Connecting neural circuit output to behaviour can be facilitated by the precise chemical manipulation of specific cell populations1,2. Engineered receptors exclusively activated by designer small molecules enable manipulation of specific neural pathways3,4. However, their application to studies of behaviour has thus far been hampered by a trade-off between the low temporal resolution of systemic injection versus the invasiveness of implanted cannulae or infusion pumps2. Here, we developed a remotely controlled chemomagnetic modulation—a nanomaterials-based technique that permits the pharmacological interrogation of targeted neural populations in freely moving subjects. The heat dissipated by magnetic nanoparticles (MNPs) in the presence of alternating magnetic fields (AMFs) triggers small-molecule release from thermally sensitive lipid vesicles with a 20 s latency. Coupled with the chemogenetic activation of engineered receptors, this technique permits the control of specific neurons with temporal and spatial precision. The delivery of chemomagnetic particles to the ventral tegmental area (VTA) allows the remote modulation of motivated behaviour in mice. Furthermore, this chemomagnetic approach activates endogenous circuits by enabling the regulated release of receptor ligands. Applied to an endogenous dopamine receptor D1 (DRD1) agonist in the nucleus accumbens (NAc), a brain area involved in mediating social interactions, chemomagnetic modulation increases sociability in mice. By offering a temporally precise control of specified ligand–receptor interactions in neurons, this approach may facilitate molecular neuroscience studies in behaving organisms.
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The data that support the findings of this study are presented within the manuscript and are available from the corresponding author upon request.
All the scripts are available from the corresponding author upon request.
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We thank B. Roth, D. Kim and F. Zhang for the generous gifts of the plasmids and cell lines, Z. He, Y. Lin, the Viral Core of Boston Children’s Hospital and the University of Pennsylvania Vector Core for packaging of the AAVs and for the support and advice on virus packaging, A. Galal for the scripts used in the analysis of behaviours and S. Lall and A. Jasanoff for their thoughtful comments on our manuscript. This work was funded in part by DARPA ElectRx Program under D. Weber (HR0011-15-C-0155), the Bose Research Grant and the National Institutes of Health BRAIN Initiative (1R01MH111872). This work made use of the Massachusetts Institute of Technology (MIT) MRSEC Shared Experimental Facilities under award no. DMR-14-19807. S.R. and R.C. are supported by a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT. Methods of analysis and additional data are included in the Supplementary Information.
The authors declare no competing interests.
Peer review information Nature Nanotechnology thanks Joao Carvalho-de-Souza, Patricia Janak and Shan Wang for their contribution to the peer review of this work
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Rao, S., Chen, R., LaRocca, A.A. et al. Remotely controlled chemomagnetic modulation of targeted neural circuits. Nat. Nanotechnol. 14, 967–973 (2019). https://doi.org/10.1038/s41565-019-0521-z
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