Hitoshi Okamoto, M.D., Ph.D.

Research Overview

1. Investigating the role of the evolutionary conserved limbic circuit within vertebrates. We investigate the role of neural circuits that control the selection and execution of emotional behaviors. We study fish and rodents using various methods including the genetics, molecular and cell biology and physiology. In mammalian telencephalon, the cortico-basal ganglia circuit is thought to be involved in selection of the behavioral programs . External physical information and related emotional information enter the cortico basal ganglia circuit via the hippocampus and amygdala, respectively, and modulate this circuit to establish ensembles of neurons encoding various behavioral programs . However, it is still unclear how a particular ensemble of neurons becomes selected through this neural circuit. Zebrafish (teleosts) have the simplest neural system in the vertebrates. By the movement of the neural tube called eversion, the hippocampus and amygdala in fish become located in the medial and lateral part of the telencephalon, respectively, showing the inside out position with respect to that of mammals. Furthermore, it has been recently shown that the zebrafish telencephalon may contain the cortico-basal ganglia circuit where the behavioral programs become stored. Zebrafish brain is so small that we can analyze the neural activities of the entire cortico-basal ganglia circuit by the calcium imaging. By combining with the optogenetics to interfere the activity of the cortico-basal ganglia circuit, we believe that the common neural mechanisms between fish and mammals which underly the establishment of the memory for the behavioral program will be unveiled.
2. Exploring the role of habenula in emotional behaviors. We also focus on the habenula, a nucleus located in the dorsal midbrain. Mammalian habenula consists of the medial and lateral nucleus, which control directly and indirectly dopaminergic neurons in the ventral tegmental area and serotonergic neurons in the Raphe, respectively. The medial and lateral parts of the habenula in mammals correspond to the dorsal and ventral habenula in fish, respectively, and the connectivity of each subnucleus is well conserved between fish and mammals. We are trying to reveal the role of this well conserved habenula circuit in the control of emotional behaviors. In deed, when the zebrafish dorsal habenula is inactivated by the neurotoxin, fish tend to select the freezing instead of the agitating behavior in the cued-fear conditioning. We study the role of the habenula in switching of the emotional behaviors, the adaptive fear learning, the aggressiveness or the social dominant-subordinate relationships, using zebrafish, rats and mice.

Main Research Fields

Complex Systems

Related Research Fields

Biological Sciences

Keywords

• neural circuit manipulation
• decision making
• emotion and fear
• social conflict and hierarchy
• neural imaging

Selected Publications

1. Torigoe M, Islam T, Kakinuma H, Fung C-C A, Isomura T, Shimazaki H, Aoki T, Fukai T, Okamoto H.
   "Zebrafish capable of generating future state prediction error show improved active avoidance behavior in virtual reality"
   Nature Communications vol.20(2021), Article number: 5712 (2021)
   doi: 10.1038/s41467-021-26010-7
2. Okamoto H, Cherng BW, Nakajo H, Chou MY, Kinoshita M.
   "Habenula as the experience-dependent controlling switchboard of behavior and attention in social conflict and learning. "
   Curr Opin Neurobiol. 68:36-43. (2021)
3. Cherng BW, Islam T, Torigoe M, Tsuboi T, Okamoto H.
   "The Dorsal Lateral Habenula-Interpeduncular Nucleus Pathway Is Essential for Left-Right-Dependent Decision Making in Zebrafish. "
   Cell Rep. 32(11):108143. (2020) doi: 10.1016/j.celrep.2020.108143. PMID: 32937118
4. Nakajo H, Chou MY, Kinoshita M, Appelbaum L, Shimazaki H, Tsuboi T, Okamoto H.
   "Hunger Potentiates the Habenular Winner Pathway for Social Conflict by Orexin-Promoted Biased Alternative Splicing of the AMPA Receptor Gene. "
   Cell Rep. 31(12):107790. (2020) doi: 10.1016/j.celrep.2020.107790. PMID: 32579920 Free article.
5. Chou M., Amo R., Kinoshita M., Cherng B., Shimazaki H., Agetsuma M., Shiraki T., Aoki T., Takahoko M., Yamazaki M., Gigashijima S., Okamoto H. :
   "Social conflict resolution regulated by two dorsal habenular subregions in zebrafish"
   Science in press (2016)
   10.1126/science.aac9508
6. Amo, R., Fredes, F., Kinoshita, M., Aoki, R., Aizawa, H., Agetsuma, M., Aoki, T., Shiraki, T., Kakinuma, H., Matsuda, M., Yamazaki, M., Takahoko, M., Tsuboi, T., Higashijima, S., Miyasaka, N., Koide, T., Yabuki, Y., Yoshihara, Y., Fukai, T. and Okamoto, H.:
   "The Habenulo-Raphe Serotonergic Circuit Encodes an Aversive Expectation Value Essential for Adaptive Active Avoidance of Danger"
   Neuron, 87 1034-1048 (2014)
   10.1016/j.neuron.2014.10.035
7. Aoki, T., Kinoshita, M., Aoki, R., Agetsuma, M., Aizawa, H., Yamazaki, M., Takahoko, M., Amo, R., Atrata, A., Higashijima, S., Tsuboi, T. and Okamoto, H.:
   "Imaging of neural ensemble for the retrieval of a learned behavioral program"
   Neuron, 78, 881-894 (2013)
   10.1016/j.neuron.2013.04.009
8. Agetsuma, M., Aizawa, H., Aoki, T., Nakayama, R., Takahoko, M., Goto, M., Sassa, T., Amo, R., Shiraki, T., Kawakami, K., Hosoya, T., Higashijima, S. and Okamoto, H.:
   "The habenula is crucial for experience-dependent modification of fear responses in zebrafish"
   Nature Neuroscience, 13(11), 1354-1356 (2010)
   10.1038/nn.2654
9. Aizawa, H., Goto, M., Sato T., and Okamoto. H.:
   "Temporally regulated asymmetric neurogenesis causes left-right difference in the zebrafish habenular structures"
   Developmental Cell, 12, 87-98 (2007)
   10.1016/j.devcel.2006.10.004
10. Aizawa,H., Bianco, I.H., Hamaoka, T., Miyashita, T., Uemura,O., Concha, M.L., Russell, Wilson, S.W., and Okamoto, H.:
    "Laterotopic Representation of Left-Right Information onto the Dorso-Ventral Axis of a Zebrafish Midbrain Target Nucleus"
    Current Biology, 15, 238-243 (2005).
    10.1016/j.cub.2005.01.014