Study sheds light on structural features of memory formation at cellular and subcellular levels

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An NIH-funded study uses cutting-edge imaging techniques to reconstruct the characteristics underlying learning and memory in the mouse brain.

This image shows a 3D view of an atypical multisynaptic bouton, a structural feature of memory engrams. Maximov Laboratory at Scripps Research

What

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In a study funded by the National Institutes of Health (NIH), researchers have revealed the structural underpinnings of memory formation across a vast network of neurons in the mouse brain. This work sheds light on the fundamentally flexible nature of how memories are created, detailing learning-related changes at the cellular and subcellular levels with unprecedented resolution. Understanding this flexibility may help explain why memory and learning processes sometimes go awry.

The results, published in Science, showed that neurons assigned to a memory trace reorganized their connections with other neurons through an atypical type of connection called a multisynaptic bouton. In a multisynaptic bouton, the axon of the neuron relaying the information signal contacts multiple neurons that receive the signal. According to the researchers, multisynaptic boutons may enable the cellular flexibility of information coding observed in previous research.

The researchers also found that neurons involved in memory formation were not preferentially connected to each other. This discovery challenges the idea that "neurons that fire together, wire together," as a traditional theory of learning would predict.

Additionally, the researchers observed that neurons assigned to a memory trace reorganized certain intracellular structures that provide energy and support communication and plasticity of neuronal connections. These neurons also exhibited enhanced interactions with support cells called astrocytes.

Using a combination of advanced genetic tools, 3D electron microscopy, and artificial intelligence, Scripps Research scientists Marco Uytiepo, Anton Maximov, Ph.D., and their colleagues reconstructed a wiring diagram of neurons involved in learning and identified structural changes in these neurons and their connections at the cellular and subcellular levels.

This image shows an AI-assisted nanoscale 3D reconstruction of neuronal synapses in the mouse hippocampus.Maximov Laboratory at Scripps Research

To examine the structural features associated with learning, the researchers exposed mice to a conditioning task and examined the hippocampal region of the brain about 1 week later. They chose this point in time because it occurs after memories are first encoded but before they are reorganized for long-term storage. Using advanced genetic techniques, the researchers permanently labeled subsets of hippocampal neurons activated during learning, allowing for reliable identification. They then used 3D electron microscopy and artificial intelligence algorithms to produce nanoscale reconstructions of the excitatory neural networks involved in learning.

This study provides an overview of the structural characteristics of memory formation in a brain region. It also raises new questions to explore. Future studies will be crucial to determine whether similar mechanisms operate at different times and in different neural circuits. Furthermore, further research on the molecular composition of multisynaptic boutons is needed to determine their precise role in memory and other cognitive processes.

This research was funded by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the BRAIN® (Brain Research Through Advancing Innovative Neurotechnologies) initiative. ® Initiative) of the NIH.Who

Jamie Driscoll, National Institute of Mental Health and Dr. Eunyoung Kim, National Institute of Mental Health

Study

Uytiepo, M., Zhu, Y., Bushong, E., Chou, K., Polli, F.S., Zhao, E., Kim, K.-Y., Luu, D., Chang, L., Yang, D., Ma, T.C., Kim, M., Zhang, Y., Walton, G., Quach, T., Haber, M., Patapoutian, L., Shahbazi, A., Zhang, Y., … Maximov, A. (2025). Synaptic architecture of a memory engram in the mouse hippocampus.

Science .http://www.science.org/doi/10.1126/science.ado8316 Brain Research Through Advancing Innovative Neurotechnologies® and The BRAIN Initiative® are registered trademarks of HHS.

About the National Institute of Mental Health (NIMH): NIMH's mission is to transform the understanding and treatment of mental illness through basic and clinical research, leading the way to prevention, recovery, and cure. For more information, visit the

NIMH website .About the National Institutes of Health (NIH):

The NIH, the nation's medical research agency, comprises 27 institutes and centers and is part of the U.S. Department of Health and Human Services. The NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and investigating the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov .The NIH… Transforming Discovery into Health

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