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Tuning arousal with optogenetic modulation of locus coeruleus neurons

Nature Neuroscience volume 13, pages 1526–1533 (2010)Cite this article

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Abstract

Neural activity in the noradrenergic locus coeruleus correlates with periods of wakefulness and arousal. However, it is unclear whether tonic or phasic activity in these neurons is necessary or sufficient to induce transitions between behavioral states and to promote long-term arousal. Using optogenetic tools in mice, we found that there is a frequency-dependent, causal relationship among locus coeruleus firing, cortical activity, sleep-to-wake transitions and general locomotor arousal. We also found that sustained, high-frequency stimulation of the locus coeruleus at frequencies of 5 Hz and above caused reversible behavioral arrests. These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders.

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Figure 1: Specific and efficient functional expression of optogenetic transgenes in locus coeruleus neurons.
Figure 2: Photoinhibition of locus coeruleus neurons causes a reduction in the duration of wakefulness.
Figure 3: Photostimulation of locus coeruleus neurons causes immediate sleep-to-wake transitions.
Figure 4: Long-term tonic versus phasic stimulation of the locus coeruleus causes differential promotion of arousal.
Figure 5: High-frequency photostimulation of the locus coeruleus causes reversible behavioral arrests.

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Acknowledgements

We thank members of the de Lecea laboratory for helpful advice and feedback, J. Shieh for assistance with confocal images, A. Hilgendorff for assistance with mouse cardiovascular measurements and S. Xie for access to custom-built SmartCages. M.E.C. received financial support from an NSF Graduate Research Fellowship and the US National Institutes of Health (NIH) National Research Service Award (F31MH83439). O.Y. is supported by a European Molecular Biology Organization long-term postdoctoral fellowship. S.C. is supported by the Excellent Young Researcher Overseas Visit Program (21-8162) of the Japan Society for the Promotion of Science. A.A. is supported by fellowships from the Fonds National de la Recherche Scientifique ('Charge de Recherche'), NIH (K99) and NARSAD. S.N. is supported by NIH grant R01MH072525. K.D. is supported by the National Science Foundation, National Institute of Mental Health, National Institute on Drug Abuse, and the McKnight, Coulter, Snyder, Albert Yu and Mary Bechmann, and Keck Foundations. L.d.L. is supported by the NIH (MH83702, MH87592, DA21880) and NARSAD.

Author information

Authors and Affiliations

  1. Neurosciences Program, Stanford University, Stanford, California, USA

    Matthew E Carter, Karl Deisseroth & Luis de Lecea

  2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA

    Matthew E Carter, Hieu Nguyen, Antoine Adamantidis & Luis de Lecea

  3. Department of Bioengineering, Stanford University, Stanford, California, USA

    Ofer Yizhar & Karl Deisseroth

  4. Sleep & Circadian Neurobiology Laboratory, Stanford University, Stanford, California, USA

    Sachiko Chikahisa & Seiji Nishino

  5. Department of Integrative Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan

    Sachiko Chikahisa

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Contributions

M.E.C. and L.d.L. designed the study and wrote the manuscript. M.E.C. performed or assisted with all experiments. O.Y. performed and analyzed electrophysiology experiments, S.C. performed HPLC analysis, and H.N. analyzed immunohistochemical co-expression data. A.A. and L.d.L. provided expertise on optogenetic and polysomnographic recording techniques, as well as substantial feedback on the manuscript. S.N., K.D. and L.d.L. provided equipment, reagents and critical feedback.

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Correspondence to Luis de Lecea.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 8230 kb)

Supplementary Movie 1

Representative sleep-to-wake transition following photostimulation of locus coeruleus neurons during NREM sleep. Photostimulation condition was 10 ms pulses at 5 Hz for 5 s. (MOV 902 kb)

Supplementary Movie 2

Representative behavioral arrest following sustained, high-frequency photostimulation of locus coeruleus neurons with 10 ms pulses at 10 Hz. (MOV 3007 kb)

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Carter, M., Yizhar, O., Chikahisa, S. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 13, 1526–1533 (2010). https://doi.org/10.1038/nn.2682

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