Genes - Circuits - Behavior
Nerve cells, or neurons, form intricate networks through which signals pass at high speed and in complex, dynamically changing patterns. The ultimate task of this nervous activity is the generation of behavior. In ways that are still largely mysterious, all sensory perception and every coordinated movement, as well as feelings, memories and motivation, arise from the bustling activity of many millions of interconnected cells. The goal of our research is to understand how the neuronal pathways in the brain convert sensory inputs into behavioral responses.
We are particularly interested in the visual system and use zebrafish as our experimental model. Zebrafish larvae are tiny vertebrates, just a few millimeters in length from head to tail, but they are effective hunters of even smaller organisms. When a Paramaecium swims into view, the animal turns towards it, pursues it and captures it by sucking it into his mouth. We recently discovered that a moving dot that is displayed on a miniature computer screen is able to elicit almost the entire prey capture routine. The animal swims toward the wiggling dot on the screen in front of it, in an apparent attempt to catch this “virtual prey”. However, when the dot on the screen is not behaving like potential food but is rather expanding in size, simulating an approaching object, then the fish reacts in an entirely different manner: he makes an escape turn to avoid the expected collision. A third behavior, the optokinetic response, is evoked by a set of space-filling black-and-white stripes that move around the fish. Then the animal’s eyes make jerky movements from side to side in pursuit of the drifting grating. Thus, specific visual stimulus configurations release particular behaviors. How does the brain distinguish between these stimuli and activate the appropriate motor programs?
To tackle these questions experimentally, we employ a diverse array of methods. All our approaches take advantage of the feature that zebrafish larvae are optically transparent. We are generating transgenic animals that express genetically encoded, fluorescent reporters that indicate changes in neuronal activity. With the help of two-photon microscopy, we can then watch neurons in the fish brain process visual stimuli and generate motor commands. It is important to note that, while imaging provides useful data on the localization of brain functions, only perturbation experiments can tell us if a part of the nervous system, e. g., a neuronal cell type or a region of the brain, is necessary for a particular behavior. With genetic tricks, we therefore often replace the fluorescent indicator with so-called “optogenetic” effectors, such as Channelrhodopsin (ChR2), Halorhodopsin (eNpHR) and light-gated glutamate receptor (LiGluR). Pulses of focused laser light, applied through the skin of the intact animal, can then turn on or off groups of neurons at will. This approach allows for the remote optical control of the nervous system. Conceivably, in the not-so-distant future, we might be able to elicit prey capture in a fish that is looking at a blank screen by “re-playing” the brain activity that is normally associated with the perception of a paramaecium. Our understanding of neuronal circuitry will remain incomplete until we are able to reconstitute its function by direct stimulation. This type of experiment will then identify the circuit components whose activity is sufficient for behavior to occur.
The wiring pattern of neurons in every area of the brain is not random, but highly specific. While the number of neurons may be staggering, they appear to fall into a finite number of cell types, which are in turn wired up with other types of neurons in a regular manner. Complementing our work on the remote optical control of behavior, we are also devising methods to identify the molecular mechanisms underlying neuronal diversity and synaptic specificity in the visual system. In summary, through our research, we want to find out how genes assemble neuronal circuits and how these circuits in turn control behavior.