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Calcium-dependent molecular fMRI using a magnetic nanosensor


Calcium ions are ubiquitous signalling molecules in all multicellular organisms, where they mediate diverse aspects of intracellular and extracellular communication over widely varying temporal and spatial scales1. Though techniques to map calcium-related activity at a high resolution by optical means are well established, there is currently no reliable method to measure calcium dynamics over large volumes in intact tissue2. Here, we address this need by introducing a family of magnetic calcium-responsive nanoparticles (MaCaReNas) that can be detected by magnetic resonance imaging (MRI). MaCaReNas respond within seconds to [Ca2+] changes in the 0.1–1.0 mM range, suitable for monitoring extracellular calcium signalling processes in the brain. We show that the probes permit the repeated detection of brain activation in response to diverse stimuli in vivo. MaCaReNas thus provide a tool for calcium-activity mapping in deep tissue and offer a precedent for the development of further nanoparticle-based sensors for dynamic molecular imaging with MRI.

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Fig. 1: Design and in vitro characterization of MaCaReNas.
Fig. 2: MaCaReNa calcium-binding activity correlates with MRI contrast in vivo.
Fig. 3: MaCaReNas report dynamic Ca2+ fluctuations in living rat brains.
Fig. 4: MaCaReNas report striatal responses to medial forebrain stimulation.

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Project funding was provided by NIH grants R01-DA038642, DP2-OD2114, BRAIN Initiative award U01-NS090451 and an MIT Simons Center for the Social Brain Seed Grant to A.J., as well as NIH grant R01-EY007023 to M.S. S.O. was supported by RGO, a JSPS Postdoctoral Fellowship for Research Abroad and an Uehara Memorial Foundation postdoctoral fellowship. E.R. was supported by a Beatriu de Pinós Fellowship from the Government of Catalonia. We thank W. White for assistance with the BLI experiments, S. Bricault for help with data analysis and D. Pheasant at the MIT Biophysical Instrumentation Facility (BIF) for training and assistance with circular dichroism and BLI measurements; BIF instruments are available thanks to NSF grant 0070319 and NIH grant S10-OD016326. We are grateful to J. T. Littleton and J. Lee for supplying the C2AB-expression clone.

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S.O., J.J.L., B.B.B. and E.R. performed the in vitro experiments. B.B.B. and J.M. performed the ex vivo experiments. B.B.B., N.L. and S.O. performed in vivo MRI. B.B.B., N.L. and V.B.-P. performed the electrophysiology with supervision and advice from M.S. S.O., B.B.B. and A.J. designed the research and wrote the paper.

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Correspondence to Alan Jasanoff.

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Supplementary Table 1, Supplementary Figures 1–7.

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Okada, S., Bartelle, B.B., Li, N. et al. Calcium-dependent molecular fMRI using a magnetic nanosensor. Nature Nanotech 13, 473–477 (2018).

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