Technique: Optical stimulation with single neuron resolution

In the September Nature Neuroscience, we have a promising new technique: Millisecond-timescale, genetically targeted optical control of neural activity.

I think several people have suggested doing something like this before but no one has actually done it. What they’ve done is genetically modified (by lentivirus, for those curious) ordinary hippocampal neurons in culture, adding the same photo-electric transducing protein — rhodopsin — found in photoreceptors. Yup. You heard me right. They’ve expressed a cation-channel-gating rhodopsin in ordinary hippocampal neurons. With an standard fluorescence microscope (Xenon lamp + Chroma GFP cube), they can photostimulate single action potentials (and sub-threshold depolarizations) in single neurons.

Now here’s my idea for bioengineers to take this to the next level: Add a second photosensitive protein tied to an inhibitory channel. Ideally, we would want total separation between the stimulating wavelengths for the two different (excitatory, inhibitory) channels. Now, you have a system where all neurons can be directly excited or inhibited with different laser lines. In other words, a network of neurons where all voltages can be fully controlled. Sweet!

This seems like a great tool to add to the existing arsenal of photostimulation techniques (like photoelectric effect-based light-on-silicon stimulation that was pioneered by Goda lab.) Here’s a question: Is this the end of multi-electrode arrays? In slice, we already have single spike detection with Ca-sensitive dyes from Yuste’s lab. Now, we have optical single spike stimulation. Perhaps MEAs will be relegated to the domain implantable devices. Regardless, I’m proud to see several of the authors are from Stanford! Read on for the full abstract.

Millisecond-timescale, genetically targeted optical control of neural activity
Nature Neuroscience 8, 1263 – 1268 (2005)
Edward S Boyden1, Feng Zhang1, Ernst Bamberg2, 3, Georg Nagel2, 5 & Karl Deisseroth

Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technology allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.

5 thoughts on “Technique: Optical stimulation with single neuron resolution

  1. Once people start using fast voltage-sensitive dyes in awake behaving animals, and begin to approach the yield that we get with extracellular arrays, and get the ability to record from the same animal for an extended period (e.g., months) like we do with multi-channel arrays extracellular arrays will probably start to drop off in use. I’ll bet within 20 years we will start to see such techniques applied regularly (though 2-photon has been done in awake rats: For a while, it will only be the ridiculously well-funded labs, though…


  2. Pingback: neurodudes » Blog Archive » Web page tracking optical control of neural activity

  3. Memory-encoding can be enhanced by norepinephrine. But is there a way to study this, in the intact brain, and with faster time resolution?

    This problem has now been solved: the Khorana lab at MIT has engineered a light-activated adrenergic receptor, by mixing the light-activated parts of mammalian rhodopsin, with the intracellular loops of the adrenergic receptor.

    Kim JM, Hwa J, Garriga P, Reeves PJ, RajBhandary UL, Khorana HG.
    Light-driven activation of beta 2-adrenergic receptor signaling by a chimeric rhodopsin containing the beta 2-adrenergic receptor cytoplasmic loops.
    Biochemistry. 2005 Feb 22;44(7):2284-92.

    Note that this method could be used to make light-activated serotonin receptors, dopamine receptors, etc.


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