Most people take motion sensing for granted. Our eyes pick up on something moving and our brains are sent a signal to let us know something has occurred in our space-time continuum. Despite the simplicity of the task, the mechanisms allowing us this ability are incredibly complex. They have been studied for over fifty years and the neural circuitry underlying motion detection is probably the best described circuitry in the brain. Yet, researchers have not discovered all the answers.
At the back of the eye is the retina, which essentially acts as the recorder and translator for higher visual centres in the brain. Light enters the pupil and through a multi-layered process, complex images are simplified and translated into an electrical code (consisting of strings of 0 and 1s, much like a computer). Specialized retinal circuits working parallel are used to encode various aspects of the visual scenes including color, motion, form etc. To accomplish this task, a variety of cell types are needed including:
- photoreceptors, the rods and cones, which respond to dim and bright light, respectively;
- bipolar cells, which bridge photoreceptors to output retinal ganglion cells (RGCs);
- Inhibitory amacrine cells, which control bipolar cell signals to RGCs; and
- RGCs, which amalgamate signals from bipolar and amacrine cells to create a binary code; they send this information to higher visual centres via their long projection cables constituting the optic nerve.
The direction of moving objects is computed by specialized set of RGCs – aptly named direction sensing cells – which respond to motion only along a ‘preferred’ but not ‘null’ direction, aligned with the cardinal axes (N,S E or W). Research into the mechanism behind direction sensing has implicated three neurotransmitters: glutamate, acetylcholine (usually called ACh) and gamma-aminobutyric acid, more popularly known as GABA. Generally speaking, bipolar cells use glutamate to activate direction sensing cells (and they do so regardless of direction).
Much of the ability of RGCs to encode direction arises from inhibitory signals evoked in the cells during null direction motion, provided by a particular group of amacrine cells, known as starburst or SACs. However, the same SACs producing critical inhibitory signals required for direction selectivity also send excitatory signals, through the release of ACh. The enigma of what might be best described as applying the brake and the accelerator at the same time has confused researchers for several decades.
There may now be an answer to this long-standing conundrum. A recent study by a team led by Dr. Gautam Awatramani at the University of Victoria, has uncovered how SACs achieve this combination of excitation and inhibition. Their results, which may forever change the way we see direction in the space-time continuum, are now available in the journal Neuron.
The team worked in the lab using retinas isolated from mice. The organs were kept ‘alive’ in a dish by providing it with oxygen and other nutrients. This allowed the RGCs to continue responding selectively to particular direction. The setup provided a unique preparation for probing the properties of an intact neural circuit.
The method of measurement was just as intricate as they used finely pulled glass electrodes to measure electrical responses from single cells. Using a procedure known as a voltage clamp they could identify the physiological properties of direction coding circuits with incredible resolution. This also allowed the team to test the effects of alterations such as drugs to inhibit certain neurotransmitters and optogenetic analyses.
As these experiments were performed, an interesting picture began to develop. As expected, they found SACs provided under natural viewing conditions both excitatory and inhibitory signals required for RGCs to produce direction selective signals. But they could finally see how the brake and accelerator signals worked together. It turns out SACs ACh/GABA signalling had an incredibly precise timing schedule.
During non-preferred directions of movement, SACs sent out ACh and GABA at the same time leading to a net inhibition of the RGCs. But when the preferred direction was recognized, ACh signals were produced a few milliseconds before GABA signals. This short but effective shift led to a strong stimulation the RGCs. This maintained the recognition of space in the form of direction and also time, even if it would be imperceptible to most.
The result was not only fascinating but also controversial. The idea SACs alone could drive direction coding went against an emerging theory stating the drivers of direction selectivity were the bipolar cells http://www.nature.com/nature/journal/v509/n7500/full/nature13240.html . To substantiate that SACs alone could drive direction selectivity in RGCs required Awatramani’s team to take their study of SACs to another level using optogenetics. This technique allowed them to directly manipulate genetically modified SACs using light and prove their results conclusively.
The actual experiment involved first blocking photoreceptors and bipolar cells with drugs so they would not send any signals; under these conditions if any direction was sensed and coded, it would have had to come from the SACs, which were genetically modified to be themselves light-sensitive. When they stimulated the SAC network, sure enough, the RGCs responded in a direction selective manner. The experiment was a complete success, nailing down the role for SAC ACh and GABA in the direction selective circuit.
The results of this study provide on a scientific level a better understanding of the complexity of direction sensing and offer a mechanism upon which future experiments can be designed. However, on a grander scale, the results suggest co-release of GABA/ACh SACs may be a perfect model for ensuring high fidelity inhibition/excitation in other parts of the brain. By having a multi-purposed “cell” with the capability of sustaining signal integrity, high-fidelity neural computations can be maintained under diverse conditions. This may ultimately serve to help improve computer network design, internet reliability, and even the resolution of audiovisual devices.
Original research article:
Sethuramanujam S, McLaughlin AJ, deRosenroll G, Hoggarth A, Schwab DJ, Awatramani GB. A Central Role for Mixed Acetylcholine/GABA Transmission in Direction Coding in the Retina. Neuron. 2016 Jun 15;90(6):1243-56.
