Neurology Central

Sonogenetics – a new approach to manipulating neurons noninvasively

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As we continue to unravel the language of the brain, it becomes evident that precise firing patterns of different cell types in appropriate brain regions must work in concert to orchestrate the symphony of the mind.  Indeed, Francis Crick, several decades ago, predicted that one of neuroscience’s major hurdles would be learning to manipulate specific neurons in order to learn more about their function.  He was not wrong: the immense complexity of the brain makes it difficult to say with certainty that any observed neuronal physiology is causally linked to some observed phenotype; there are so many processes and so many interconnections that correlations can emerge seemingly out of anywhere. Given that neurons and other cell types in the brain communicate with each other using changes in electrochemical gradients, electrodes and magnetic fields were initially used to manipulate target cells.  While these approaches can target certain brain regions, they cannot discriminate between cell types.  The mouse brain has approximately 92,000 cells/mm3 (perhaps upwards of 100,000 cells/mm3 in a primate) [1] and one billion synapses [2]. So, even the smallest possible activation zone of the electrical and magnetic fields (in the order of cubic millimeters) contains many neurons and other cell types as well as a multitude of diverse synaptic connections.

One approach to localize the activation of target cells within a heterogeneous cell population was the development of a new technique that used genetic and chemical components to confer light sensitivity to neurons [3, 4]. In 2005, two research groups independently improved these methods (now dubbed ‘optogenetics’) when they used microbial opsin genes to convey light sensitivity to neurons controlling their activity [5, 6]. These opsin proteins are ion channels that are embedded in the plasma membrane of the target neurons and, when activated with the appropriate wavelength of light, undergo a conformational change that allows ions to flow through their pores. The most commonly used opsin, channelrhodopsin, isolated from the bacteria C. reinhardtii, is sensitive to blue light and includes seven transmembrane alpha helixes along with a pocket for binding all-transretinal. Channelrhodopsin depolarizes the target neurons by allowing cations (Na+, K+, Ca++ and H+) into the cell [7]. All-transretinal absorbs a proton, which promotes the conformational change in the protein that relaxes in milliseconds [7, 8]. This allows scientists to induce action potentials at high temporal precision.

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