Precisely tracking the formation of learning and memories

A group of Harvard scientists has revealed a method to chart the molecular foundations of learning and memory formation, an innovative technique anticipated to yield insights that might lead to new therapies for neurological issues such as dementia.

“This method offers a perspective into the synaptic structure of memory, something previously inaccessible in such granularity,” noted Adam Cohen, professor of chemistry and chemical biology as well as physics and senior co-author of the research article, published in Nature Neuroscience.

Memory exists within a complex network of billions of neurons in the brain. We depend on synaptic plasticity — the enhancement and adjustment of connections among these neurons — to enable learning and memory.

Synapses, or the points of communication between neurons, form the foundation for every memory we create, from a childhood song to a beloved face and what we had for breakfast.

In their recent publication, the group described their novel technique, termed Extracellular Protein Surface Labeling in Neurons (EPSILON), which concentrates on mapping the essential proteins for the transfer of signals across synaptic connections in the brain.

These specific proteins, known as AMPARs, are regarded as crucial contributors to synaptic plasticity, the mechanism that permits the brain to adapt and reorganize itself in reaction to new information.

By utilizing sequential labeling with specialized dyes, EPSILON enabled the researchers to observe these proteins’ movements with high precision. Traditionally, gaining insight into such detailed microscopic phenomena has necessitated more invasive techniques. Employing EPSILON to scrutinize AMPARs’ activity in neurons signifies a considerable leap in scientific progress.

This research was conducted by various members of Cohen’s laboratory, including Harvard Griffin GSAS student Doyeon Kim and postdoctoral researchers Pojeong Park, Xiuyuan Li, J. David Wong-Campos, He Tian, and Eric M. Moult, alongside scientists from the Howard Hughes Medical Institute.

A blend of fluorescent labeling and advanced microscopy permitted the researchers to illuminate synaptic behavior at an unparalleled level of detail. The accuracy of the technique was akin to illuminating some of the brain’s most intricate functions, allowing the team to observe the synaptic interactions crucial for learning.

As synaptic alterations of specific memories became clearer, patterns began to illustrate the principles governing how the brain determines which synapses to reinforce or diminish when encoding a memory.

Previous investigations into synaptic processes often lacked such depth, rendering EPSILON’s insights especially valuable for future research into conditions like Alzheimer’s, characterized by synaptic dysfunction that leads to memory and learning deficits.

As synaptic alterations of specific memories became clearer, patterns started to reveal principles governing how the brain decides which synapses to strengthen or weaken while encoding a memory.

“Our foremost breakthrough is our technique that can chart the historical trajectory of synthetic plasticity in a living brain,” stated Kim. “We can examine the history of synaptic plasticity, analyzing where and how much synaptic potentiation has occurred during a defined time window during memory formation.

“By mapping synaptic plasticity over time across multiple time points, we can accurately illustrate the dynamics of the synapses,” Kim added. “We’ll also be capable of applying this to various types of memories exhibiting different patterns of synaptic plasticity.”

The initial application of the technique has already produced fascinating results. By applying EPSILON to investigate mice undergoing contextual fear conditioning — a method that enables animals to link a neutral context with a fear-inducing stimulus — researchers demonstrated a correlation between AMPARs and the expression of the immediate early gene product cFos, a signal indicating when brain cells are active.

These results hint that AMPAR trafficking is closely associated with persistent memory traces, or engrams, within the brain, where particular neurons become activated following learning experiences.

Cohen acknowledges the significant and occasionally unexpected contributions that fundamental science can make in fostering advancement and enabling their study to flourish.

“The HaloTag technology, which is utilized for protein labeling, was derived from a gene discovered in 1997 by a team of researchers in Ireland who were examining a soil bacterium, known for its unique ability to break down pollutants,” Cohen remarked. “It represents a generational journey from basic research on the natural world to unveiling discoveries that enhance human health. We truly need to support the entire continuum to achieve progress.”

Looking ahead, Cohen is eager to see how EPSILON can be further employed to explore numerous cognitive phenomena and possibly enhance therapeutic approaches aimed at memory deficits.

“We’ve already distributed the molecular tool to laboratories worldwide, which are now beginning to utilize these tools to investigate how synaptic strength is regulated in their particular query and context,” he stated.

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This research was partially funded by the National Institutes of Health.