From gene to behavior

We are interested in the molecular and cellular mechanisms underlying animal behavior. The genes that prescribe the assembly and function of the nervous system form a complex network, acting in changing combinations, in different tissues and at different developmental stages. In order to gain insights into the genetic architecture of behavior, we are searching for the genes that play specific roles in a given behavioral process. The litmus test for an individual gene’s requirement is its loss-of-function phenotype. Forward genetic screens provide an unbiased strategy for the discovery of these genes.

Zebrafish (Danio rerio) provides three main advantages for a genetic approach to behavior:

• Optics: The zebrafish brain is transparent from embryonic well into larval stages, allowing in vivo imaging of fluorescently labeled neurons, as well as their neurites and synapses.

• Genetics: Forward-genetic screens can be carried out for the purpose of gene discovery. Moreover, we are employing transgenic probes that are designed to interfere with neuronal activity as a novel tool for circuit analysis.

• Psychophysics: Precise measurements of behavior and perception are possible in zebrafish. For example, it is straightforward to evoke behavioral responses by exposing fish larvae to computer-generated visual stimuli and to quantify the frequency and magnitude of these responses.

Behavioral assays

In zebrafish, visual motion of large-field gratings elicits two innate reflexes, the optomotor response (OMR) and the optokinetic response (OKR) [click to watch movies]. To build a catalog of genes important for the execution of OMR and OKR, we are screening for mutations that disrupt (or otherwise alter) either or both of these responses in mutagenized zebrafish. Hundreds of thousands of mutagenized animals can be generated for our experiments, and their visual and motor abilities can be assessed in high-throughput screens. We have already discovered 70 specific mutations that cause a broad spectrum of visual dysfunctions. Each mutation has tagged an important gene, which can be positionally cloned, and each identified gene serves as an entry point into a molecular process essential for normal vision.
Besides continuing our studies of OMR and OKR, we are now also investigating capture of prey (paramecia), as well as energy balance and mating behaviors. These are potentially suitable for a systematic analysis of neuronal circuitry. [Click to watch prey capture movie].

From circuit to behavior

In addition to our gene discovery approach, the lab has recently moved into the area of neuronal circuit analysis, using targeted manipulations of synaptic activity in genetically defined subpopulations of neurons.

Our collaborators in these and other projects include the labs of Holly Ingraham (UCSF), Didier Stainier (UCSF), Hao Li (UCSF), Jeff Chuang (Boston University), Rachel O. Wong (Washington University, now U Washington), Mu-ming Poo (UC Berkeley), Huizhong Tao (USC), Brian Link (Medical College of Wisconsin), Stephen J. Smith (Stanford), Ehud Isacoff (UC Berkeley), and Juan Korenbrot (UCSF).