Acoustically targeted chemogenetics for the non-invasive control of neural circuits

Abstract

Neurological and psychiatric disorders are often characterized by dysfunctional neural circuits in specific regions of the brain. Existing treatment strategies, including the use of drugs and implantable brain stimulators, aim to modulate the activity of these circuits. However, they are not cell-type-specific, lack spatial targeting or require invasive procedures. Here, we report a cell-type-specific and non-invasive approach based on acoustically targeted chemogenetics that enables the modulation of neural circuits with spatiotemporal specificity. The approach uses ultrasound waves to transiently open the blood–brain barrier and transduce neurons at specific locations in the brain with virally encoded engineered G-protein-coupled receptors. The engineered neurons subsequently respond to systemically administered designer compounds to activate or inhibit their activity. In a mouse model of memory formation, the approach can modify and subsequently activate or inhibit excitatory neurons within the hippocampus, with selective control over individual brain regions. This technology overcomes some of the key limitations associated with conventional brain therapies.

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Fig. 1: ATAC paradigm.
Fig. 2: BBBO and targeted expression of DREADD in the hippocampus.
Fig. 3: Spatial and cell-type specificity of DREADD expression.
Fig. 4: ATAC with excitatory DREADDs results in neuronal activation.
Fig. 5: Inhibition of fear memory formation using ATAC.
Fig. 6: Intersectional ATAC in the midbrain of Cre transgenic mice.

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Acknowledgements

The authors thank M. Zelikowsky for discussions and assistance with the design of the fear conditioning experiments, E. Dumont, R. Jacobs, A. Mukharjee and G. Lu for discussions and R. McCardell for assistance with the initial experiments. We thank the UCLA Translational Pathology Core Laboratory for assistance with the histological samples and Caltech’s Office of Laboratory Animal Research for help with rodent husbandry. This research was supported by the Heritage Medical Research Institute, the Jacobs Institute for Molecular Engineering in Medicine and the Defense Advanced Research Projects Agency (grant W911NF-17-2-0036). Related research in the Shapiro Laboratory is also supported by the Packard Fellowship in Science and Engineering and the Sontag Foundation Distinguished Scientist Award.

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J.O.S. and M.G.S. conceived and planned the research. J.O.S. performed the in vivo experiments. J.O.S., B.L., A.L.-G. and D.M. performed the histological experiments. J.O.S. and B.L. analysed the data. J.O.S. and M.G.S. wrote the manuscript with input from all other authors. M.G.S. supervised the research.

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Correspondence to Mikhail G. Shapiro.

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Szablowski, J.O., Lee-Gosselin, A., Lue, B. et al. Acoustically targeted chemogenetics for the non-invasive control of neural circuits. Nat Biomed Eng 2, 475–484 (2018). https://doi.org/10.1038/s41551-018-0258-2

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