Biochemists rejoice as they receive optogenetic control of signaling pathways
Optogenetic tools have already changed the face of neuroscience research. From its humble beginnings as a cation-selective algal channel, channelrhodopsin and its variants have been employed to do many things:
- Drive neuronal firing in a dish
- Drive perceptual learning in the rodent and influence decisions
- Demonstrate the role for nociceptive neurons in larvae escape behavior from parisitoid wasps
- Initiate sleep state transitions when expressed and activated in orexin-producing neurons
- Assist in identifying the circuit responsible for zebrafish escape behavior
- Assist in the fine-scale mapping of cortical microcircuits
But all these experiments involved a direct manipulation of the electrical circuitry connecting various brain nuclei or cortical layers, making this channel the darling of the electrophysiologists’ world. What about the biochemist? Yeah, that guy/gal pouring neurotoxic acrylamide gels to assist in the dissection of signaling pathways, asking which phosphorylated protein was connected to another, either physically or functionally. They like light too, don’t they? (at least when we let them out of the basement lab…). (cont.)
Well fret no longer, Mr/s. Biochemist. The lab of Karl Deisseroth has introduced to you a brand new set of optogenetic tools designed for the manipulation of signaling pathways with the specificity of genetic targeting and the precision of light control. In their new paper, published AOP in Nature today, Deisseroth and colleagues demonstrate the use of chimeric GPCRs — with the external bits of rhodopsin for light activation and the internal bits of either the β2-adrenergic receptor or the α1-adrenergic receptor. These adrenergic receptors are coupled to different G-protein signaling pathways, which can influence excitability in neurons and alter the threshold to fire action potentials. Since only the internal portions of the adrenergic receptors are used, there are no additional signaling responses by the chimeras when catecholamines are released, only upon light exposure.
In the paper, the authors demonstrate that these tools are not only functional in vitro, but also in vivo. In a really cool experiment, the OptoXRs (as they are called) were expressed in the nucleus accumbens, known to play a role in reward-based signaling in the brain. A conditioned place preference (CPP) experiment was carried out where the signaling pathways in the NuAcc neurons were turned on using a fiber optic cable every time the freely moving mouse was in a particular corner of the cage. This was designed to mimic reward. In subsequent trials, the mice spent a significantly longer period of time in the corner where the light bursts were delivered, the same behavior rodents display when they receive a drug or food reward in a particular spot. So not only did the optogenetic activation influence behavior, it essentially acted as a surrogate for reward. In theory, from the reward circuitry perspective, the mouse could not discern actual reward from reward circuit activation. Man, does this open up a lot of doors for future work…
Only time will tell what other neuroscience labs will be able to accomplish with these new toys, but at least now the biochemists can join the light-activated party.
Airan, R., Thompson, K., Fenno, L., Bernstein, H., & Deisseroth, K. (2009). Temporally precise in vivo control of intracellular signalling Nature DOI: 10.1038/nature07926