Involvement of the lateral habenula homolog in the active avoidance learning in zebrafish

Amo Ryunosuke1, Agetsuma Masakazu1, Kinoshita Masae1, Shiraki Toshiyuki1,Yamazaki Masako1, Aoki Tazu1, Higashijima Shin-ichi2, Matsuda Masaru3, Suster Maximiliano4, Kawakami Koichi4, Ohshima Toshio5, Aizawa Hidenori1, Okamoto Hitoshi1,5

1)RIKEN BSI, Saitama, Japan
2)NIPS, Okazaki Institute for Integrative Bioscience, Aichi, Japan
3)Center for Bioscience Research and Education, Utsunomiya Univ, Tochigi, Japan
4)Division of Molecular and Developmental Biology, NIG, Shizuoka, Japan
5)Department of Life Science and Medical Bioscience, Waseda Univ, Tokyo, Japan

The appropriate goal-directed behavior is necessary for animals to avoid the danger to survive. Monoaminergic modulation of the cortico-basal ganglia circuit is one of the key mechanisms regulating this behavior. Recent studies suggested the diencephalic lateral habenula that relays information from the telencephalon to the mid- and hindbrain, is activated by prediction of the aversive stimuli and reception of the unpredictable aversive stimuli. In addition, anatomical and electrophysiological studies suggested that the lateral habenula negatively regulates the activity of dopaminergic and serotonergic neurons. Therefore the lateral habenula might play a critical role for the establishment of the program to avoid the aversive stimuli. We previously identified the homolog of the mammalian lateral habenula in zebrafish (the ventral habenula) based on neural connectivity and gene expression. By using a BAC clone containing the regulatory elements of the diamine oxidase gene, we successfully established a transgenic line for the genetic inhibition of neural transmission in the ventral habenula by tetanus toxin. Interestingly, inhibition of the ventral habenula impaired active avoidance learning while their level of anxiety and locomotion remained similar. Notably, inhibition of the ventral habenula did not affect acquisition of the fear memory in cued-fear conditioning, suggesting that the learning of appropriate goal-directed behavior is specifically impaired by inhibition of the ventral habenula. Taken together, our study indicates that the evolutionarily conserved lateral habenular pathways control adaptive goal-directed behavior probably through the regulation of the activity of monoaminergic neurons.