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In situ electrochemical generation of nitric oxide for neuronal modulation

Nature Nanotechnology volume 15, pages 690–697 (2020)Cite this article

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Abstract

Understanding the function of nitric oxide, a lipophilic messenger in physiological processes across nervous, cardiovascular and immune systems, is currently impeded by the dearth of tools to deliver this gaseous molecule in situ to specific cells. To address this need, we have developed iron sulfide nanoclusters that catalyse nitric oxide generation from benign sodium nitrite in the presence of modest electric fields. Locally generated nitric oxide activates the nitric oxide-sensitive cation channel, transient receptor potential vanilloid family member 1 (TRPV1), and the latency of TRPV1-mediated Ca2+ responses can be controlled by varying the applied voltage. Integrating these electrocatalytic nanoclusters with multimaterial fibres allows nitric oxide-mediated neuronal interrogation in vivo. The in situ generation of nitric oxide in the ventral tegmental area with the electrocatalytic fibres evoked neuronal excitation in the targeted brain region and its excitatory projections. This nitric oxide generation platform may advance mechanistic studies of the role of nitric oxide in the nervous system and other organs.

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Fig. 1: Fe3S4 and Pt-Fe3S4 nanocatalysts for the electrochemical reduction of NO2– to NO.
Fig. 2: Electrochemically produced NO triggers TRPV1.
Fig. 3: Signalling pathways mediated by electrocatalytic NO generation in vitro.
Fig. 4: Fabrication and characterization of the NO delivery fibre.
Fig. 5: Neuronal stimulation mediated by NO delivery through implanted fibres in vivo.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

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All scripts are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank D. Kim and F. Zhang for the generous gifts of the plasmids and cell lines. This work was funded in part by the National Institute of Neurological Disorders and Stroke (5R01NS086804) and the National Institutes of Health (NIH) BRAIN Initiative (1R01MH111872). This work made use of the MIT MRSEC Shared Experimental Facilities under award number DMR-14-19807 from the National Science Foundation (NSF). Funding for this research was also provided by the Department of Chemical Engineering at MIT. J.P. is a recipient of a scholarship from the Kwanjeong Educational Foundation. J.H.M. and Z.J.S. are supported by NSF Graduate Research Fellowships under grant number 1122374. T.T. was supported by the NEC Corporation. S.R. acknowledges funding support from the NIH Pathway to Independence Award (National Institute of Mental Health 1K99MH120279-01) and a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT.

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Author notes

  1. These authors contributed equally: Jimin Park, Kyoungsuk Jin.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Yoel Fink & Polina Anikeeva

  2. Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Atharva Sahasrabudhe, Po-Han Chiang, Florian Koehler, Dekel Rosenfeld, Siyuan Rao, Tomo Tanaka, Tural Khudiyev, Yoel Fink & Polina Anikeeva

  3. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Atharva Sahasrabudhe, Po-Han Chiang, Florian Koehler, Dekel Rosenfeld, Siyuan Rao & Polina Anikeeva

  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Kyoungsuk Jin, Joseph H. Maalouf, Zachary J. Schiffer & Karthish Manthiram

  5. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Atharva Sahasrabudhe

  6. Institute of Biomedical Engineering, National Chiao Tung University, Taiwan, Taiwan

    Po-Han Chiang

  7. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Florian Koehler

  8. Simons Center for Social Brain, Massachusetts Institute of Technology, Cambridge, MA, USA

    Siyuan Rao

  9. System Platform Research Laboratories, NEC Corporation, Tsukuba, Japan

    Tomo Tanaka

  10. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, USA

    Tural Khudiyev & Yoel Fink

  11. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

    Ofer Yizhar

  12. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    Polina Anikeeva

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Contributions

J.P., K.J., K.M. and P.A. designed all experiments and performed all analyses. K.J. and J.H.M. synthesized the nanocatalysts and evaluated their electrocatalytic activity for NO generation. K.J. and Z.J.S. calculated diffusion profiles of NO. A.S., T.T., and T.K. fabricated the NO-delivery fibre. Y.F. offered insights into fibre fabrication. J.P., K.J. and P.C. performed in vitro TRPV1 modulation using the electrochemical NO delivery system. J.P. and P.C. conducted in vivo neuronal stimulation with the NO-delivery fibre. J.P., S.R. and D.R. performed immunohistochemistry analyses. J.P., F.K. and O.Y. conducted the electrophysiology analyses. J.P. and D.R. performed the cGMP assays. All co-authors contributed to the writing of the manuscript.

Corresponding authors

Correspondence to Karthish Manthiram or Polina Anikeeva.

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Peer review information Nature Nanotechnology thanks Fabio Benfenati, Jennifer Dionne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary methods, Figs. 1–29 and refs. 1–7.

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Park, J., Jin, K., Sahasrabudhe, A. et al. In situ electrochemical generation of nitric oxide for neuronal modulation. Nat. Nanotechnol. 15, 690–697 (2020). https://doi.org/10.1038/s41565-020-0701-x

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