Alternative Light-Sensitive Proteins Expand Brain Cell Research

Opsins are light-sensitive proteins that have been put to great use in the field of optogenetics-the control and monitoring of neurons in various cells through exposure to specific wavelengths of light. For optogenetic studies, neurons are modified by scientists and engineered to express opsins that alter voltage via ion transport across cell membranes. When these opsins are exposed to light, they change the voltage and either halt a neuron's firing (through lower voltage) or stimulate it to fire (through higher voltage).

Optogenetics is often used to study brain cells to determine the functions of different cell types, because the effect of the opsins is reversible and extremely fast-the response time is in the millisecond range, allowing for real-time feedback. The downside of opsins is that they all tend to work in the same lower wavelength blue-green light ranges, and thus only one population of cells can be studied at any one time. Opsins that responded to other wavelengths of light also responded to blue light, and that lack of selectivity ruled out simultaneous use. However, thanks to work by a diverse research team, at least one opsin has been identified that is sensitive to longer wavelength red light without blue overlap-allowing for independent activation of two different populations of cells and real-time study of interactions between cell populations.

The team, whose work was published in a recent online edition of Nature Methods, included members from MIT, the University of Pennsylvania, the University of Alberta, the Howard Hughes Medical Institute, the Beijing Genomics Institute and the University of Cologne.

Opsins are typically found in varieties of bacteria and algae, and earlier attempts at improvement focused on modifying naturally occurring opsins to expand their utility. These attempts did not succeed, because attempts to strengthen one property generally weakened other useful properties. Rather than search for further modifications, the research team took a different approach and undertook a massive search for other natural opsins with high efficiency and sensitivity to different wavelengths of light.

The search began with sequencing of transcriptomes (genes expressed by cells) from 1,000 plants, including multiple algae strains. Any sequences that were thought to contain code for opsins were subjected to further testing in brain tissue for the ability to respond to light at various wavelengths. This search yielded an effective red opsin that responds to 735 nm (nanometer) wavelengths, and a new opsin that is sensitive to blue light but has a greater speed and around 5-6 times higher sensitivity to dim light than existing blue-sensitive opsins. These new discoveries, known as Chrimson and Chronos respectively, can lead to major advances in the understanding of brain function through more effective use of optogenetics.

Aside from the ability to simultaneously study two cell populations and their interactions, there may be other avenues of study enabled by these new opsins. For example, scientists can move beyond manipulation of a particular cell population to secreting neurotransmitters, controlling upstream cells that can have a separate effect on the population under study. Also, since red light is typically gentler on tissues than blue light, opsins may be able to assist in future therapeutic uses, such as partial restoration of vision from lost photoreceptor cells.

Research is likely to continue in both areas-finding new, more selective and sensitive opsins, and using them to expand knowledge in biosystems, leading to practical applications.