Optogenetics and Neuroscience

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Optogenetics: An understanding and mastery of brain function

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Written by William Godfrey and Christopher Weir.

 

Before we get into the article, I would first like to welcome the newest addition to our writing team here at Mostly Science, William Godfrey. Will and I are both alumni of the University of Queensland, which is where he went to the T.C. Berne School of Law and graduated with an L.L.B. After being unable to resist the intrigue of science, he made the bold decision to head back to UQ this year to begin a Bachelor of Biomedical Science with a view to engaging in neuroscience research (specifically, optogenetics). With that, I would like to leave you to enjoy Will’s first article.

For those who are unaware, the relatively new field of optogenetics can be simply described as using light to control neurons that have been genetically engineered to respond to certain wavelengths of light. The technique was developed based on a re-evaluation of how the brain functions and in this new paradigm the brain is not just an organ in the traditional sense, but a combination of sophisticated electrical circuitry combined with computational power. If this sounds enticing and exciting, then you can see why optogenetics was selected as the Method of the Year (2010) by the prestigious journal Nature Methods.

However, before we get into the technicalities, some initial history is in order. The idea of using light to control neuronal activity for research purposes was first proposed by Nobel laureate Francis Crick in 1999 during a lecture he delivered at the University of California, San Diego. However, it was not until 4 years later in 2002 that Boris Zemelman and Gero Miesenböck genetically engineered neurons (Drosophila fruit fly rhodopsin photoreceptors were spliced in) for the control of neuronal activity in mammalian neurons that they’d successfully cultured. Following on from this was several years of development by other labs that had become interested in the technology, including Susana Lima (in collaboration with Miesenböck) who was the first to use the technique to control the behaviour on an animal (Drosophila spp.). Around a decade later, optogenetics became a well-established tool in neuroscience labs around the world (with applications in drug dependence studies and responses to fear), with Ernst Bamberg, Ed Boyden, Karl Deisseroth, Peter Hegemann, Gero Miesenböck and Georg Nagel all being awarded the Brain Prize in 2013 for their discovery and implementation and refinement of optogenetics.

 

Brief description of how optogenetics technology works (image from http://www.cobolt.se/optogenetics.html)

Brief description of how optogenetics technology works (image from http://www.cobolt.se/optogenetics.html)

 

Now for the more technical stuff (see the figure above for a brief run-down of the technology). Optogenetic tools enables different cell types in the brain (which have different functions) to be accurately controlled using Channelrhodopsins (proteins which function as ion channels), derived from the genes of photosensitive green algae, which convert light into electricity (Boyden et al. 2005). These respond to stimulation from certain wavelengths of light, for example if blue light is used the ion channel opens allowing ions to flow through the Channelrhodopsins creating an electrical current, conversely, yellow light closes the ion channel, stopping the electrical current (Boyden et al. 2005). This gene is then inserted into an artificially constructed inert virus vector (normally used in gene therapy) to target specific types of brain cells. This depends on which virus vector is used, therefore allowing only intended cell types (in this case a neuron) to express the gene and respond to light without affecting other surrounding cells of a different type (Boyden et al. 2005). These neurons then synthesise the Channelrhodopsin protein and install it as part of its physical apparatus (Boyden et al. 2005).

Then rapid pulses of light are delivered through optical fibres and lasers to a mammalian brain, which depending on which series of light pulses are used, change neural and synaptic activity which then artificially induces a change in the mental state of the organism within a millisecond timescale (Boyden et al. 2005).

Optogenetics allows mental states (averse and otherwise) such as thought patterns and learning (Johansen et al. 2010), memory (Goshen et al. 2011), motor control and behaviour (Tsai et al. 2009; Lobo et al 2010; Witten et al. 2011; Stuber et al. 2012; Lin et al 2011) as well as the neuropathology of brain diseases like Parkinson’s (Gradinaru et al. 2009), mental illnesses such as schizophrenia (Yizar et al. 2011), Depression (Covington et al. 2010), anxiety (Tye et al. 2011) to be replicated, studied and even therapeutically controlled and manipulated using neuroprosthesis (Miesenböck et al. 2005; Zhang et al. 2007; Fortin et al. 2008; Arenkiel et al 2008; Nagel et al. 2003; Zhang et al. 2007; Huber et al. 2008).

 

There’s many potential future benefits that could arise from optogenetics research, including mapping the brain and behavior, applications in gene therapy in diseases such as Lebers Congenital Amaurosis ((you could use Adeno Associated Viruses to deliver missing components of the retina, namely the retinal isomerase), recovery of vision and treatments for epilepsy and Parkinson’s disease. So hopefully you are a bit more informed on the exciting and relatively recent technology that is optogenetics. For those who crave more technical information, please seek out the information in the references provided below.

 

[Note, the top image of the optogenetics mouse experiment has been adapted from http://www.genengnews.com/best-of-the-web/optogenetics-resource-page/2525/]

 

References:

 

  1. Boyden E, Zhang F, Bamberg, E, Nagel G, Deisseroth K: Millisecond-timescale, genetically targeted optical control of neural activity; Nature Neuroscience Volume 8, Number 9, September 2005 p.1263
  2. Johansen JP, Wolff SBE, Lüthi A, LeDoux JE (2012): Controlling the elements: an optogenetic approach to understanding the neural circuits of fear. Biol Psychiatry 71:1053–1060
  3. Haubensak W, Kunwar PS, Cai H, Ciocchi S, Wall NR, Ponnusamy R,et al. (2010): Genetic dissection of an amygdala microcircuit that gates conditioned fear .Nature468:270 –276
  4. Goshen I, Brodsky M, Prakash R, Wallace J, Gradinaru V, Ramakrishnan C, Deisseroth K (2011): Dynamics of retrieval strategies for remote memories. Cell 147:678 – 689
  5. Tsai H.-C., Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L, Deisseroth K. (2009): Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.Science 324:1080 –1084.
  6. Lobo MK, Covington HE 3rd, Chaudhury D, Friedman AK, Sun H, DamezWerno D,et al.(2010): Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.Science 330:385–390
  7. Witten IB, Steinberg EE, Lee SY, Davidson TJ, Zalocusky KA, Brodsky M,et al.(2011): Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement.Neuron72:721–733.
  8. Stuber GD, Britt JP, Bonci A (2012): Optogenetic modulation of neural circuits that underlie reward seeking.Biol Psychiatry71:1061–1067
  9. Lin D, Boyle MP, Dollar P, Lee H, Lein ES, Perona P, Anderson DJ (2011): Functional identification of an aggression locus in the mouse hypothalamus.Nature470:221–226
  10. Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K (2009): Optical deconstruction of parkinsonian neural circuitry.Science 324:354 –359.
  11. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ,et al. (2011): Neocortical excitation/inhibition balance in information processing and social dysfunction.Nature477:171–178
  12. Covington HE, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S,et al. (2010): Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.J Neurosci30:16082–16090
  13. Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H,et al.(2011): Amygdala circuitry mediating reversible and bidirectional control of anxiety.Nature471:358 –362.
  14. Miesenböck, G. & Kevrekidis, I.G. Annu. Rev. Neurosci. 28, 533–663 (2005).
  15. Zhang, F., Aravanis, A.M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Nat. Rev. Neurosci. 8, 577–581 (2007)
  16. Fortin, D.L. et al. Nat. Methods 5, 331–338 (2008)
  17. Arenkiel, B.R., Klein, M.E., Davison, I.G., Katz, L.C. & Ehlers, M.D. Nat. Methods 5, 299–302 (2008)
  18. Nagel G, Tanjef S, Wolfram H, Suneel K, Nona A, Peter B, Doris O, Peter H, Ernst B, Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).
  19. Zhang F, Li-Ping W, Brauner M, Liewald JF, Kay K, Watzke N, Wood PG, Bamberg E, Nagel G, Gottschalk A and Deisseroth K Nature 446, 633–639 (2007)
  20. Huber D, Petreanu L, Ghitani N, Ranade S, Hromadka T, Mainen Z and Svoboda K Nature 451, 61–64 (2008)
Dr. Christopher Haggarty-Weir
Dr. Christopher Haggarty-Weir

Vaccines, Immunology, Infectious Disease, Drug Discovery/Design, Molecular Biology, Business and Philosophy.

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