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A pronghorn antelope in the Grand Teton National Park captured by a DSLR camera using the image stabilization function (left). The image on the right was artificially blurred to simulate vision without the work of direction-sensitive ganglion cells. Image Credit: Johns Hopkins Medicine

How our brain plugs in vision stabilization

A new study reveals how important neurons find their way from the retina to our inner brain.

Just as most cameras have an autostabilization feature to compensate for movement during picture taking, our eyes execute an imperceptible reflex that prevents our vision from blurring when we, or our field of vision, are in motion. But before that reflex can work, wirelike projections (axons) of specialized nerve cells must travel from the retina to an exact area of the developing embryonic brain. New research, published in the journal Neuron, describes how these axons make their connection. The finding has implications for treatment of eye movement disorders as well as regeneration of damaged vision-sensing nerve cells.

"Our eyes are constantly making small adjustments to keep our vision from getting blurry as we move our heads. Specialized cells in our retina convey direction specific information to our brain, which then directs compensating eye movements. Now, we better understand how the axons from these neurons get to where they need to be."

Alex Kolodkin, Ph.D., professor of neuroscience, Johns Hopkins University School of Medicine, and a Howard Hughes Medical Institute investigator.

The neurons in question are a type of direction-sensitive ganglion found in the retina. Each subset of these neurons is in charge of monitoring vertical, horizontal, forward and backward movements. Kolodkin and his group identified the cells that specifically report slow, vertical movement to the brain — what one might experience looking straight ahead while riding a Ferris wheel. Recent work from another research group revealed that slow, vertical movement cells connect their axons to an area of the brain called the medial terminal nucleus (MTN), but not how they reached the MTN during fetal development.

For years, Kolodkin has been studying how nerve cell axons arrive at precise locations in the brain. As part of his work, his group discovered guidance proteins called semaphorins (Semas). Their previous work had shown them that the Sema6A protein is required for axon connections within the visual system of the brain. So, the researchers began looking for Sema6A protein in their vertically sensitive cells. After identifying Sema6A was present on the membranes of mouse cells, Lu Sun PhD, first author on the study, genetically deleted Sema6A from mice to assess its exact function. The mice displayed as normally developed during their early embryonic period. However, their axons couldn't recognize when they had reached their target in the brain and retracted. This left the mice unable to appropriately adjust their eyes while viewing vertically moving stripes.

If Sema6A was helping guide the axons, the researchers determined that something must exist within the target region of the brain for the cells to recognize in order to establish axon connection. As the Sema6A protein usually interacts with a class of proteins called plexins, the team then looked for plexin proteins in the MTN region of the brain.

But something was curious to the research team: "Normally, Sema6A acts as a bait for plexins, not the other way around," noted Kolodkin.

To determine how plexins were actually working in this scenario, Kolodkin's team genetically removed plexins from retinal neurons, while maintaining normal levels of Sema6A. If axons needed plexins in order to be guided to their brain target region, their removal would make that connection fail. But they didn't. The plexins in the MTN region were sufficient to coax the Sema6A-laden axons home. This establishes that Sema6A acts as a receptor on the axon cells, recognizing plexins in the target region to allow circuits to be formed, explains Kolodkin.

The researchers hope identifying these protein connections will help substantiate what is behind eye movement disorders — as well as nerve regeneration. Specifically, the team's use of moving stripes and infrared light to monitor eye movement can be used to show whether vision can be restored in mice where nerve regeneration is required following eye injury. In the future, they also plan to isolate how these circuits ultimately wire muscles that control eye movement.

Abstract Highlights

•Sema6A is expressed in On DSGCs innervating AOS brain targets

•Sema6A is required for the development of AOS axon trajectories

•PlexA2 and PlexA4 serve as attractive ligands for Sema6A+ On DSGCs

•PlexA2/A4-Sema6A reverse signaling facilitates compensatory eye movements

Summary
Accurate motion detection requires neural circuitry that compensates for global visual field motion. Select subtypes of retinal ganglion cells perceive image motion and connect to the accessory optic system (AOS) in the brain, which generates compensatory eye movements that stabilize images during slow visual field motion. Here, we show that the murine transmembrane semaphorin 6A (Sema6A) is expressed in a subset of On direction-selective ganglion cells (On DSGCs) and is required for retinorecipient axonal targeting to the medial terminal nucleus (MTN) of the AOS. Plexin A2 and A4, two Sema6A binding partners, are expressed in MTN cells, attract Sema6A+ On DSGC axons, and mediate MTN targeting of Sema6A+ RGC projections. Furthermore, Sema6A/Plexin-A2/A4 signaling is required for the functional output of the AOS. These data reveal molecular mechanisms underlying the assembly of AOS circuits critical for moving image perception.

Other authors of the report include Colleen Brady, Hugh Cahill, Timour Al-Khindi and Jeremy Nathans of the Johns Hopkins University School of Medicine; Hiraki Sakuta and Masaharu Noda of the National Institute for Basic Biology in Okazaki, Japan; and Onkar Dhande and Andrew Huberman of the University of California, San Diego.

This work was supported by grants from the National Eye Institute (RO1 EY022157-01), a Pew Scholar Award and the Howard Hughes Medical Institute.

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