Neural substrates of awakening probed with optogenetic control of hypocretin neurons
Open accessAbstract
The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.
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Selective loss of hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy.
“Selective loss of the hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy,5–9”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [6]
Cites
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity
de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X.-B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.322 · Cited by 3,878 · see citing works
Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks
Pace-Schott, E. F., & Hobson, J. A. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn895 · Cited by 937 · see citing works
Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections
Petreanu, L., Huber, D., Sobczyk, A., & Svoboda, K. (2007) · Nature Neuroscience · doi:10.1038/nn1891 · Cited by 930 · see citing works
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Self-citationRegulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry
Kravitz, A. V., Freeze, B. S., Parker, P. R. L., Kay, K., Thwin, M. T., Deisseroth, K., & Kreitzer, A. C. (2010) · Nature · doi:10.1038/nature09159 · Cited by 1,885 · see citing works
Self-citationOptogenetics in neural systems
Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M., & Deisseroth, K. (2011) · Neuron · doi:10.1016/j.neuron.2011.06.004 · Cited by 1,881 · see citing works
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Self-citationControl of sleep and wakefulness
Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E., & McCarley, R. W. (2012) · Physiological Reviews · doi:10.1152/physrev.00032.2011 · Cited by 1,477 · see citing works
Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J., & Scammell, T. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.032 · Cited by 1,404 · see citing works
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Scammell, T. E., Arrigoni, E., & Lipton, J. O. (2017) · Neuron · doi:10.1016/j.neuron.2017.01.014 · Cited by 966 · see citing works
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Mahler, S. V., Smith, R. J., Moorman, D. E., Sartor, G. C., & Aston-Jones, G. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-59489-1.00007-0 · Cited by 215 · see citing works
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Klein, T. A., Ullsperger, M., & Danielmeier, C. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00014 · Cited by 210 · see citing works
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Clasadonte, J., Scemes, E., Wang, Z., Boison, D., & Haydon, P. G. (2017) · Neuron · doi:10.1016/j.neuron.2017.08.022 · Cited by 200 · see citing works
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Adamantidis, A., & De Lecea, L. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.164400 · Cited by 112 · see citing works
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de Lecea, L., Carter, M. E., & Adamantidis, A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.032 · Cited by 103 · see citing works
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Flores, Á., Saravia, R., Maldonado, R., & Berrendero, F. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.06.005 · Cited by 102 · see citing works
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Dorsey, A., de Lecea, L., & Jennings, K. J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.625397 · Cited by 100 · see citing works
Optogenetic and electrical microstimulation systematically bias visuospatial choice in primates
Dai, J., Brooks, D. I., & Sheinberg, D. L. (2014) · Current Biology · doi:10.1016/j.cub.2013.11.011 · Cited by 97 · see citing works
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Lu, L., Ren, Y., Yu, T., Liu, Z., Wang, S., Tan, L., Zeng, J., Feng, Q., Lin, R., Liu, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14116-y · Cited by 84 · see citing works
Hypocretin as a Hub for Arousal and Motivation
Tyree, S. M., Borniger, J. C., & de Lecea, L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00413 · Cited by 83 · see citing works
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- Authors
- Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K., & de Lecea, L.
- Affiliations
- Stanford University (US)
- Corresponding author
- Deisseroth, Karl
- Venue
- Nature
- Published
- 2007-10-17
- Volume
- 450
- Issue
- 7168
- Pages
- 420-424
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6744371
- OpenAlex
- W2063210874
- Cited by
- 1,341
- References
- 4
- Citations by year
- 2026: 41 · 2025: 55 · 2024: 53 · 2023: 57 · 2022: 65 · 2021: 69 · 2020: 70 · 2019: 65 · 2018: 95 · 2017: 90 · 2016: 83 · 2015: 94 · 2014: 81 · 2013: 90 · 2012: 97
- FWCI
- 24.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- National Institutes of Health (DP1OD000616)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- hypocretin neurons, orexin, sleep-wake transition, awakening, optogenetic stimulation, channelrhodopsin-2, lateral hypothalamus, arousal, sleep disorders, narcolepsy, slow-wave sleep, REM sleep, mouse behavior
- MeSH terms
- Orexins, Animals, Circadian Rhythm, Hypothalamus, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptides, Rhodopsin, Sleep, Sleep, REM, Wakefulness, Receptors, Neuropeptide, Patch-Clamp Techniques, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors
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