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Oregon researchers have identified the pathway that shifts the brain from plasticity to stability

The work in the developing nervous system of Drosophila larvae includes the same cells and genes as the human brain

Eugene, pray. – April 8, 2021 – Researchers exploring the evolution of the central nervous system of fruit flies have identified nonelectric cells that transform the brain from higher plastic to a less formable and mature state.

The cells, known as astrocytes for their star-like shapes, and the genes associated with them, could eventually become therapeutic targets, said Sarah Ackerman, a researcher at the University of Oregon who led the research.

“All of the cell types and signaling pathways that I’ve looked at are in humans,” Ackerman said. “Two of the genes I have identified are susceptible genes associated with neurodevelopmental disorders including autism and schizophrenia.”

She added that failure to close the so-called critical periods of brain plasticity in development, when learning occurs quickly and helps shape the brain, is also associated with epilepsy.

The discovery is detailed in a paper published online April 7 in the journal Temperate nature. The research was performed in the laboratory of the Neuroscience Institute of co-author Chris Doe, a researcher at the Howard Hughes Medical Institute and a professor in the Department of Biology at the University of Oklahoma.

Astrocytes are glial cells that are found in large numbers in the central nervous system. They play a variety of roles depending on which areas of the brain and spinal cord they are active in. They are “protectors of clamps in terms of ensuring their proper functioning in both their formation and their subsequent performance,” Ackerman said.

In the research, Ackerman focused on the motor circuits of Drosophila melanogaster larvae at specific points under development. These invertebrate fruit flies are standard research models that are easy to open for rapid genetic exploration of molecular mechanisms.

Ackerman used optogenetics, a light-based technique, to selectively turn off and on motor neurons. And it found that these neurons show surprising changes in their shape and connections – plasticity – in response to the manipulation processes.

Intriguingly, Ackerman and his colleagues watched astrocytes flow through the nervous system, enlarging subtle projections and encapsulating neural connections in time to transform circuits from plastic to steady state.

Ackerman then examined the candidate genes associated with astrocytes to identify the molecular pathways directing the window to turn on and off kinematic plasticity.

This work directly pointed to neuroligen, a protein on projections of astrocytes, which binds to norexin, a receptor protein on the dendrites of developing neurons. Elimination of this genetic pathway resulted in increased plasticity, while early expression of these proteins closed the plasticity very early in development.

Such changes in the timing of plasticity were also found to later affect the behavior. The extension of plasticity resulted in an abnormal creep of the larvae. Ackerman said that extended periods of flexibility critical to human development have been linked to neurodevelopmental disorders.

Du said one tragic human example of how important this critical period might be was the case of abandoned Roman children found in an orphanage in the 1980s. News reports say hundreds of children have been neglected except when fed or washed.

Du said neglect would have occurred during that key period of plasticity when experiences and learning cause the formation of the brain. When four out of five children were later removed from the orphanage, they were unable to integrate into society, according to research that has followed children into adulthood.

“My work is designed to understand the reasons for the shift from having a really flexible and resilient child’s brain to a more stable and stable brain,” Ackerman said. “Instead of focusing on neurons, I found that these wonderful star-shaped cells called astrocytes come into the nervous system and ask the neurons to switch from being really flexible to being stable.”

Du said the implications for Ackerman’s research could be profound.

“If we can understand the mechanism of closing this critical developmental period, we can reopen resilience in older adults who want, for example, to learn a new language or learn a new task,” Du said.

University of Oklahoma researchers say this therapeutic potential is far-fetched, but a major future goal. Ackerman’s research would then move on to similar studies in vertebrates, specifically using zebrafish, which were developed to become a model organism for medical research at Ohio University in the 1970s.

Ackerman warned that any transition to therapies will require careful titration of which drugs can be developed until they find the “sweet spot of plasticity.”

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The co-authors with Ackerman and Doe were a former University of Oregon undergraduate student, Nelson A. Perez Catalan, now on a post-baccalaureate program at the University of Chicago, and Mark R. Freeman, director and chief scientist of the Volum Institute at Oregon University of Health and Science in Portland.

The Howard Hughes Medical Institute and the National Institutes of Health funded the research. Ackerman is supported by a Milton Savinoitz Postdoctoral Fellowship awarded in 2017 by the ALS Association for Research Related to Amyotrophic Lateral Sclerosis, also known as Lou Gehrig’s disease.

Related Links:

Paper: https: //Resonate.Deer /10.1038 /s41586-021-03441-2

About Chris Doe: https: //Ion.Eurigon.Edo /Content /Chris Du 0

Doe Lab: https: //www.Lab.Deer /

Temperate nature Overview of news and opinions: https: //www.Temperate nature.Com /Articles /d41586-021-00680-1

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