Chondroitin Fragments Are Odorants that Trigger Fear Behavior in Fish

The ability to detect and avoid predators is essential to survival. Various animals, from sea urchins to damselfly larvae, use injury of conspecifics to infer the presence of predators [1-7]. In many fish [1, 8, 9], skin damage causes the release of chemicals that elicit escape and fear in members of the shoal. The chemical nature of the alarm substance (Schreckstoff in German) [1], the neural circuits mediating the complex response, and the evolutionary origins of a signal with little obvious benefit to the sender, are unresolved. To address these questions, we use biochemical fractionation to molecularly characterize Schreckstoff. Although hypoxanthine-3 N-oxide has been proposed to be the alarm substance [10, 11], it has not been reliably detected in the skin [12] and there may be other active components [13, 14]. We show that the alarm substance is a mixture that includes the glycosaminoglycan (GAG) chondroitin. Purified chondroitins trigger fear responses. Like skin extract, chondroitins activate the mediodorsal posterior olfactory bulb, a region innervated by crypt neurons [15] that has a unique projection to the habenula [16]. These findings establish GAGs as a new class of odorants in fish, which trigger alarm behavior possibly via a specialized circuit.