Suresh Jesuthasan : The biology of the fear substance "Schreckstoff"

Understanding fear using zebrafish

Suresh Lab is interested in understanding how behavior is generated by environmental triggers and modulated by internal states and experience. They currently focus on fear responses, and are examining questions such as how the brain computes the appropriate response for a given threat. We investigate feedback mechanisms that regulate the level of fear, and are also interested in how the duration of a state of fear is determined.

All experiments are conducted using the zebrafish. In addition to allowing genetic analysis, this organism enables imaging of neural activity at single-cell resolution; transgenic lines also enable the manipulation of specific cells. The emphasis is on using larval fish, as this is the stage when the animal is transparent.

The lab uses two behavioral paradigms. The first, a robust example of innate fear, is the alarm response, while the second is classical conditioning.

The Alarm Response

In the 1930’s Karl von Frisch noticed that injury to a European minnow caused a fright reaction in other members of the fish school. He demonstrated that the skin contained substances, termed Schreckstoff, which act via the olfactory system to trigger a state of fear. The fish change their swimming behavior dramatically - either darting or freezing - in response to this alarm pheromone. 

Subsequent experiments by other scientists established that many freshwater fish species have this response. All the classical hallmarks of fear, including physiological changes such as increase in blood cortisol levels, can be triggered by Schreckstoff.

They have used classical biochemical separation to characterize the alarm substance. Unexpectedly, a major component of the alarm substance is a glycan, chondroitin sulfate. Calcium imaging of the olfactory bulb has enabled identification of regions that are activated following detection of the alarm substance. Current experiments are focused on characterization of the receptor neurons, as well as the higher brain regions involved in the response.

Classical conditioning

One of the regions downstream of the olfactory bulb is the habenula. Lesion experiments in mammals have implicated the habenula, a node in information flow to the midbrain, in the selection of an appropriate fear response. To identify specific neurons involved and to enable high-resolution activity imaging, we have developed an assay for fear conditioning in larval zebrafish. Using light-mediated neuronal inactivation, we have shown that  fish have increased fear when the medial habenula is disrupted. We are currently investigating how the medial habenula modulates fear.

Social modulation

Fish that are in a school show a milder response to the alarm substance. We are examining the neural basis of social buffering, a phenomenon which is widespread in the animal kingdom.