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Developmental biology - Brain function|
How Visual Experience Affects Learning
The work is published in eLife,
Tadpoles have naturally translucent skin — which makes them an excellent model for peering into the wirings of a living brain. Kept in the dark for four hours and then exposed to either ambient light (in the control group) or a screen with moving bars (in the experimental group), the tadpoles had unique responses.
Working closely with Professor John Yates, PhD, of the Scripps Research Department of Molecular Medicine, Cline's team measured changes in proteins expressed before and after each experiment and found expression of 83 proteins shifted either up or down in the experimental group.
Many of these 83 proteins were effector proteins responsible for routine jobs in cells. But, three were unique: eIF3A, FUS and RPS17. These are regulatory proteins that construct molecules that bind to a selected protein in order to regulate its function. In this manner they can increase or decrease gene expression, or cell signals between cells. Cline was surprised. She and her colleagues always thought regulatory protein expression would hold steady even if visual stimulation varied.
"The idea that visual experience can influence how we make proteins is something brand new. This is interesting to think about because we live in a very busy sensory world. We just thought the regulatory machine would be just humming along. So, we were surprised to see them on our list. We thought, 'Is this accurate? Is this true?'"
It turns out these regulatory proteins are essential for learning from visual experience. Cells are better at building connections and reinforcing learning when they synthesize these proteins during visual exposures. In fact, researchers could tag neurons with fluorescent proteins to follow the physical signature a visual experience left on a tadpole brain. Thanks to eIF3A, FUS and RPS17, tadpoles had significant neuron growth — expressed as branch-like tendrils extending from neurons — after just four hours of a unique visual experience.
Next, the scientists investigated whether changes in protein expression affected tadpole behavior. How important were these proteins in teaching tadpoles? To find out, researchers took advantage of a natural tadpole behavior: their instinct to avoid any large shape that may be a looming predator. Researchers had tadpoles swim above a screen that projected large, predator-like spots, then tracked whether a tadpole would turn to avoid the dark spots.
Tadpoles with exposure to visually large spots did significantly better on the avoidance test than tadpoles in the control group.
This suggests they had formed the neural circuits to better process visual information. Interestingly, tadpoles did not do as well on the test — even after exposure to visual experience — when they could not express all three of those key proteins (eIF3A, FUS and RPS17). This finding further confirmed the importance of these regulatory proteins.
Finally, researchers were curious whether the 83 proteins they identified were expressed differently in human brain disorders. So, they cross referenced their list with two databases — one of people with risk factors for autism spectrum disorders, and one with people with fragile X syndrome, which has similar characteristics as autism.
The results came as a surprise. Twenty-five percent of the proteins on the Scripps Research list overlapped with the database lists of genes thought to cause autism spectrum disorder and fragile X syndrome. That was a much bigger number than expected and prompted new questions about what makes an autism "risk factor" actually risky.
Cline thinks mutations in regulatory proteins might keep some people from expressing the proteins needed for processing sights, smells, textures, tastes even sounds. Future studies could focus on understanding all of the 83 synthesized proteins. She is also reconsidering the visual experiences humans take in every day.
"This brings to mind a new dimension for understanding autism. It's fascinating to think how sensory experience affects the brains of our children. We may wittingly or unwittingly be affecting how their brains develop."
Experience-dependent synaptic plasticity refines brain circuits during development. To identify novel protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we conducted a quantitative proteomic screen of the nascent proteome in response to visual experience in Xenopus optic tectum using bio-orthogonal metabolic labeling (BONCAT). We identified 83 differentially synthesized candidate plasticity proteins (CPPs). The CPPs form strongly interconnected networks and are annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs revealed the requirement for eukaryotic initiation factor three subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity in tectal neurons and behavioral plasticity in tadpoles. These results demonstrate that the nascent proteome is dynamic in response to visual experience and that de novo synthesis of machinery that regulates RNA splicing and protein translation is required for experience-dependent plasticity.
Authors: Han-Hsuan Liu, Daniel B McClatchy, Lucio Schiapparelli, Wanhua Shen, John R Yates III, Hollis T Cline.
The study was supported by the National Institutes of Health (grants EY011261, EY019005, MH099799, MH067880 and MH100175), DartNeuroScience LLC, the Helen Dorris Foundation and an endowment from the Hahn Family Foundation.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu.
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Transparent Xenopus (frog) tadpoles provide an easily measured target for watching neurons grow.
Commonly known as the clawed frog, they are highly aquatic and native to sub-Saharan Africa.
Image credit: Public domain