Researchers discover direct feedback loop in brain circuit connecting memories and emotions

A newly identified part of a brain circuit mixes sensory information, memories, and emotions to tell whether things are familiar or new, and important or just "background noise."

Led by researchers from NYU Langone Health, the work found that a circuit known to carry messages from a brain region that processes sensory information, the entorhinal cortex (EC), to the memory processing center in the hippocampus (HC) has a previously unrecognized pathway that carries messages directly back to the EC. 

Publishing online Feb. 18 in Nature Neuroscience, the study results show that this direct feedback loop sends signals fast enough to instantly tag sights and sounds linked to certain objects and places as more important by considering them in the context of memories and emotions.

Ours is the first anatomical and functional analysis of both the new direct hippocampal-cortical feedback loop, and the indirect loop found decades ago."

Jayeeta Basu, PhD, senior study author, assistant professor, Departments of Psychiatry and Neuroscience, NYU Grossman School of Medicine

"The differences we found in their wiring, timing, and location suggest that the loops have separate but parallel roles that let them work together to encode even more complex information," added Basu, faculty in the Institute for Translational Neuroscience at NYU Langone Health and a recent winner of the Presidential Early Career Award for Scientists and Engineers.

A better understanding of the interplay between the two brain regions may yield new solutions to problems within related circuits, researchers say, like those seen in patients with post-traumatic stress disorder who struggle to tell apart past trauma from current loud noises, or in the sensory overload experienced by some children with autism as they try to tell apart objects or interact with people. 

Delicate signals

The long-understood model of the studied circuit posits that the hippocampus (HC) receives sensory information about the outside world from entorhinal cortex (EC) surface layers 2 and 3, but sends back signals to the EC only by indirectly wiring first into a deep EC layer (layer 5), which then routes them into EC surface layers 2 and 3. The indirect route can cause time lags that change the HC feedback signals.

Using modern methods, the current research team found a second loop that directly connects the HC to EC layers 2 and 3, letting memories and emotions stored in the HC quickly add weight to perceived sights and sounds as part of learning. A paradox in the field has been that there is no known direct pathway connecting the hippocampal memory center with the brain's emotional center, the amygdala. The newfound connections to the EC may serve as a crossroads.

Other results of the study map connections between brain cells based on their ability to pump charged particles through channels, building up charge imbalances (potentials) along their membranes. Upon receiving the right signal, cells open their channels, enabling the particles to rush out (depolarize) under electrochemical force, with charge flows acting like switches.

Brain cells in signaling pathways "fire" as their membrane potential shift, which causes each nerve cell's extensions (axons) to depolarize until the electric pulse reaches a synapse, a gap between one cell and the next. When it reaches a gap, the electric pulse is converted into a chemical signal that either turns up (excites) or turns downs (inhibits) the strength of the message passed to the next cell, with their mixture sculpting signals underlying thoughts and memories.

Importantly, the current study measured these properties for the first time in both loops. Dr. Basu's team found the previously known indirect loop to be excitatory, often triggering all-or-nothing signals called action potentials, large depolarizations that encode information based on their frequency.

The new direct feedback loop, however, in response to the same range of incoming signal strength, was found to recruit strong inhibition in brain cells (neurons) in EC layers 2 and 3, never eliciting action potentials. This newfound circuit activity instead sends small depolarizing potentials from the HC to EC layers 2 and 3. The authors say these delicate, repeated signals can combine with messages from other brain regions to make possible more intricate computations, accelerated learning, and greater plasticity, the strengthening of connections between neurons.

Moving forward, the research team plans to study how hippocampal output related to emotions and memories shapes decision-making functions in prefrontal cortex or the emotional coding of fear in the amygdala. The team will also examine what happens to their newfound direct circuit over the course of aging and in Alzheimer's disease in study mice, and its parallels in humans.

Along with Dr. Basu, study authors from the the NYU Langone Institute for Translational Neuroscience were first author Tanvi Butola as well as Melissa Hernandez Frausto, Lulu Peng, Ariel Hairston, Cara Johnson, Margot Elmaleh, Amanda Amilcar, and Fabliha Hussain. Also authors were transgenic tool builder Cliff Kentros and his team members - Stefan Blankvoort and Michael Flatset, of the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology; along with Claudia Clopath, head of the computational neuroscience laboratory, Department of Bioengineering, Imperial College in London. Dr. Basu led a National Institutes of Health (NIH) BRAIN initiative project grant (2018-2023) with Drs. Clopath and Kentros to build the tools, approaches, and models used in current circuit mapping study.

The work was also supported by NIH grants R01NS109994, R01NS109362-01, 5013R01MH122391, RM1NS132981, Alzheimer's Association grant AARGD-NTF-23-23 21151101, 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, New York University Whitehead fellowship for junior faculty, and a Leon Levy Foundation award.