The research 鈥渇ills in a substantial gap in the understanding of how long-range inputs control neuronal circuits essential for memory recall,鈥 said Dr. Jayeeta Basu, the senior study author.
Credit: Getty Images/Andriy Onufriyenko
Newly decoded brain circuits make memories more stable as part of learning, according to a new study led by 黑料福利社 Langone Health researchers.
Published online in Science on October 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鈥攚here 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鈥檚 brain wrongly recalls a bomb blast.
鈥淥ur 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,鈥 said senior study author , an assistant professor in the Departments of and at 黑料福利社 Langone Health.
鈥淎 better understanding of circuits supporting place maps may guide the future design of more precise treatments for conditions that affect memory,鈥 added Dr, Basu, who is also a faculty member at the Institute for Translational Neuroscience at 黑料福利社 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 鈥渇ire鈥濃攇enerate quick swings in the balance of their positive and negative charges鈥攖o transmit electrical signals that coordinate thoughts and memories.
As a charge reaches the end of one brain cell鈥檚 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 鈥渘oise鈥 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鈥攕uch as a mouse learning where sugar water rewards are in one maze versus another.
The current study鈥檚 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 鈥渇eed-forward鈥 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.
鈥淭his 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,鈥 says first study author Vincent Robert, PhD, a postdoctoral scholar in Basu鈥檚 lab. 鈥淭he 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.鈥
Along with Dr. Basu and Dr. Robert, study authors from the Department of Neuroscience are Keelin O鈥橬eil, Jason Moore, Shannon Rashid, Cara Johnson, and Rodrigo De La Torre from the . 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, Dr. Basu鈥檚 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鈥檚 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.
About 黑料福利社 Langone Health
黑料福利社 Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient, Inc., has ranked 黑料福利社 Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. 黑料福利社 Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.
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