title: The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger.
abstract: Anticipation of danger at first elicits panic in animals, but later it helps them to avoid the real threat adaptively. In zebrafish, as fish experience more and more danger, neurons in the ventral habenula (vHb) showed tonic increase in the activity to the presented cue and activated serotonergic neurons in the median raphe (MR). This neuronal activity could represent the expectation of a dangerous outcome and be used for comparison with a real outcome when the fish is learning how to escape from a dangerous to a safer environment. Indeed, inhibiting synaptic transmission from vHb to MR impaired adaptive avoidance learning, while panic behavior induced by classical fear conditioning remained intact. Furthermore, artificially triggering this negative outcome expectation signal by optogenetic stimulation of vHb neurons evoked place avoidance behavior. Thus, vHb-MR circuit is essential for representing the level of expected danger and behavioral programming to adaptively avoid potential hazard.
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo 162-8430, Japan.
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Amo
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Felipe
authors.initials: F
authors.lastname: Fredes
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Masae
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Aoki
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Aizawa
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Agetsuma
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tazu
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shiraki
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Hisaya
authors.initials: H
authors.lastname: Kakinuma
authors.affiliation: Center for Bioscience Research and Education, Utsunomiya University, Tochigi 321-8505, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Takahoko
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuboi
authors.affiliation: National Institutes of Natural Sciences, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Aichi 444-8787, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Higashijima
authors.affiliation: Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Koide
authors.affiliation: Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshihara
authors.affiliation: Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Fukai
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Saitama 351-0198, Japan; Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo 162-8430, Japan; Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan. Electronic address: hitoshi@brain.riken.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamoto
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology; D000223:Adaptation, Psychological / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001362:Avoidance Learning / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D003463:Cues; D005239:Fear / Q000502:physiology; D019262:Habenula / Q000166:cytology / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology / Q000502:physiology*; D059326:Serotonergic Neurons / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C521369:FEV protein, zebrafish; D008164:Luminescent Proteins; D018377:Neurotransmitter Agents; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D029961:Zebrafish Proteins; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin