Optogenetics offers cell type-specific activation of neurones for treatment of neural disorders

Ed Boyden
In January it was announced that Ed Boyden, optogenetics researcher, was the first winner of the IET’s newly established A. F. Harvey Engineering Research Prize for outstanding contributions to medical engineering, worth £300,000 — about $460,000. (Photo: MIT.)

What?

Developed in large part as a treatment for psychiatric illness, optogenetics is a method of turning neurons on and off with millisecond resolution by activation of light-sensitive proteins with specific wavelengths of light. The light-sensitive proteins, called opsins, are genetically encoded ion channels embedded in a neuron’s outer surface that essentially convert light into changes in the electrical potential across the neuron’s membrane; sufficient positive changes trigger individual action potentials or ‘spikes’, whereas sufficient negative changes prevent spikes from occurring.

Why?

Individual brain functions are thought to be controlled by distinct populations of neurons, motivating neuroscientists interested in modifying brain function to develop tools to selectively activate specific neural populations. Though electrical stimulation of neural tissue has been possible for decades, it is difficult to control the spatial spread of the stimulation; even modest electrical current activates hundreds to thousands of neurons. More importantly, the diffuse nature of this type of stimulation makes it impossible to produce cell-type specific neural activation, possibly leading to unwanted side effects.

Optogenetic tools, on the other hand, can target specific cell types (e.g., only cells that express a certain type of protein), providing detailed information about their functions. Also, the ability to control the firing of specific populations of neurons within well-described neural circuits with laser light can lead to therapies for many types of perceptual,[1]movement,[2] and affect disorders. These therapies can work because, often, the disorders they treat are caused by deficiencies in a single cell type, which can be selectively targeted with optogenetics. For example, some forms of blindness that are caused by degeneration of the eye’s photoreceptors can be treated by opsin-mediated light activation of bipolar cells,[1] a type of neuron immediately downstream from photoreceptors that transmits visual information to the brain.

Who, Where, and When?

Stanford University neuroscientist Karl Deisseroth, who is also a practicing psychiatrist, has been working to develop optogenetics in mammals since 2005.[3] He initially conceived the technology as a way to selectively manipulate specific populations of cells that have been implicated in a number of psychiatric disorders like depression and addiction.

Deisseroth has shared his optogenetic tools, which have been successfully used in monkeys, mice, rats, zebrafish, worms and fruitflies, with hundreds of labs around the world. Two former students of Deisseroth’s, Ed Boyden and Feng Zhang, have contributed significantly to the technological advancement of optogenetics at their own labs at MIT.

Alexander Gottschalk of Goethe University has also been developing optogenetic tools since 2005, recently demonstrating a multimodal illumination system that can both track the behavior of ‘freely’ moving worms and direct the worms’ movements via light-activated control of motor neurons.[4]

Peter Hegemann of Humboldt-Universitat has made important modifications to opsin molecules to greatly expand their functionality, giving researchers finer control over the timing of light-driven neural activation.[5],[6]

How?

Genes controlling the production of opsins in microorganisms, such as green algae, can be introduced to brain tissue by direct injection of a virus into which the opsin gene and a promoter have been spliced. The promoter ensures that only specific kinds of neurons will express the opsin protein. More recently, a transgenic line of mice that endogenously express opsin genes has been developed.[7]

Light of a specific wavelength activates the opsin, opening its internal ion channel and leading to rapid fluxes of ions into or out of the cell and either the activation (via channelrhodopsins) or inhibition (via halorhodopsins and bacteriorhodopsins) of the neuron. Molecular modifications to these opsins, as well as the discovery of additional opsins in the natural world, are giving researchers the option to control the activity of mixed populations of neurons (for example, via two types of channelrhodopsin – one activated by blue light[3] and the other by yellow light[8]), control the timing and duration of action potentials (via “fast”\cite[5] and “slow”[6] channelrhodopsin mutants), and even control biochemical events within specific cells.[9]

Implanted LEDs can be used to activate neurons close to the surface of the brain, whereas fiberoptic-coupled diodes are needed to illuminate and activate neurons in deep brain structures.[10] A wireless, head-mounted interface incorporating a compact LED has recently been developed to allow experiments to be conducted remotely and in an automated fashion.[11] The device, dubbed a “wireless router for the brain”, weighs only three grams and makes possible high-throughput studies of the brain’s control of behavior.

But?

Despite being chosen as 2010 ‘Method of the Year’ across all scientific and engineering disciplines by Nature Methods, optogenetics has a number of limitations preventing this relatively new field from delivering medical therapies.

No natural opsin has been found that has an absorption maximum greater than 535 nm, limiting their use in high light-scattering media such as the brain. Also, the current classes of opsins in the optogenetic toolbox are not optimized for ion selectivity or ion conductance, conferring less fine-tuned control and making them less efficient, respectively. Efforts are being made to modify existing ion channels with more favorable properties to be light sensitive.

Many behaviors are controlled by neurons that are distributed over several brain regions. However, in vivo optical stimulation is currently limited to single brain regions no larger than 1 mm[12], extremely limiting the ability to optogenetically control complex behaviors.

Another problem is that, a safe method for the viral transference of the genes encoding light-sensitive opsins to neurons—clearly critical for any practical application of the technique—has yet to be found. Finally, although the technique has been shown to produce dramatic effects (for example, wireless control of locomotion in freely behaving mice[11]), it is so far quite invasive and not ready for therapeutic use in humans.

Literature
E. Boyden, F. Zhang, E. Bamberg, G. Nagel, K. Deisseroth, Millisecond-timescale, genetically targeted optical control of neural activity, Nature Neuroscience, 14 August 2005.
E. Pastrana, Optogenetics: controlling cell function with light, Nature Methods, 20 December 2010.
P. Hegemann, A. Moglich, Channelrhodopsin engineering and exploration of new optogenetic tools, Nature Methods, 20 December 2010.
Background
Optogenetics: Circuits, Genes and Photons in Biological Systems, Gero Miesenboeck, Wiley-Liss, 2011.

References

  1. M. Mehdi Doroudchi, Kenneth P. Greenberg, Jianwen Liu, Kimberly A. Silka, Edward S. Boyden, Jennifer A. Lockridge, A. Cyrus Arman, Ramesh Janani, Shannon E. Boye, Sanford L. Boye, Gabriel M. Gordon, Benjamin C. Matteo, Alapakkam P. Sampath, William W. Hauswirth, and Alan Horsager, Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness, Mol. Ther. 19, p. 1220–1229, 2011.
  2. Alexxai V. Kravitz, Benjamin S. Freeze, Philip R. L. Parker, Kenneth Kay, Myo T. Thwin, Karl Deisseroth, and Anatol C. Kreitzerr, Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry, Nature 466, p. 622–626, 2010.
  3. Edward S Boyden, Feng Zhang, Ernst Bamberg, Georg Nagel, and Karl Deisseroth, Millisecond-timescale, genetically targeted optical control of neural activity, Nat. Neurosci. 8, p. 1263–1268, 2005.
  4. Jeffrey N Stirman, Matthew M Crane, Steven J Husson, Sebastian Wabnig, Christian Schultheis, Alexander Gottschalk, and Hang Lu, Real-time multimodal optical control of neurons and muscles in freely behaving Caenorhabditis elegans, Nat. Methods. 7, p. 153–158, 2011.
  5. L.A. Gunaydin, O. Yizhar, A. Berndt, V. S. Sohal, K. Deisseroth, and P. Hegemann, Ultrafast optogenetic control, Nat. Neurosci. 13, p. 387–392, 2010.
  6. Katja Stehfest, Eglof Ritter, André Berndt, Franz Bartl, and Peter Hegemann, The Branched Photocycle of the Slow-Cycling Channelrhodopsin-2 Mutant C128T, J. Mol. Biol. 398, p. 690–702, 2010.
  7. Shengli Zhao, Jonathan T. Ting, Hisham E. Atallah, Li Qiu, Jie Tan, Bernd Gloss, George J. Augustine, Karl Deisseroth, Minmin Luo, Ann M. Graybiel, and Guoping Feng, Cell type–specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function, Nat. Methods. 8(9), p. 745–752, 2011.
  8. Feng Zhang, Matthias Prigge, Florent Beyrière, Satoshi P Tsunoda, Joanna Mattis, Ofer Yizhar, Peter Hegemann, and Karl Deisseroth, Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri, Nat. Neurosci. 11, p. 631–633, 2008.
  9. Raag D. Airan, Kimberly R. Thompson, Lief E. Fenno, Hannah Bernstein & Karl Deisseroth, Temporally precise in vivo control of intracellular signalling, Nature 458, p. 1025–1029, 2009.
  10. Alexander M Aravanis, Li-Ping Wang, Feng Zhang, Leslie A Meltzer, Murtaza Z Mogri, M Bret Schneider, and Karl Deisseroth, An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology, J. Neural Eng. 4, 2007.
  11. Christian T Wentz, Jacob G Bernstein, Patrick Monahan, Alexander Guerra, Alex Rodriguez, and Edward S Boyden, A wirelessly powered and controlled device for optical neural control of freely-behaving animals, J. Neural Eng. 8, 2011.
  12. Herbert E. Covington III , Mary Kay Lobo, Ian Maze, Vincent Vialou, James M. Hyman, Samir Zaman, Quincey LaPlant , Ezekiel Mouzon , Subroto Ghose, Carol A. Tamminga, Rachael L. Neve, Karl Deisseroth, and Eric J. Nestler, Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex, J. Neurosci. 30(48), p. 16082–16090, 2010.

Books

Jobs

Quality Officer at Minnesota Department of Human Services Recruitment
Expires: 01/29/2021 Employer: Minnesota Department of Human Services Recruitment
Intelligence Analyst at Minnesota Department of Human Services Recruitment
Expires: 01/21/2021 Employer: Minnesota Department of Human Services Recruitment
Systems and Architecture Engineer, Entry Level at NXP Semiconductors
Expires: 02/15/2021 Employer: NXP Semiconductors
Plant Health Safeguarding Specialist, PPQ Technician, and various other entry-level positions at U.S. Department of Agriculture's Animal and Plant Health Inspection Service (APHIS)
Expires: 01/20/2021 Employer: U.S. Department of Agriculture's Animal and Plant Health Inspection Service (APHIS)
Behavioral Health Specialist - Qualified Mental Health Professional (QMHP) at Oregon Youth Authority
Expires: 01/29/2021 Employer: Oregon Youth Authority
Renewable Energy Engineer at California Public Utilities Commission
Expires: 01/24/2021 Employer: California Public Utilities Commission
Associate Toxicologist at California Department of Pesticide Regulation
Expires: 01/30/2021 Employer: California Department of Pesticide Regulation
Informatics Liaison & Public Health Informatician(Job Id 15513) at South Dakota State Government
Expires: 01/29/2021 Employer: South Dakota State Government - Department of Health
IC Design Engineer Internship at Power Integrations
Expires: 02/27/2021 Employer: Power Integrations
Physical Security Command Center Technician at Van Andel Institute
Expires: 02/14/2021 Employer: Van Andel Institute
Epidemiologist I(Job Id 15512) at South Dakota State Government
Expires: 01/22/2021 Employer: South Dakota State Government - Department of Health
Management Analyst I - Non-Merit at Baltimore County Government
Expires: 01/22/2021 Employer: Baltimore County Government
Assignment Assistant for Central Assignment Office - Non-Merit at Baltimore County Government
Expires: 01/27/2021 Employer: Baltimore County Government
Environmental Specialist - Science and Engineering Division at City of Tacoma
Expires: 02/02/2021 Employer: City of Tacoma
Probation Officer I - Adult Probation at Franklin County PA
Expires: 01/29/2021 Employer: Franklin County PA
Legal Secretary at California Department of Toxic Substances Control (DTSC)
Expires: 01/26/2021 Employer: California Department of Toxic Substances Control (DTSC)
IT Associate / Project Analyst at California Department of Toxic Substances Control (DTSC)
Expires: 01/22/2021 Employer: California Department of Toxic Substances Control (DTSC)
Manager Braille & Talking Book(Job Id 15491) at South Dakota State Government
Expires: 02/04/2021 Employer: South Dakota State Government - Department of Education
Assistant Electrical Chief (Operations & Policy Analyst 3) at Oregon Department of Consumer and Business Services
Expires: 01/27/2021 Employer: Oregon Department of Consumer and Business Services
Behavioral Health Senior Clinician at Fairfax County Government
Expires: 01/23/2021 Employer: Fairfax County Government - Fairfax County Human Resources
Behavioral Health Specialist II - Residential Treatment & Detox Services at Fairfax County Government
Expires: 01/23/2021 Employer: Fairfax County Government - Fairfax County Human Resources
Deputy Director Community Services Board / Administrative Operations at Fairfax County Government
Expires: 01/30/2021 Employer: Fairfax County Government - Fairfax County Human Resources
Occupational Safety Consultant (Occupational Safety Specialist 3) at Oregon Department of Consumer and Business Services
Expires: 02/02/2021 Employer: Oregon Department of Consumer and Business Services
Deputy Director, Department of Public Works and Environmental Services, Capital Facilities at Fairfax County Government
Expires: 01/30/2021 Employer: Fairfax County Government - Fairfax County Human Resources
Human Resources Intern at Virginia State Corporation Commission
Expires: 02/26/2021 Employer: Virginia State Corporation Commission
Member and Committee Vacancies at U.S. Congress
Expires: 01/27/2021 Employer: U.S. Congress
Grants and CJAB Coordinator at Franklin County PA
Expires: 01/28/2021 Employer: Franklin County PA
Engineering Technician I at City of Carlsbad
Expires: 02/09/2021 Employer: City of Carlsbad
Postdoctoral Fellow- Biologics Optimization: CHO Cell Engineering for Targeted Integration at Amgen
Expires: 02/26/2021 Employer: Amgen - Fulltime Recruiting
Associate, Data Strategy at Tempus, Inc.
Expires: 01/29/2021 Employer: Tempus, Inc.
Engineer I - II (Region Bridge Engineer) (Job Id 15468) at South Dakota State Government
Expires: 02/05/2021 Employer: South Dakota State Government - Department of Transporation
Trauma Program Manager/EMS Specialist (Registered Nurse)(Job Id 15477) at South Dakota State Government
Expires: 01/26/2021 Employer: South Dakota State Government - Department of Health