How Does the Brain Learn from Experience?

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We are constantly making new connections, linking associations like the touch of a sharp edge of a knife with danger.

Neuroscientists have long questioned how our brains learn to associate and change our behavior based on experience. In 1949, psychologist Donald Hebb theorized that repeated experiences causing neurons to fire from one to the next can strengthen their connections over time, which gave rise to the maxim “neurons that fire together, wire together.” However, no one knew how Hebb’s model would work on a molecular level.

Research from neuroscientists Michael Greenberg, Christine Holt, and Erin Schuman has shed light on the molecular processes of plasticity — winning them the 2023 Brain Prize, the world’s largest brain research prize. BrainFacts spoke with Greenberg and Schuman about their research and its implications for the neuroscience field.

What is plasticity, and how does it work at a molecular level?

Our brains don’t start out mature. They change as we interact with our environment. Plasticity refers to how sensory input changes brain structure and function. “It is the process of learning, memory, and behavior, and how the brain carries that out,” says Greenberg, a professor at Harvard Medical School.

“You can study plasticity at many different levels, like understanding how brain areas or circuitry activate in response to the environment,” says Schuman, Director of the Max Planck Institute for Brain Research. “Or you can look at it at a microscopic level, like what I study, which is how individual synapses, the connections between brain cells, change in response to inputs.”

Sensory experiences form the basis of our behaviors and learning. Receiving sensory input like light, odor, or pressure triggers a cascade of events in nerve cells resulting in our perceptions like sight, smell, or touch and initiating learning. It begins with sensory inputs triggering sensory neurons to release neurotransmitters: the chemical messengers that convey signals to nearby neurons.

Once received, the neuron springs into action, expressing genes by transcribing the instructions housed in DNA into RNA molecules that the cell’s molecular machinery uses to synthesize proteins.

These proteins have many functions, including modifying neuronal connectivity and synaptic strength, and thereby impacting the brain’s plasticity.

What was your Brain Prize winning research, and how did it change the way we previously understood the molecular basis of plasticity?

Scientists originally thought gene expression couldn’t change on a rapid timescale. But Greenberg challenged that idea by homing in on two sets of findings: 1) that cells could be stimulated to re-enter the cell cycle and divide, and 2) that plasticity required protein synthesis. “In both cases, the genes that were affected weren’t shown,” says Greenberg. He discovered that within minutes of adding a cellular growth factor to nerve cells, the levels of a transcription regulatory protein called Fos increased. The transcription factors (Fos, Jun, and Npas4) identified by Greenberg produce proteins that control synaptic stability: a balancing act that plays a key role in memory formation and the brain’s evolving response to sensory input.

Schuman’s work revolutionized the way scientists viewed protein synthesis in neurons. She demonstrated protein synthesis processes exist near synapses. “This really went against what most people thought at the time, which was that all the proteins for neurons likely come from the cell body,” says Schuman. Furthermore, after disrupting these processes, enhancement of synaptic strength didn’t happen. The research established the existence of local protein synthesis and its importance for synaptic plasticity and memory formation.

Holt focused on the direction axons grow in response to the environment, an area of study called axonal navigation. Inspired in part by Schuman’s groundbreaking work, Holt set out to see if axonal navigation was related to protein synthesis. Her team found that axons had their own RNA translation processes. What's more, axons unable to synthesize proteins couldn't navigate correctly in the brain.

What drives your interest in the molecular basis of plasticity and learning?

Greenberg’s doctoral thesis advisor’s words — “get out of the practice room and into the concert hall” — remained with him as he finished his doctoral work, inspiring him to investigate a big question that he might spend a lifetime answering. He decided to tackle how extracellular stimuli send signals to cells and elicit responses from them. “I became interested in knowing if there might be a common mechanism for how all cells respond to a change in their environment,” Greenberg says.

Holt’s undergraduate classes in developmental neuroscience sparked her interest in neuronal connections. Her fascination led her to study the organization of axons in the visual system.

Schuman also became interested in the brain during her undergraduate years. While she started with studying behavior, she later dove deeper into the molecular level. “As you focus in, things don’t get simpler but maintain the same level of complexity — some people might even argue that it gets more complicated up close,” says Schuman, “I feel like I’m getting to the root of the problem, and that satisfies me.”

How does your research inform neurology and neuroscience?

Many of the gene regulators Greenberg identified are also risk factors for neurological diseases, such as Rett Syndrome, a rare disorder that stunts brain growth and development. Disruption of protein synthesis holds implications for many neurodegenerative diseases. “We can see how vulnerabilities could arise, just by getting very basic information about how proteins are made at synapses,” says Schuman, “I think the basic stuff we do is very important for those fields.”

Wider research on Fos, inspired by Greenberg’s studies, shows that over 1,000 different stimuli in the brain induce the factor. Since Schuman’s work, thousands of different RNAs have been sequenced from the dendrites of a neuron. And Holt’s research has shown the significance of local protein synthesis for maintaining axons, which may prove critical to understanding and treating neurodegenerative diseases.

About the Author

Daphne Yao

Daphne is currently studying for her master's in science journalism at Northwestern University. Before turning her sights on journalism, she studied the mind, obtaining a bachelor’s degree in Philosophy-Neuroscience-Psychology from Washington University in St. Louis.