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Viewpoint | Scientific Discovery and the Future of Medicine

Optogenetics and the Circuit Dynamics of Psychiatric Disease

Karl Deisseroth, MD, PhD1,2,3; Amit Etkin, MD, PhD1; Robert C. Malenka, MD, PhD1
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
2Department of Bioengineering, Stanford University, Stanford, California
3Howard Hughes Medical Institute, Stanford University, Stanford, California
JAMA. 2015;313(20):2019-2020. doi:10.1001/jama.2015.2544.
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This Viewpoint discusses the key breakthroughs, reviews some of the resulting insights into pathophysiology of psychiatry-related symptoms, and illustrates the implications of this emerging vision for circuit-guided psychiatry.

Optogenetics is a method for delivering millisecond-precision control (for activation or inhibition) to targeted cells using light within freely behaving mammals.1 The components of this method, as practiced today, involve (1) lasers and fiber optics for light delivery into the nervous system and (2) genes called microbial opsins, which encode light-activated proteins that regulate transmembrane ion conductance (Figure). Microbial opsins display diverse color sensitivity and conductance properties, with diversity generated by mutagenesis or arising naturally in the biosphere. Constituted by single genes, these microbial opsins can be targeted using a toolbox of genetic techniques, thereby specifying light-induced current flow in cells defined by function (eg, with excitatory, inhibitory, or dopaminergic properties) and anatomy (eg, with cell bodies in one location and projections going to another specific location across the brain). Light guidance with versatile fiber optics or spatial light modulators allows further resolution. Rapid advances in materials and electrical engineering have enabled opsin activation in neural tissue wirelessly using tiny LEDs.

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Steps in Optogenetic Research

Diverse opsin genes from microbes are engineered in the laboratory to allow light-activated regulation of ion flow and biochemical pathways. Targeted opsins allow cell-specific control with light with precision not achievable by electrodes. Mice can be implanted with fiberoptics that can both deliver optogenetic control and collect fluorescent readout of neural activity with fiber photometry. At left, black trace shows neuronal membrane voltage; blue ticks show pulses of light driving ChR2 to elicit action potentials (spikes in the membrane voltage); and yellow bar shows steady light providing inhibition of the neuron through NpHR. At right, red ticks indicate rewarding sucrose solution ingestion; black trace shows corresponding elevations in deep brain dopamine neuron activity.2

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