Restoring Embryonic Vision
The cavefish that Soares anticipates could yield such neurobiological insights is Astyanax mexicanus. Several inches in length and able to be bred in the laboratory, the species has a single surface-dwelling form and several cave-dwelling forms.
“The cave dwellers are born with eyes but then undergo developmental changes so that the eye basically dies as the fish grows,” Soares explains. "The lens atrophies and is genetically programmed to die, then the whole eye sinks into the orbit and disappears. The cave dwellers are programmed for this cell death and raising larvae in the light does not change that.”
For their research, Soares and her students will restore sight in one eye of cavefish larvae by transplanting a lens from surface-relative donors, lenses that will not die as the cave dwellers grow. She will examine if that restores the function of the retina and visual part of the brain.
“With vision in one eye restored, the basic question we will be asking is what does this mean for the brain,” Soares says. "How well can the fish see, or can they see at all? We intend to study their subsequent behavior, brain activity and anatomical changes using techniques such as calcium imaging to understand how the brain adapts to having vision again.
“We know already that the part of the brain associated with the viable eye will be bigger. But does this mean it has more cells, more connections, and what does this larger area mean in terms of behavior?”
In addition to assessing behavior, Soares is intrigued by questions such as the developmental influence of the lens itself. She says we know that programmed cell death of the lens is responsible for the retina eventually degenerating as the cavefish grow. So the lens in fish that retain sight most likely creates conditions that keep the retina alive.
Another question, one bearing on neural plasticity, is the degree to which the visual part of the brain is malleable after the restoration in the sight of one eye. It’s Soares’ expectation that not only will there be more connections from the retina itself, but different types of connections. There may be different types of cells and more of certain types.
Is Restoration Relevant?
It is also uncertain as to how the fish will use restored vision, or if it will use visual information to behave. Because they have evolved to become blind, Soares says that other sensory modalities may still predominate for making behavioral decisions.
“Some behavioral experiments indicate that when the larvae are small and still have eyes they use visual information to catch prey, for example. But after a certain age they switch from visual information to tactile information — sensing the movement of prey that they ‘feel’ with receptors in their skin. This is something that the closest living surface relative that we also have in the lab doesn’t do.
In a broader context, the knowledge of neurobiology and neural plasticity that could be gained from this research may have significant human implications. In terms of vision, it could add to our understanding of diseases such as macular degeneration, possibly leading to better management and treatment.
Further, Soares says, we really don’t understand what happens in the brain when a sensory modality is restored. One example she cites is the experience of some people with compromised hearing after they receive successful cochlear implants. She adds, “It’s an interesting phenomenon that sometimes people who get this modality back ultimately decide that they don’t want it. They take the implant out or just don’t use it. It’s sensory overload, it’s too much for them.
“In essence, there may be a period of plasticity in the brain that’s more receptive to such changes. But when it passes, the brain may have trouble processing the restored input and a person may be more comfortable without the sensory modality. For example, they may find that it’s far too difficult to focus on one conversation in an environment with background noises.”
The support that Soares has received from the National Institutes of Health will allow her and the students in her lab to investigate these questions over the next several years. They may also encounter exciting unknowns. She says, “This grant is terrific because it gives us the opportunity to explore various ideas that I’ve been trying to understand for a long time, which may very well lead to even more questions. That is the nature of science.”