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Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window

Nature Biomedical Engineering volume 6, pages 754–770 (2022)Cite this article

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Abstract

Neural circuitry is typically modulated via invasive brain implants and tethered optical fibres in restrained animals. Here we show that wide-field illumination in the second near-infrared spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromolecular photothermal transducers activating neurons ectopically expressing the temperature-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromolecular transducers, ~40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71% at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400–1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal’s head and at an incident power density of 10 mW mm–2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioural studies in small animals.

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Fig. 1: Efficient photothermal conversion of MINDS in the NIR-II window.
Fig. 2: NIR-II photothermal activation of MINDS-sensitized TRPV1 in vitro.
Fig. 3: Through-scalp NIR-II neuromodulation of the mouse hippocampus and motor cortex.
Fig. 4: Immunohistology of the M2 region after NIR-II illumination.
Fig. 5: Through-scalp NIR-II stimulation of a deep-brain region.
Fig. 6: Immunohistology of the VTA region after NIR-II illumination.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

Code availability

The custom MATLAB code used in this study is available at https://github.com/XiangWu96/Wu_NBME_21_code.

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Acknowledgements

We thank W. T. Newsome, M. Z. Lin, X. Chen, L. Luo, H. Dai, D. Jiang and J. R. Sanes for helpful discussions; the Stanford Animal Histology Services for help with preparation of histologic specimens; G.H. acknowledges startup support from the Wu Tsai Neurosciences Institute of Stanford University, a National Institutes of Health (NIH) Pathway to Independence Award (National Institute on Aging 5R00AG056636-04), a National Science Foundation (NSF) CAREER Award (2045120), the Rita Allen Foundation Scholars Program, a gift from the Spinal Muscular Atrophy (SMA) Foundation, and seed grants from the Wu Tsai Neurosciences Institute and the Bio-X Initiative of Stanford University. X.W. acknowledges support from the Stanford Graduate Fellowship. K.S.O. acknowledges the NeuroTech training programme supported by the National Science Foundation under Grant No. 1828993. This work was performed in part at the Stanford Nano Shared Facilities (SNSF) and Cell Sciences Imaging Facility (CSIF) of Stanford University. K.P. thanks Nanyang Technological University (startup grant: M4081627) and Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-1-098) for financial support. Some schematics were created with BioRender.com.

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  1. These authors contributed equally: Xiang Wu, Yuyan Jiang.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Xiang Wu, Fan Yang, Qi Zhou, Rongkang Yin, Junlang Liu, Sa Cai, Wei Ren, Andrew Shin, Kyrstyn S. Ong & Guosong Hong

  2. Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA

    Xiang Wu, Nicholas J. Rommelfanger, Fan Yang, Qi Zhou, Rongkang Yin, Junlang Liu, Sa Cai, Wei Ren, Kyrstyn S. Ong & Guosong Hong

  3. School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore

    Yuyan Jiang & Kanyi Pu

  4. Department of Applied Physics, Stanford University, Stanford, CA, USA

    Nicholas J. Rommelfanger

  5. Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore

    Kanyi Pu

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Contributions

X.W., Y.J., K.P. and G.H. conceived and designed the project; X.W., Y.J., N.J.R., F.Y., Q.Z., R.Y., J.L., S.C., W.R., A.S. and K.S.O. performed the experiments; X.W., Y.J., N.J.R., F.Y., Q.Z., R.Y., J.L., S.C., W.R., K.P. and G.H. analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Kanyi Pu or Guosong Hong.

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Supplementary Video 1

Distant 1,064 nm illumination induces mouse circling through the scalp in a freely behaving mouse.

Supplementary Video 2

Mouse trajectory in a Y maze during the pre-test.

Supplementary Video 3

Mouse trajectory in a Y maze during the post-test.

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Wu, X., Jiang, Y., Rommelfanger, N.J. et al. Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nat. Biomed. Eng 6, 754–770 (2022). https://doi.org/10.1038/s41551-022-00862-w

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