Study uncovers neural mechanisms behind memory stabilization

Newly decoded brain circuits make memories more stable as part of learning, according to a new study led by NYU Langone Health researchers.

Published online in Science on Oct. 30, the study shows that activity in signaling pathways connecting two brain regions, the entorhinal cortex and the CA3 region of the hippocampus, help mice encode in brain circuitry maps of places.

The entorhinal/hippocampal circuit is known from past studies to be crucial for both memory formation, and the recalling of memories by completing patterns from partial cues. Reliable recall requires that hippocampal place maps remain stable, withstanding to some degree changes in the environment.

Problems with CA3 neural computations can lead to symptoms similar to those of schizophrenia or post-traumatic stress disorder, the study authors say – where the stability and precision of memories fail. In these instances, a balloon pop at a party might result in a freezing fear response as a soldier’s brain wrongly recalls a bomb blast.

Our study, by focusing on the stability of hippocampal representations, fills in a substantial gap in the understanding of how long-range inputs control neuronal circuits essential for memory recall.”

Jayeeta Basu, PhD, senior study author, assistant professor, departments of Psychiatry and Neuroscience, NYU Langone Health

“A better understanding of circuits supporting place maps may guide the future design of more precise treatments for conditions that affect memory,” added Basu, a faculty member at the Institute for Translational Neuroscience at NYU Langone Health and recent winner of the Presidential Early Career Award for Scientists and Engineers.

Repeated circuit activity sets memory templates

The new study revolves around brain cells called neurons, which “fire” – or generate quick swings in the balance of their positive and negative charges – to transmit electrical signals that coordinate thoughts and memories.

As a charge reaches the end of one brain cell’s extensions, it triggers the release of neurotransmitter chemicals that float across the gap between one cell and the next. On the other side, they dock into proteins that, depending on their nature, either encourage the downstream nerve cell to fire (excitation) or inhibit its firing, the researchers say.

This combination of excitation and inhibition achieves a balance that sculpts “noise” into thoughts, a balance that is maintained when the brain is not learning (in a resting state). During learning, however, boosts in excitation encode new memories, and the activity patterns of neurons determine the specificity of the memories they represent. Reactivating these neurons in a set pattern recalls a specific memory, and produces the related behavior – such as a mouse learning where sugar water rewards are in one maze versus another.

The current study’s focus is on neurons with long extensions that coordinate activity among distant brain regions. Little is known about how long-range cell inputs influence local circuits as the brain balances stable templates (of what is already known) against new data (about constantly changing experiences) to form memories.

The research team determined that two types of long-range extensions from the lateral entorhinal cortex to the CA3 region signal at the same time to stabilize the activity of brain cell learning networks. Specifically, long-range excitatory glutamatergic (LECGLU) and inhibitory GABAergic (LECGABA) extensions were found to increase the activity of ensembles of interconnected neurons to support learning.

The study authors examined the interactions between LEC long-range inputs and CA3 circuits at the single cell level. LECGLU was found to drive excitation in CA3 but also feedforward inhibition that fine-tuned firing, while LECGABA suppressed this local inhibition to disinhibit (encourage) CA3 activity. This combined action supported stability in CA3 by triggering recurrent activity in certain circuits, encoding memories of places.

“This work dissected the mechanism whereby the brain boosts excitation of brain cells to pay more attention to certain sensory information by dialing down inhibition in key microcircuits,” says first study author Vincent Robert, PhD, a post-doctoral scholar in Basu’s lab. “The team detailed a circuit mechanism that fine-tunes the dialogue among excitation, inhibition, and disinhibition in service of context-dependent memory formation and place map stability.” 

Along with Basu and Robert, study authors from the Department of Neuroscience at NYU Langone Health are Keelin O’Neil, Jason Moore, Shannon Rashid, Cara Johnson, and Rodrigo De La Torre from the Basu lab. Other authors are Boris Zemelman of the Center for Learning and Memory at the University of Texas, Austin, and Claudia Clopath of the Department of Bioengineering at Imperial College London, Basu’s co-principal investigator for a National Institutes of Health (NIH) BRAIN Initiative R01 grant.

Funding for the study was provided by NIH grants 1R01NS109994, 1R01NS109362-01, 1RM1NS132981-01, 5T32MH019524-30, T32GM007308 training grant, 3R01MH122391-04S1, R01MH122391, 1U01 NS099720 (BVZ), and 1U01 NS094330. Also providing support were a McKnight Scholar Award in Neuroscience, the Klingenstein-Simons Fellowship Award in Neuroscience, an Alzheimer’s Association Research Grant to Promote Diversity, a Sloan Research Fellowship, a Mathers Foundation Award, a Whitehall Foundation Research Grant, an American Epilepsy Society Junior Investigator Research Award, a Blas Frangione Young Investigator Research Grant from New York University, a Leon Levy Foundation Award, a Young Researchers Bettencourt Prize, and the Emerald Foundation.