Norepinephrine changes behavioral state via astroglial purinergic signaling
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1.
California Institute of Technology
Abstract
Both neurons and glia communicate via diffusible neuromodulatory substances, but the substrates of computation in such neuromodulatory networks are unclear. During behavioral transitions in the larval zebrafish, the neuromodulator norepinephrine drives fast excitation and delayed inhibition of behavior and circuit activity. We find that the inhibitory arm of this feedforward motif is implemented by astroglial purinergic signaling. Neuromodulator imaging, behavioral pharmacology, and perturbations of neurons and astroglia reveal that norepinephrine triggers astroglial release of adenosine triphosphate, extracellular conversion into adenosine, and behavioral suppression through activation of hindbrain neuronal adenosine receptors. This work, along with a companion piece by Lefton and colleagues demonstrating an analogous pathway mediating the effect of norepinephrine on synaptic connectivity in mice, identifies a computational and behavioral role for an evolutionarily conserved astroglial purinergic signaling axis in norepinephrine-mediated behavioral and brain state transitions.
Copyright and License
he copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Acknowledgement
We would like to thank Dr. Mark Ellisman, Dr. Dwight Bergles, Dr. Yu Mu, and Dr. Loren Looger, as well as members of the Engert and Ahrens labs for discussions and feedback.
Funding
Howard Hughes Medical Institute (ABC, MD, SN, MBA)
Boehringer Ingelheim Fonds Graduate Fellowship (MD, AR)
European Research Council (ERC Consolidator ERC-CoG-101002870)
European Union’s Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant No. 813457 (CW)
Fondation Bettencourt Schueller (FBS-don-0031) NIH Grant R35 NS122172 (DAP)
NIH Grant U19NS104653 (FE)
NIH Grant 1R01NS124017 (FE)
NIH Grant U19NS123719 (GY)
NIH Grant R01MH110504 (GY)
NSF Grant IIS-1912293 (FE)
NSF GRFP DGE1745303 (ABC)
Simons Foundation SCGB 542943SPI (FE, MBA)
Contributions
Conceptualization: ABC, MBA
Methodology: ABC, MD, VMW, XM, AR, SN, DAP, GY
Investigation: ABC, MD
Visualization: MD, ABC, VMW, XM
Funding acquisition: DAP, GY, FE,
MBA Project administration: ABC, FE, MBA
Writing (original draft): ABC, MBA
Writing (revising and editing): all authors Supervision: DAP, GY, FE, MBA
Data Availability
All data are available in the main text or the supplementary materials. Jupyter notebooks (Python 3.7) were used to process raw data. Raw data will be made available by the corresponding author upon request. Python and C++ code used will be made available by the corresponding author upon request. Fish lines will be made available upon request and deposited to ZIRC.
Conflict of Interest
Authors declare that they have no competing interests.
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Additional details
- PMCID
- PMC11142163
- Howard Hughes Medical Institute
- Boehringer Ingelheim Fonds
- European Research Council
- 101002870
- European Research Council
- Marie Skłodowska-Curie Fellowship 813457
- Fondation Bettencourt Schueller
- FBS-don-0031
- National Institutes of Health
- R35 NS122172
- National Institutes of Health
- U19NS104653
- National Institutes of Health
- 1R01NS124017
- National Institutes of Health
- U19NS123719
- National Institutes of Health
- R01MH110504
- National Science Foundation
- IIS-1912293
- National Science Foundation
- NSF Graduate Research Fellowship DGE-1745303
- Simons Foundation
- SCGB 542943SPI
- Caltech groups
- Division of Biology and Biological Engineering, Tianqiao and Chrissy Chen Institute for Neuroscience