In humans, the learning process is driven by different groups of brain cells firing together. For example, when neurons associated with the process of recognizing a dog start firing in a coordinated manner in response to cells that code for a dog’s characteristics (four legs, fur, tail, etc.), a young child will eventually be able to identify dogs. But brain wiring begins before humans are born, before they have experiences or senses like sight to guide this cellular circuitry. How does that happen?
In a new study published August 15 in ScienceYale researchers identified how brain cells begin to link together into this network of wires early in development, before experience has a chance to shape the brain. It turns out that very early development follows the same rules as later development: cells that fire together wire together. But instead of experience being the driving force, it’s spontaneous cellular activity.
“One of the fundamental questions we’re trying to answer is how the brain is wired during development,” said Michael Crair, co-senior author of the study and the William Ziegler III Professor of Neuroscience at the Yale School of Medicine. “What are the rules and mechanisms that govern brain wiring? These findings help answer that question.”
For the study, the researchers focused on mouse retinal ganglion cells, which project from the retina to a brain region called the superior colliculus, where they connect with downstream target neurons. The researchers simultaneously measured the activity of a single retinal ganglion cell, the anatomical changes that occurred in that cell during development, and the activity of surrounding cells in awake neonatal mice whose eyes had not yet opened. This technically complex experiment was made possible by advanced microscopy techniques and fluorescent proteins that indicate cell activity and anatomical changes.
Previous research has shown that before sensory experience can take place (for example, when humans are in the womb or in the days before young mice open their eyes), spontaneously generated neural activity becomes correlated and forms waves. In the new study, the researchers found that when the activity of a single retinal ganglion cell was highly synchronized with waves of spontaneous activity in surrounding cells, the individual cell’s axon (the part of the cell that connects to other cells) generated new branches. When the activity was poorly synchronized, the axon’s branches were eliminated.
“This tells us that when these cells fire together, the associations are strengthened,” said Liang Liang, co-senior author of the study and an assistant professor of neuroscience at Yale School of Medicine. “The branching of the axons allows for more connections to be made between the retinal ganglion cell and neurons that share synchronized activity in the superior colliculus circuit.”
This finding follows what is known as “Hebb’s rule,” an idea proposed by psychologist Donald Hebb in 1949; at that time Hebb proposed that when one cell causes another cell to fire repeatedly, the connections between the two are strengthened.
“Hebb’s rule is widely applied in psychology to explain the brain basis of learning,” said Crair, who is also vice provost for research and professor of ophthalmology and visual sciences. “Here we show that it also applies during early brain development with subcellular precision.”
In the new study, the researchers were also able to determine where in the cell branch formation was most likely to occur, a pattern that was disrupted when the researchers altered the timing between the cell and the spontaneous waves.
Spontaneous activity occurs during development in several other neural circuits, including the spinal cord, hippocampus and cochlea. While the specific pattern of cellular activity would be different in each of those areas, it’s possible that there are similar rules governing how cellular wiring is done in those circuits, Crair said.
In the future, the researchers will explore whether these axonal branching patterns persist after a mouse’s eyes open and what happens to the downstream connected neuron when a new axonal branch forms.
“The Crair and Liang labs will continue to combine our expertise in brain development and single-cell imaging to examine how the assembly and refinement of brain circuits are guided by precise patterns of neural activity at different stages of development,” Liang said.
The research was funded in part by the Kavli Institute for Neuroscience at Yale School of Medicine.