. Multimodal fast optical interrogation of neural circuitry. Nature. 2007 Apr 5;446(7136):633-9. PubMed.

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  1. This article describes very concrete applications for a class of optically-activated ion channels/pumps based on the rhodopsin protein. These light-activated G-protein coupled receptors can be genetically manipulated and expressed in many cell types in order to control electrical excitability. They are therefore powerful tools for neurophysiology. This study describes the kinetics and functional output of the excitatory channel rhodopsin (ChR2) and the inhibitory halorhodopsin (NpHR); the former activates a non-selective cation channel while the latter actives a chloride pump. These and other genetically encoded rhodopsins were discussed in a recent Cold Spring Harbor meeting on Imaging Neurons and Neural Activity, and are neatly outlined in a review by Herlitze and Landmesser (2007).

    This novel approach allows for ‘hands free’ manipulation of neuronal activity simply by exposing the rhodopsin-expressing cells to light of a select wavelength. In certain proteins, such as the two discussed in this study, the excitation wavelengths are distinct, and therefore can be co-expressed and controlled independently. The beauty is in the design, and the details are being ironed out in studies such as this. Optically controlling neuronal activity, rather than direct electrical stimulation, is powerful for several reasons. Importantly, it removes the invasive and potentially confounding stimulating electrodes from the tissue preparation. It also permits precise spatial, as well as temporal, control when activating individual cells or circuits. By changing the light source aperture, individual cells, subcellular compartments, or entire regions of tissue can be selectively activated. This level of spatial resolution is one of the more intriguing, and novel, aspects of optical stimulation. Changing the temporal or intensity parameters can control the duration or amplitude of the ion flux, similar to extending the pulse duration, or increasing the current intensity, of conventional stimulating electrodes – yet without the spatial control. When combined with existing optical indicators, such as Ca2+- or voltage -sensitive dyes, many of the invasive techniques conventionally used to probe neuronal activity are obviated, such as electrodes and sensors. The authors here take the degree of manipulation one step further and control the movements of entire organisms – shedding light on much untapped potential with this technique.

    The widespread use of genetically-encoded rhodopsins is still, for the time being, limited by the techniques required to get these vectors into, and expressed by, neurons and other cells. Viral vectors, electroporation, and other transfection tools are not amenable to all preparations or protocols. Here it is a case of molecular techniques keeping up with the biological application. Hopefully it is just a matter of time before inserting these proteins into cells of choice becomes commonplace. Certainly, for experimental purposes, the development of transgenic mice will be invaluable. As a tool, many may feel that optogenetic techniques are inherently simpler to use and more precise in its ability to control cellular activity than conventional electrical stimulation and recording. Yet, imprecision exists in the variability of expression patterns and levels associated with all exogenously expressed proteins. In addition, the tunability of channel flux still appears rather limited, and the cellular output response can depend largely on the subcellular channel/pump distribution, as well as endogenously expressed regulators and buffers. Hopefully, genetic alterations to these optically activated channels can improve their functional characteristics, analogous to the development of eGFP and the XFP variants. Plasticity studies, transgenic animals, and human applications will hopefully soon follow.

    My feeling is that once some of the mundane and practical hurdles are overcome, optogenetic techniques will not only stay, but provide vastly new insight into neuronal circuitry. Its use as a therapeutic clinical tool are already being discussed as potential improvements to deep brain stimulation for Parkinson’s, recovery of neuronal function in select brain regions such as in Alzheimer’s, injury, and stroke, and activation of entire circuits to restore sensory and motor system impairments. In theory, these are viable applications for optical stimulation of light-sensitive receptors. And, because of the potential power of ‘optogenetics’ , many research groups will likely make the concerted effort to characterize and improve these proteins, and make them accessible for both basic research and clinical realms.

    References:

    . New optical tools for controlling neuronal activity. Curr Opin Neurobiol. 2007 Feb;17(1):87-94. PubMed.

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