ＭＺＴ（株）ゼブラフィッシュ創薬研究所

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optogeneticsも、zebrafish行動解析へシフト

本日開催されているWCP2018のプレナリーレクチャーであるphotogeneticsのフロンティアーである Karl Deisserothも、ついにマウスからゼブラフィッシュ行動解析へシフトしていました。今後、多くの分野でゼブラフィッシュへのパラダイムシフトが、明白となり、我が国の研究者も大きな関心をよせていました。今後の医学生物学におけるゼブラフィッシュの展開が楽しみです。

Plenary Lecture 2
Linking real-time activity with detailed anatomy at cellular resolution across the vertebrate brain

Jul 3, 2018 11:15 - 12:15　Main Hall | 1F, Kyoto International Conference Center
D.H. Chen Professor, Departments of Bioengineering and of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

Diverse cells underlie basic drives and actions essential for animal survival, including behaviors such as those related to thirst, hunger, and sleep. Cell-type-specific activity signals that underlie these animal behaviors have been elucidated, interestingly, using proteins essential for plant behaviors1. These channelrhodopsin proteins are light-gated ion channels that enable motile algae to seek light conditions suitable for photosynthesis1; we have been able to discover principles of function by solving the key high-resolution channelrhodopsin crystal structures and by structure-guided redesign for altered ion selectivity, kinetics, and spectral properties1,2. These discoveries not only revealed basic principles governing operation of light-gated ion channels for plant survival-drive behavior, but also enabled the creation of new proteins for illuminating (via optogenetics)3 fundamental animal survival-drive behavior via application to circuit function. Here we will present our structures and structure-guided tool redesign outcomes, and our application of these tools to uncover basic hypothalamic mechanisms underlying thirst4,5, feeding6,7, sleep8, and other fundamental drives9, via identification of internal cellular-resolution brain states that dynamically control the elements of drive-motivated behavior. And we will present in detail a new general method for identifying the cellular manifestation of internal states by integrating brain-wide single-cell activity imaging and control with hydrogel-tissue chemistry10 for high-content cellular-resolution molecular phenotyping11. Together, these experiments have established an approach for unbiased discovery of cellular elements underlying behavior, and have revealed an evolutionarily-conserved set of diverse cellular systems that collectively govern survival drive-related internal states.
1Deisseroth K & Hegemann P (2017). The form and function of channelrhodopsin. Science 357: eaan5544.
2Kato et al. (2012). Crystal structure of the channelrhodopsin light-gated cation channel. Nature 482: 369-74.
3Deisseroth K (2015). Optogenetics: ten years of microbial opsins in neuroscience. Nature Neuroscience 18: 1213-25.
4Allen WE et al. (2017). Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357: 1149-55.
5Augustine et al. (2018). Hierarchical neural architecture underlying thirst regulation. Nature, doi: 10.1038/nature25488.
6Domingos et al. (2011). Leptin regulates the reward value of nutrient. Nature Neuroscience 14: 1562-8.
7Ferenczi et al. (2016). Prefrontal regulation of brainwide circuit dynamics and reward-related behavior. Science 351 (6268): aac9698.
8Adamantidis et al. (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450: 420-4.
9Kim et al. (2013). Assembling behavioral states: divergent neural pathways recruit separable anxiety features. Nature 496: 219-23.
10Gradinaru et al. (2018). Hydrogel-tissue chemistry: principles and applications. Annual Review of Biophysics, in press.
11Lovett-Barron et al. (2017). Ancestral circuits for the coordinated modulation of brain state. Cell 171: 1411-23.
D.H. Chen Professor, Departments of Bioengineering and of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
Diverse cells underlie basic drives and actions essential for animal survival, including behaviors such as those related to thirst, hunger, and sleep. Cell-type-specific activity signals that underlie these animal behaviors have been elucidated, interestingly, using proteins essential for plant behaviors1. These channelrhodopsin proteins are light-gated ion channels that enable motile algae to seek light conditions suitable for photosynthesis1; we have been able to discover principles of function by solving the key high-resolution channelrhodopsin crystal structures and by structure-guided redesign for altered ion selectivity, kinetics, and spectral properties1,2. These discoveries not only revealed basic principles governing operation of light-gated ion channels for plant survival-drive behavior, but also enabled the creation of new proteins for illuminating (via optogenetics)3 fundamental animal survival-drive behavior via application to circuit function. Here we will present our structures and structure-guided tool redesign outcomes, and our application of these tools to uncover basic hypothalamic mechanisms underlying thirst4,5, feeding6,7, sleep8, and other fundamental drives9, via identification of internal cellular-resolution brain states that dynamically control the elements of drive-motivated behavior. And we will present in detail a new general method for identifying the cellular manifestation of internal states by integrating brain-wide single-cell activity imaging and control with hydrogel-tissue chemistry10 for high-content cellular-resolution molecular phenotyping11. Together, these experiments have established an approach for unbiased discovery of cellular elements underlying behavior, and have revealed an evolutionarily-conserved set of diverse cellular systems that collectively govern survival drive-related internal states.
1Deisseroth K & Hegemann P (2017). The form and function of channelrhodopsin. Science 357: eaan5544.
2Kato et al. (2012). Crystal structure of the channelrhodopsin light-gated cation channel. Nature 482: 369-74.
3Deisseroth K (2015). Optogenetics: ten years of microbial opsins in neuroscience. Nature Neuroscience 18: 1213-25.
4Allen WE et al. (2017). Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357: 1149-55.
5Augustine et al. (2018). Hierarchical neural architecture underlying thirst regulation. Nature, doi: 10.1038/nature25488.
6Domingos et al. (2011). Leptin regulates the reward value of nutrient. Nature Neuroscience 14: 1562-8.
7Ferenczi et al. (2016). Prefrontal regulation of brainwide circuit dynamics and reward-related behavior. Science 351 (6268): aac9698.
8Adamantidis et al. (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450: 420-4.
9Kim et al. (2013). Assembling behavioral states: divergent neural pathways recruit separable anxiety features. Nature 496: 219-23.
10Gradinaru et al. (2018). Hydrogel-tissue chemistry: principles and applications. Annual Review of Biophysics, in press.
11Lovett-Barron et al. (2017). Ancestral circuits for the coordinated modulation of brain state. Cell 171: 1411-23.

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optogeneticsも、zebrafish行動解析へシフト

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