In humans, learning occurs when different groups of brain cells activate simultaneously. For example, when the neurons involved in recognizing a dog start firing together in response to signals from cells that represent the dog’s characteristics, such as having four legs, fur, and a tail, a child learns to identify dogs in the future. However, this wiring of the brain begins even before birth, long before individuals have any sensory experiences like sight. How does this process take place?
A recent study published on August 15 in Science by Yale researchers sheds light on how brain cells form a connected network during early development, prior to experiences influencing brain structure. It appears that the principles guiding this initial development mirror those applied later on; specifically, cells that activate together tend to wire together. Instead of being shaped by external experiences, this early wiring is driven by random cellular activities.
“One of the key questions we are investigating is how the brain is structured during its development,” explained Michael Crair, co-senior author of the study and the William Ziegler III Professor of Neuroscience at Yale School of Medicine. “What principles and processes govern the wiring of the brain? These discoveries help illuminate that matter.”
In their investigation, researchers zeroed in on mouse retinal ganglion cells, which extend from the retina to the superior colliculus, a part of the brain where they link up with other neurons. The team examined the activity of a single retinal ganglion cell, the anatomical changes in that cell over time, and the behavior of neighboring cells in awake neonatal mice that had not yet opened their eyes. This sophisticated experimentation was made possible through advanced microscopy techniques combined with fluorescent proteins that show cell activity and anatomical alterations.
Prior studies indicated that, before any sensory experiences occur—such as when humans are developing in the womb or during the early days before young mice open their eyes—spontaneous neural activity leads to the formation of waves. The latest research revealed that when a single retinal ganglion cell’s activity was well synchronised with surrounding cells’ activity waves, its axon— which connects to other neurons—developed new branches. Conversely, when the activity was poorly synchronized, the axon branches were eliminated.
“This demonstrates that when these cells activate together, their connections become stronger,” said Liang Liang, co-senior author of the study and an assistant professor of neuroscience at Yale School of Medicine. “The growth of axon branches enables increased connections between the retinal ganglion cell and the neurons exhibiting synchronized activity within the superior colliculus circuit.”
This aligns with “Hebb’s rule,” a principle proposed by psychologist Donald Hebb in 1949, which stated that when one cell repeatedly triggers another cell, the connection between them becomes stronger.
“Hebb’s rule is frequently referenced in psychology when discussing the neurological basis of learning,” said Crair, who also serves as the vice provost for research and is a professor of ophthalmology and visual science. “Our findings show that this principle also applies during the early stages of brain development, down to the subcellular level.”
In this study, the researchers also identified where axon branching was most likely to occur, noting that this pattern was disrupted when synchronization between the cell and the spontaneous waves was altered.
Spontaneous neural activity is observed during the development of various neural circuits, including those in the spinal cord, hippocampus, and cochlea. Although the specific patterns of activity may differ in these areas, the underlying principles governing neuronal wiring could be similar, according to Crair.
Looking ahead, researchers plan to investigate whether these axon branching patterns remain after a mouse’s eyes open and to observe the effects on downstream connected neurons when a new axon branch develops.
“The Crair and Liang laboratories will continue to merge our expertise in brain development and single-cell imaging to study how the assembly and refinement of brain circuits is influenced by distinct patterns of neural activity at various developmental stages,” Liang remarked.
This research received partial support from the Kavli Institute of Neuroscience at Yale School of Medicine.
