ReviewOPTOGENETICS

Beyond the brain: Optogenetic control in the spinal cord and peripheral nervous system

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Science Translational Medicine  04 May 2016:
Vol. 8, Issue 337, pp. 337rv5
DOI: 10.1126/scitranslmed.aad7577
  • Fig. 1. Challenges of optogenetically targeting cells outside of the brain.

    (A) Wide variations in expression of opsin proteins, tissue structure, and the mechanical environment of the peripheral nervous system may make it difficult to develop modular and adaptable light and opsin expression systems. Excitable cells in the peripheral nervous system may be sparsely scattered throughout a large volume of tissue, necessitating broad areas of illumination. Opsin expression over long distances may be required because of the length of axons in the spinal cord and peripheral nervous system. Outside of the spinal cord and brain, the immune system may impair opsin expression. Various tissues, such as muscle, may be opaque to light. Relative movement of targeted cells during locomotion may complicate light delivery; because of large variations in targeted cell size and structure, custom light delivery strategies may be required. (B) There may be variations in opsin expression even when using the same viral construct and promoter. (C) Opsin expression in the peripheral nervous system may be improved over time by modulating the immune response. (D) Engineering opsins to have greater sensitivity to light may lower the expression threshold for functional optogenetic experiments.

  • Fig. 2. Light delivery strategies in the spinal cord and peripheral nervous system.

    (A) For peripheral nerves, such as the sciatic nerve, pudendal nerve, or vagus nerve, fiber-optic coupled nerve cuffs can be placed under the skin from an attachment site on the skull (top) (4). Small wirelessly powered devices can directly illuminate the nerve (bottom) (48). (B) For the spinal cord, wirelessly powered devices can be implanted dorsal to the spinal column (top left) (48), or epidural flexible light-emitting diode (LED) arrays can be placed within the spinal column itself (top right) (49). In the future, optical fibers may be directly cemented dorsal to the intervertebral space (bottom). (C) Transdermal illumination is a frequently used approach for light delivery to sensory nerve endings (top left) (6, 7, 9, 11, 12, 14). Alternatives include LEDs implanted subcutaneously (bottom) (48). In the future, light may be delivered using light-emitting fabrics (top right). (D) For internal organs, wirelessly powered devices could be implanted next to the organs (top right), flexible light-emitting meshes could be developed that would wrap around opsin-expressing organs (top left), or intrinsic light-emission systems such as luciferin/luciferase expressed within the organ could be used to activate opsins (bottom) (106).

  • Fig. 3. Optogenetic targets outside of the brain.

    Given recent technical innovations, spinal cord sensory and motor circuits are ripe for optogenetic interrogation. Early demonstrations of genetically specified control of sympathetic nerves should encourage new explorations of parasympathetic and sympathetic nervous system function. Optogenetic studies of sensory terminals in the skin and cornea will improve our understanding of pain and other types of sensation. In addition to neuronal targets, other peripheral excitable cells may be appropriate targets for optogenetic modulation. These include endothelial cells for vasoconstriction, pancreatic β cells for glucose homeostasis, glioma tumor cells for elucidating therapeutic potential against cancer, skeletal muscle cells for direct motor control, smooth muscle cells in erectile tissue and organ vasculature for direct effector control, and cardiomyocytes for pacing of the heart.

  • Fig. 4. Overview of studies using optogenetics beyond the brain.

    The schematic indicates studies using optogenetics to control mammalian excitable cells by delivering light to intact tissue outside of the brain. Each square represents one or more studies indicated by the reference numbers in parentheses at the top. The key explains the features of each study through the background color of the square. Also indicated in each square is the approximate location of light delivery, the approximate color of light used, and the name of the opsin or chemical employed. The top three rows represent studies completed in ex vivo samples of intact mammalian tissue, such as excised vascular smooth muscle (40). The second three rows represent studies completed in anesthetized mammals. The bottom three rows represent studies completed in awake mammals. If more than one type of experiment was used in a study, the study square is placed in the lowest row applicable. The first three columns represent studies in which transgenesis was used to confer light sensitivity. The second three columns represent studies that used more translationally relevant strategies such as viral transduction, cell transplant, and chemical photoswitches. The bottom three rows and right three columns represent studies that are the most translationally relevant including the demonstration of the optogenetic inhibition of pain (6), the optogenetic stimulation of motor neurons (4), and the optogenetic control of glucose homeostasis (9). Arch, archaerhodopsin; bPAC, a photoactivated adenylate cyclase derived from Beggiatoa; ChETA, engineered channelrhodopsin-2 mutants with fast-time kinetics; ChR2, channelrhodopsin-2; EROS, an erectile optogenetic stimulator; NpHR, halorhodopsin; QAQ, quaternary ammonium–azobenzene–quaternary ammonium.

  • Table 1. Selected studies of translational optogenetics.
    TargetKey translational findings and innovations
    DiabetesMelanopsin-mediated transcription to optically control glucose tolerance in a mouse model of type 2 diabetes (9)
    Optogenetic control of insulin release through transplantation of a mouse β cell line transfected with ChR2 (44)
    ObesityDirect neural control of lipolysis and fat mass reduction using optogenetic activation of sympathetic nerve fibers (52)
    CancerChETA-mediated membrane depolarization leading to selective apoptosis of transduced glioma cells and increased survival (5)
    Skeletal muscleOptogenetic control of contraction in mammalian skeletal laryngeal muscle through muscle transduction (40)
    Attenuated atrophy of denervated skeletal muscle through optogenetic stimulation of muscle cells (51)
    Cardiovascular dysfunctionChR2 used for optogenetic control of heart muscle in vivo (38)
    Systemic gene delivery of ChR2 enabled optogenetic pacing of mouse hearts (39)
    Multisite optogenetic control of cardiac resynchronization (46)
    Motor disordersRescue of patterned breathing after spinal cord hemisection (36)
    Optogenetic control of peripheral motor neurons reduced muscle fatigue (37)
    Optogenetic inhibition of peripheral motor neurons (19)
    Restoration of muscle function in a denervated mouse model through embryonic stem cell–derived optically sensitive motor neuron
    engraftment (8)
    PainOptogenetic stimulation of pain-related behavior using a Nav1.8-ChR2 transgenic mouse (13)
    Viral vector delivery to express opsins in nociceptors enabled optogenetic stimulation and suppression of pain (6)
    Increased mechanical thresholds in rats with optogenetic inhibition of fast-conducting high-threshold mechanoreceptors (7)
    A TRPV1 promoter driving expression of ArchT in nociceptors enabled optogenetic inhibition of pain (27)
    New devicesOptogenetic modulation of the spinal cord in freely moving mice (10)
    Implantable light delivery system with targeted viral transduction of peripheral motor neurons controlled muscle activity in walking rats (4)
    Fully internal wireless device for optogenetic control of the spinal cord and periphery (48)
    Implantable, flexible wireless optogenetic system for control of spinal and peripheral neural circuits (49)

Supplementary Materials

  • Supplementary Material for:

    Beyond the brain: Optogenetic control in the spinal cord and peripheral nervous system

    Kate L. Montgomery, Shrivats M. Iyer, Amelia J. Christensen, Karl Deisseroth, Scott L. Delp*

    *Corresponding author. Email: delp{at}stanford.edu

    Published 4 May 2016, Sci. Transl. Med. 8, 337rv5 (2016)
    DOI: 10.1126/scitranslmed.aad7577

    This PDF file includes:

    • Fig. S1. Increase in the number of publications since the initial development of optogenetics.

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