Using optogenetics, two researchers challenge our notions of movement and offer new and more reliable ways to model movement disorders in animals.
Modern science is technically challenging, often requiring large, multi-faceted groups of scientists to publish in the best journals. Harking back to days of yore, emulating two of my personal electrophysiology heroes Hodgkin and Huxley (see their two-author, seminal series of five back-to-back papers defining the nerve action potential 1952a, 1952b, 1952c, 1952d, and 1952e), two researchers from The Howard Hughes Medical Institute’s Janelia Research Campus in Virginia have bucked the trend. Eric Yttri & Joshua Dudman’s elegant behavioural optogenetics study, upending how we view motor control, is both technically bleeding-edge yet beautifully simple, and is now published in Nature.
Optogenetics is a technique that uses ion channels (proteins that control the electrical activity in nerves/neurons, and hence generate nerve impulses or action potentials along neurons) genetically engineered to be opened by light. Different ‘flavours’ of these light sensitive ion channels allow the electrical activity of neurons to be finely tuned: one type, opened by a specific light frequency, can increase neuronal excitability, firing more action potentials; a second, activated by a different light frequency, can inhibit or dampen neuronal excitability. From my perspective, as a neuroscientist studying ion channels, the vistas of research opened up by optogenetics are wide and exciting; the ability to control neuronal excitability at the flick of a light switch has incredible potential to advance neuroscience. Though biased, I’m not the only one enthralled by the potential that optogenetics offers: Nature made it their Method of the Year in 2010 (you can watch their YouTube video here) and I’d be surprised if Karl Deisseroth, a key founder and proponent of optogenetics, doesn’t receive a call from the Nobel Prize committee in the next few years.
Though offering great potential in new avenues of research, optogenetics does have some technical hurdles that need to be overcome in order for the benefits of this technology to be fully realized. Key amongst these is how to deliver the light to the neurons expressing your light-sensitive ion channels. Flexible fibre optics can deliver laser light, but require tethering power cables affecting behavioural studies. University of Illinois-Urbana scientists Sun II Park et al., created a small, flexible implant with radio-frequency powered light-emitting diodes to supply light without the tethering cables. Their findings were described last year in Nature Biotechnology and detailed in this blog by Dr. Sarah Lilley, University of Sussex. Another problem—the invasive nature of fibre-optics—has also been addressed recently by Harvard scientists Sedat Nizamoglu et al., in their recent study in Nature Communications: bioabsorbable light guides were created that could deliver laser light to deep tissue areas for optogenetics-based treatment, and following light treatment would break down naturally in the body, removing the need for further invasive surgery.
A gear shift in thinking
Using optogenetics to control the electrical excitability of specific neurons in mice basal ganglia, Yttri and Dudman turn present thinking of motion control on its head. Till their paper it was thought that in the basal ganglia two types of neuron controlled the speed of voluntary movements: one type acted to promote (like the accelerator pedal in a car) whilst another type suppressed movement (like the brake pedal). In their study, which was conducted in mice, this dogma was challenged: their experiments found that both types of neuron, when optogenetically stimulated, could speed up the trained mice movements; if mice were trained to make slow movements, both types of neurons, when stimulated, would lead to even slower movements. In other words, control of motion is more complex than originally thought, with both ‘accelerator’ and ‘brake’ neurons able to speed-up or slow down movements, and both being used in concert to finely control movement. Dudman likens this combined accelerator-brake control to a race-car driver speeding around a circuit: the driver doesn’t simply independently speed up or slow down but actually uses a combination of accelerator and brake together to make carefully controlled and fast turns around the circuit.
These movement studies have implications for disease states where control is impaired. For instance, Parkinson’s disease (PD) patients have slowed movement, and even loss of control over their movements. To investigate the implications of this research in PD, Yttri and Dudman mimicked the loss and death of dopamine-secreting cells that are symptomatic of PD by injecting mice with dopamine blockers. The optogenetic stimulation that previously increased or decreased movement speed now had no effect. When I emailed Dr. Dudman (full disclosure: he’s an old friend from our time together at Columbia University, so there may be a hint of bias in choosing his paper) it was obvious that this aspect of his study was what excited him the most:
“[Our study helps to] explain one of the most pervasive phenotypes of Parkinson’s disease: bradykinesia,” he told me. “There really isn’t a good quantitative account of this in existing models, but we can fit the PD phenotype perfectly.”
In conclusion, Yttri and Dudman’s study is a great example of optogenetics used to control and define animal behaviour, and in so doing provide a more robust and accurate hypothesis of motion control in animal (and hence human) physiology and pathophysiology.
Perhaps, most importantly, it may provide the first reliable animal model for the study of diseases like PD.
How to cite:
Bell, Damian. Lights, experiment, action. Eureka blog. June 14, 2016. Available: https://eureka.criver.com/lights-experiment-action/