Neuroscientists have identified a novel part of a brain circuit that merges sensory information, memories, and emotions to judge if stimuli are familiar or new, and important or merely background noise.
Published online on February 18 in Nature Neuroscience, the study provides the first detailed anatomical and functional insights into this newly discovered direct hippocampal-cortical feedback loop, as well as a previously known indirect loop.
Our research is the first to anatomically and functionally analyze both the new direct hippocampal-cortical feedback loop, and the indirect loop identified decades ago.
—Jayeeta Basu, PhD, senior study author and assistant professor, Departments of Psychiatry and Neuroscience, NYU Grossman School of Medicine
According to Basu, who is also a faculty member in the Institute for Translational Neuroscience at NYU Langone Health, the differences in wiring, timing, and location suggest separate but cooperative functions, enabling the circuits to process even more complex information.
Efficient Signal Processing
Traditionally, it was believed that the hippocampus (HC) receives sensory data from the entorhinal cortex (EC) surface layers 2 and 3 but sends feedback signals indirectly via layer 5 of EC, which introduces time delays that can alter the HC signals.
New research uncovered a direct pathway connecting the HC to EC layers 2 and 3, allowing memories and emotions stored in the HC to rapidly influence perceived stimuli as part of the learning process. This discovery challenges previous assumptions since there was no known direct link between the hippocampus and the amygdala, the brain’s emotional center. The newly found EC connections may act as a crossover between these regions.
The Role of Neurons
Neurons in signaling pathways generate electrical pulses when their membrane potential changes, causing axons to transmit these signals to synapses. At these gaps, the pulses convert into chemical messages that either enhance or weaken the transmission to subsequent neurons, shaping thoughts and memories.
The newly identified direct feedback loop operates differently. Instead of eliciting action potentials, it induces strong inhibition in EC layers 2 and 3 neurons. This subtle, repetitive signaling can integrate inputs from other brain areas, supporting more intricate computations, faster learning, and enhanced neural plasticity.
Research Team and Funding
This groundbreaking study was led by Dr. Basu, alongside first author Tanvi Butola and fellow researchers Melissa Hernandez Frausto, Lulu Peng, Ariel Hairston, Cara Johnson, Margot Elmaleh, Amanda Amilcar, and Fabliha Hussain, all affiliated with the NYU Langone Institute for Translational Neuroscience. Additionally, Cliff Kentros and his team members Stefan Blankvoort and Michael Flatset from the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology, along with Claudia Clopath, head of the computational neuroscience laboratory at Imperial College in London, contributed to the study.
The project received support from multiple National Institutes of Health (NIH) grants, an Alzheimer’s Association grant, a Parekh Center for Interdisciplinary Neurology pilot research grant, a Mathers Foundation Award, a McKnight Scholar Award, a Klingenstein Fund-Simons Foundation fellowship award in neuroscience, an Alfred P. Sloan fellowship, a Whitehall research grant, an American Epilepsy Society junior investigator award, a Blas Frangione young investigator grant, a New York University Whitehead fellowship for junior faculty, and a Leon Levy Foundation award.
Implications of the Discovery
The identification of this direct hippocampal-cortical feedback loop enhances our understanding of how the brain recognizes and processes sensory information. This knowledge could lead to advancements in the treatment of neurological disorders related to memory and emotional processing.
Further research in this area promises to illuminate additional mechanisms by which our brains handle and encode complex information, potentially impacting various neurological and psychiatric conditions.
Dr. Basu and her colleagues have laid a solid foundation for future studies, instrumental in unlocking more secrets of the brain’s intricate network.
Journal reference:
Butola, T., et al. (2025). Hippocampus shapes entorhinal cortical output through a direct feedback circuit. Nature Neuroscience. doi.org/10.1038/s41593-025-01883-9.
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