In a technical feat with ramifications for our understanding of how experiences imprint themselves as lasting memories, and how faulty circuit wiring leads to neurological disease, UC San Francisco scientists have caught brain circuits in the act of rewiring themselves to change how they respond to sensory input.

The study — published October 7, 2019 in Proceedings of the National Academy of Sciences — provides a close observation of the circuit changes behind a classic demonstration of the brain’s capacity for change, also known as “plasticity,” first conducted nearly 60 years ago.

In those classic experiments, conducted by the Nobel Prize–winning team of David Hubel and Torsten Wiesel, researchers covered one of a young animal’s eyes and found that neurons in the brain’s visual cortex rapidly switched their allegiance from the closed to the open eye. This dramatic example of plasticity was only possible during a limited “critical period” of brain development in early life: If the researchers uncovered the closed eye within this critical period, the neurons could learn to respond to the re-opened eye again, but otherwise the changes were permanent. (This finding explains why correcting life-long eye problems in adults doesn’t always restore their vision in the affected eye.)

Researchers have long believed that these changes must be mediated by a re-arrangement of the synaptic connections that convey information from the closed and open eyes onto visual cortex neurons, but until now it has not been possible to observe these changes directly. 

In the new study, researchers in the UCSF lab of Michael Stryker, PhD, repeated Hubel and Wiesel’s classic experiment in mice, using high-resolution two-photon microscopes that make it possible to observe neurons near the surface of the rodents’ brains that are known involved in critical period rewiring. In addition to monitoring changes in the neurons’ responses to the open or closed eye, Stryker’s group used new imaging processing algorithms and fluorescent chemical tags to track tiny neural protrusions called dendritic spines, which represent the receiving end of synaptic inputs carrying visual information to the cells. 

By making observations of the same precise location in the animal’s brain day after day, the researchers were able to observe dramatic turnover in these synaptic inputs at the same time as the neurons were changing their preference from the closed to the open eye — and then back again when the closed eye was re-opened. 

“For a long time we’ve had ideas and stories we could tell about how brain circuits must be rewiring to produce the functional changes we could observe in animals’ brains,” said Stryker, a professor of physiology at UCSF. “But they were just stories — a sort of neuromythology that was sometimes based on rather fragile chains of inference. Now we can actually observe and measure how circuits are rewiring to produce the functional changes we see, which I hope will elevate our understanding of learning and development in the brain to a completely different kind of epistemological grounding.”

More than half a century after the original experiments, scientists study still study critical period plasticity because it represents an extreme case of the brain’s life-long capacity for change, as well as the limits on that change in the mature brain. Similar changes to brain circuitry — though subtler and harder to study — presumably underlie our ability to remember and learn from our experiences. Defects in the rules of circuit rewiring are thought to underlie the faulty circuitry responsible for psychiatric and neurological diseases — from autism and sensory processing disorders to schizophrenia and depression.