respond to repeated but non-threatening visual, tactile or acoustic stimuli. In humans, habituation and other sensory thresholding processes are disrupted in multiple psychiatric and neurodegenerative disorders. Despite its importance, the genetic programs and molecular mechanisms that govern the assembly and function of the neuronal circuits critical for habituation learning are not well understood. Zebrafish exhibit numerous complex behaviors relevant to the study of neuropsychiatric disorders, including acoustic startle habituation, with kinematic and pharmacodynamic parameters identical to those observed in adult zebrafish and mammals (Wolman et al, PNAS 2011).
To identify the genetic programs that govern vertebrate habituation learning, we have conducted the first forward genetic screen for genes critical for zebrafish startle habituation. This screen has yielded fifteen mutants with deficits in habituation learning, and through whole genome sequencing (WGS) we identified the PAPPAA metalloprotease as a novel regulator of IGF-dependent habituation learning (Wolman et al, Neuron 2015). Using WGS, we have since mapped 3 additional habituation mutants, identifying presumptive null mutations in ap2s1, cacna2d3 and zdhhc17/hip14, implicating diverse cellular processes from Clathrin-mediated endocytosis to protein palmitoylation in modulating habituation learning. HIP14, or Huntingtin-Interacting Protein 14, is a palmitoyl acyl transferase that physically interacts with the Huntington's disease-associated Huntingtin protein. We will present behavioral analyses of all mutants, as well as a characterization of neuronal and synaptic morphology in known circuit components in hip14 mutants. Together, these genes represent an unique opportunity to probe the cell and molecular mechanisms critical for the formation and function of the circuits underlying vertebrate learning behaviors.