Anticipation of danger at first elicits panic in animals but later it helps
them to avoid the real threat adaptively (e.g. active avoidance). The neural
circuit enabling such proactive use of danger expectation is unknown. A can
didate site responsible for active avoidance is the lateral habenula (LHb).
In mammals, LHb neurons are suggested to have a role in transmitting anti-re
ward and aversive information. The Hb is conserved in vertebrates, and the z
ebrafish homolog of the mammalian LHb, the ventral habenula (vHb) has a simp
le structure including an exclusive direct projection to the serotonergic me
dian raphe (MR). Using adult zebrafish as a model, we found that tetanus tox
in mediated genetic inhibition of synaptic transmission from the vHb to the
MR impaired active avoidance learning, while Pavlovian fear conditioning rem
ained intact. in vivo electrophysiolosy (loose-patch recording) from
genetically labeled vHb neurons during pavlovian fear conditioning showed th
at the vHb neuronal activity generated an expectation signal for a dangerous
context. Accordingly, artificially triggering an expectation signal by opto
genetic stimulation of vHb neurons in free-moving fish evoked place avoidanc
e. We also found that optogenetic stimulation of the vHb axons in acute slic
e activated genetically labeled serotonergic neurons in the raphe. Thus, the
vHb-MR circuit is essential for presenting danger expectation and programmi
ng active avoidance. These results reveal how perceived risk in the environm
ent is communicated to the serotonin system to avoid potential hazard.