Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Optetrode: a multichannel readout for optogenetic control in freely moving mice

Nature Neuroscience volume 15, pages 163–170 (2012)Cite this article

Subjects

This article has been updated

Abstract

Recent advances in optogenetics have improved the precision with which defined circuit elements can be controlled optically in freely moving mammals; in particular, recombinase-dependent opsin viruses, used with a growing pool of transgenic mice expressing recombinases, allow manipulation of specific cell types. However, although optogenetic control has allowed neural circuits to be manipulated in increasingly powerful ways, combining optogenetic stimulation with simultaneous multichannel electrophysiological readout of isolated units in freely moving mice remains a challenge. We designed and validated the optetrode, a device that allows for colocalized multi-tetrode electrophysiological recording and optical stimulation in freely moving mice. Optetrode manufacture employs a unique optical fiber-centric coaxial design approach that yields a lightweight (2 g), compact and robust device that is suitable for behaving mice. This low-cost device is easy to construct (2.5 h to build without specialized equipment). We found that the drive design produced stable high-quality recordings and continued to do so for at least 6 weeks following implantation. We validated the optetrode by quantifying, for the first time, the response of cells in the medial prefrontal cortex to local optical excitation and inhibition, probing multiple different genetically defined classes of cells in the mouse during open field exploration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Optetrode design.
Figure 2: Optetrode-facilitated electrophysiology during broad optogenetic stimulation during the OFT.
Figure 3: Optetrode-facilitated electrophysiology during cell type–specific optogenetic stimulation in the context of the OFT.
Figure 4: Behavioral and neural activity effects of optogenetic stimulation during the OFT.
Figure 5: Optetrode projection targeting: driving axonal inputs from BLA into mPFC.

Similar content being viewed by others

Change history

  • 11 December 2011

    In the version of this article initially published online, the middle initial of author Lisa A. Gunaydin was missing. The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Nestler, E.J. & Hyman, S.E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13, 1161–1169 (2010).

    Article  CAS  Google Scholar 

  2. Costa, R.M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002).

    Article  CAS  Google Scholar 

  3. Leypold, B.G. et al. Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl. Acad. Sci. USA 99, 6376–6381 (2002).

    Article  CAS  Google Scholar 

  4. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    Article  CAS  Google Scholar 

  5. Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    Article  CAS  Google Scholar 

  6. Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2–assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).

    Article  CAS  Google Scholar 

  7. Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deisseroth, K. & de Lecea, L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450, 420–424 (2007).

    Article  CAS  Google Scholar 

  8. Arenkiel, B.R. et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron 54, 205–218 (2007).

    Article  CAS  Google Scholar 

  9. Huang, Z.J., Yu, W., Lovett, C. & Tonegawa, S. Cre/loxP recombination-activated neuronal markers in mouse neocortex and hippocampus. Genesis 32, 209–217 (2002).

    Article  CAS  Google Scholar 

  10. Lindeberg, J. et al. Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus. Genesis 40, 67–73 (2004).

    Article  CAS  Google Scholar 

  11. Gong, S. et al. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J. Neurosci. 27, 9817–9823 (2007).

    Article  CAS  Google Scholar 

  12. Young, P. et al. Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice. Nat. Neurosci. 11, 721–728 (2008).

    Article  CAS  Google Scholar 

  13. Tsai, H.C. et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324, 1080–1084 (2009).

    Article  CAS  Google Scholar 

  14. Sohal, V.S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).

    Article  CAS  Google Scholar 

  15. Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    Article  CAS  Google Scholar 

  16. Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J. Neurosci. 27, 14231–14238 (2007).

    Article  CAS  Google Scholar 

  17. Brown, E.N., Purdon, P.L. & Van Dort, C.J. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu. Rev. Neurosci. 34, 601–628 (2011).

    Article  CAS  Google Scholar 

  18. McNaughton, B.L., O'Keefe, J. & Barnes, C.A. The stereotrode: a new technique for simultaneous isolation of several single units in the central nervous system from multiple unit records. J. Neurosci. Methods 8, 391–397 (1983).

    Article  CAS  Google Scholar 

  19. Wilson, M.A. & McNaughton, B.L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).

    Article  CAS  Google Scholar 

  20. Gray, C.M., Maldonado, P.E., Wilson, M. & McNaughton, B.L.J. Tetrodes markedly improve the reliability and yield of multiple single-unit isolation from multi-unit recordings in cat striate cortex. J. Neurosci. Methods 63, 43–54 (1995).

    Article  CAS  Google Scholar 

  21. Jog, M.S. et al. Tetrode technology: advances in implantable hardware, neuroimaging, and data analysis techniques. J. Neurosci. Methods 117, 141–152 (2002).

    Article  CAS  Google Scholar 

  22. Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297, 211–218 (2002).

    Article  CAS  Google Scholar 

  23. Wiltgen, B.J., Brown, R.A., Talton, L.E. & Silva, A.J. New circuits for old memories: the role of the neocortex in consolidation. Neuron 44, 101–108 (2004).

    Article  CAS  Google Scholar 

  24. Chawla, M.K. & Barnes, C.A. Hippocampal granule cells in normal aging: insights from electrophysiological and functional imaging experiments. Prog. Brain Res. 163, 661–678 (2007).

    Article  CAS  Google Scholar 

  25. Gerrard, J.L., Burke, S.N., McNaughton, B.L. & Barnes, C.A. Sequence reactivation in the hippocampus is impaired in aged rats. J. Neurosci. 28, 7883–7890 (2008).

    Article  CAS  Google Scholar 

  26. Scanziani, M. & Häusser, M. Electrophysiology in the age of light. Nature 461, 930–939 (2009).

    Article  CAS  Google Scholar 

  27. McHugh, T.J., Blum, K.I., Tsien, J.Z., Tonegawa, S. & Wilson, M.A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87, 1339–1349 (1996).

    Article  CAS  Google Scholar 

  28. Jeantet, Y. & Cho, Y.H. Design of a twin tetrode microdrive and headstage for hippocampal single unit recordings in behaving mice. J. Neurosci. Methods 129, 129–134 (2003).

    Article  Google Scholar 

  29. Royer, S. et al. Multi-array silicon probes with integrated optical fibers: light-assisted perturbation and recording of local neural circuits in the behaving animal. Eur. J. Neurosci. 31, 2279–2291 (2010).

    Article  Google Scholar 

  30. Schmitzer-Tobert, N., Jackson, J., Henze, D., Harris, K. & Redish, A.D. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005).

    Article  Google Scholar 

  31. Aravanis, A.M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143–S156 (2007).

    Article  Google Scholar 

  32. Diester, I. et al. An optogenetic toolbox designed for primates. Nat. Neurosci. 14, 387–397 (2011).

    Article  CAS  Google Scholar 

  33. Benabid, A.L., Chabardes, S., Mitrofanis, J. & Pollak, P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol. 8, 67–81 (2009).

    Article  Google Scholar 

  34. Ponce, F.A. & Lozano, A.M. Deep brain stimulation state of the art and novel stimulation targets. Prog. Brain Res. 184, 311–324 (2010).

    Article  Google Scholar 

  35. Mayberg, H.S. Targeted electrode-based modulation of neural circuits for depression. J. Clin. Invest. 119, 717–725 (2009).

    Article  CAS  Google Scholar 

  36. Histed, M.H., Bonin, V. & Reid, R.C. Direct activation of sparse, distributed populations of cortical neurons by electrical microstimulation. Neuron 63, 508–522 (2009).

    Article  CAS  Google Scholar 

  37. Thiel, G., Greengard, P. & Südhof, T.C. Characterization of tissue-specific transcription by the human synapsin I gene promoter. Proc. Natl. Acad. Sci. USA 88, 3431–3435 (1991).

    Article  CAS  Google Scholar 

  38. Hippenmeyer, S. et al. A Developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 3, e159 (2005).

    Article  Google Scholar 

  39. Britton, D.R. & Britton, K.T. A sensitive open field measure of anxiolytic drug activity. Pharmacol. Biochem. Behav. 15, 577–582 (1981).

    Article  CAS  Google Scholar 

  40. Gradinaru, V., Mogri, M., Thompson, K.R., Henderson, J.M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

    Article  CAS  Google Scholar 

  41. Bacon, S.J., Headlam, A.J., Gabbott, P.L. & Smith, A.D. Amygdala input to medial prefrontal cortex (mPFC) in the rat: a light and electron microscope study. Brain Res. 720, 211–219 (1996).

    Article  CAS  Google Scholar 

  42. Yizhar, O. et al. Neocortical excitation-inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).

    Article  CAS  Google Scholar 

  43. Halassa, M.M. et al. Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. Nat. Neurosci. 14, 1118–1120 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Arber for the PV::Cre transgenic mouse line. P.A. thanks D.G. Walker for advice on mechanical design. P.A. was supported by a Dean's fellowship from Stanford University School of Medicine, I.W. was supported by the Helen Hay Whitney Foundation, I.G. was supported by a Machiah fellowship and the Weizmann Institute Women in Science award, L.G. was supported by a National Science Foundation Integrative Graduate Education and Research Traineeship Award, and L.A.G. was supported by a BioX fellowship from Stanford University. L.M.F. and K.D. received support from a GO grant from the National Institute of Neurological Disorders and Stroke. Full funding information for K.D. is listed at http://www.stanford.edu/group/dlab/optogenetics/funding/ and includes the Gatsby Charitable Foundation, the Defense Advanced Research Projects Agency Reorganization and Plasticity to Accelerate Injury Recovery Program, the California Institute for Regenerative Medicine, the McKnight Foundation, the National Institute of Mental Health, and the National Institute on Drug Abuse.

Author information

Author notes

  1. Polina Anikeeva and Aaron S Andalman: These authors contributed equally to this work.

Authors and Affiliations

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

    Polina Anikeeva, Aaron S Andalman, Ilana Witten, Melissa Warden, Inbal Goshen, Logan Grosenick, Lisa A Gunaydin & Karl Deisseroth

  2. Department of Physiology, University of California, San Francisco, California, USA

    Loren M Frank

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

    Karl Deisseroth

  4. Howard Hughes Medical Institute, Stanford University, Stanford, California, USA

    Karl Deisseroth

  5. Howard Hughes Medical Institute, Stanford University, Stanford, California, USA

    Polina Anikeeva

Authors
  1. Polina Anikeeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron S Andalman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ilana Witten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melissa Warden
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Inbal Goshen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Logan Grosenick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lisa A Gunaydin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Loren M Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karl Deisseroth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.A., A.S.A. and K.D. designed the experiments and analyzed the data. P.A. devised and designed the device. P.A. and A.S.A. collected and analyzed electrophysiological and behavioral data. P.A., A.S.A. and I.G. performed immunohistochemical processing and confocal imaging. M.W. and I.W. aided in the development of the device and surgical procedure. M.W. and L.M.F. aided with neuronal sorting procedures. L.G. aided in statistical analysis. L.A.G. contributed data regarding defined-projection manipulation. L.M.F. aided the analysis of the electrophysiological data. K.D. supervised all aspects of the work. P.A., A.S.A. and K.D. wrote the paper.

Corresponding author

Correspondence to Karl Deisseroth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Note (PDF 2190 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anikeeva, P., Andalman, A., Witten, I. et al. Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat Neurosci 15, 163–170 (2012). https://doi.org/10.1038/nn.2992

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2992

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing