Summary: Neuroscientists at Johns Hopkins Medicine have reactivated a specific memory circuit in mice, prompting the animals to seek shelter even when no shelter was present. By selectively stimulating neurons tied to spatial memory, the researchers drove a replay of a previously formed shelter-seeking behavior.
This work clarifies how discrete memory modules are organized in the mammalian brain and suggests possible avenues for preserving or restoring memory function in conditions that cause cognitive decline. The results point toward approaches that could, in the future, help slow memory loss associated with Alzheimer’s disease and other neurodegenerative disorders.
Key Facts:
- Targeted reactivation of neurons made mice search for a shelter that was no longer present.
- The memory circuit links spatial memory with prior defensive experiences and involves dopamine signaling.
- Mapping and reactivating such circuits may inform treatments for memory loss in neurodegenerative disease.
Source: Johns Hopkins University
Using an advanced brain-imaging and manipulation system, researchers report they reactivated a defined memory module in mice that produced a shelter-seeking response in the absence of any external threat or shelter.
Published Sept. 27 in Nature Neuroscience, the study advances our understanding of how goal-directed spatial memories are encoded and later recalled in the mammalian brain. The findings identify a specific combination of brain regions and inputs that together form a memory module capable of guiding navigation toward a remembered goal.
The team focused on two brain areas: the nucleus accumbens (NAc), a region that integrates dopamine-dependent signals linked to motivation and reward, and the dorsal periaqueductal gray (dPAG), a midbrain area involved in defensive actions. Stimulating neurons in both sites reactivated a spatial memory of shelter location and caused mice to navigate toward where the shelter had been, even when it was no longer present.
“When we artificially reactivate those memory circuits, the mouse reproduces the same shelter-seeking behavior it displayed naturally, without any threat cues,” said Hyungbae Kwon, Ph.D., associate professor of neuroscience at Johns Hopkins University School of Medicine and the senior author of the study.
To map the circuits underlying goal-directed navigation, the researchers allowed mice to explore a testing arena containing a shelter in one corner and various visual landmarks—triangles, circles and stripes—so the animals could form a spatial memory linking the shelter to nearby cues. Mice explored the arena for several minutes and used the landmarks to learn the shelter’s location.
The team then introduced a looming visual or auditory threat to trigger escape behavior and reinforce the shelter memory. During these shelter experiences, the investigators selectively tagged the neurons active during the memory formation using a light-controlled gene-expression system called Cal-Light, a method developed by Kwon in 2017 that enables precise labeling of neurons based on both activity and light exposure.
After identifying the shelter-associated neurons in the nucleus accumbens, the researchers reactivated those cells and concurrently stimulated neurons in the dPAG. This artificial co-activation was sufficient to elicit directed, memory-guided escape behavior: mice moved to the location where the shelter had been, even though neither the original threat nor any shelter was present.
The team tested the contribution of each region separately. Activating the nucleus accumbens neurons alone did not reliably drive the directed shelter search. Stimulating dPAG neurons alone produced random defensive reactions but did not guide the animals specifically to the former shelter location. Only coordinated activation of the goal-related NAc ensemble together with dPAG neurons produced memory-guided navigation.
These results indicate that a goal-related memory is encoded by a subpopulation of nucleus accumbens neurons that receive convergent dopaminergic input from the ventral tegmental area and glutamatergic input from hippocampal regions involved in spatial coding. Optogenetically induced dopamine signals were sufficient to create a place memory that could direct escape navigation, offering causal evidence that these inputs form a functional memory module linking stored information to goal-directed action.
Kwon and colleagues emphasize that the Cal-Light system made it possible to tag and manipulate a specific neuronal population tied to a single behavioral function, allowing the team to map memory at a cellular and circuit level. Understanding these macro- and micro-level structures of memory could be foundational for developing methods to reactivate or engineer memory circuits in people affected by dementia and related disorders.
“By revealing how memory modules are organized and how they drive specific goal-directed behaviors, this work points toward strategies to preserve or restore memory function in neurodegenerative disease,” Kwon said. The authors plan to extend this approach by tagging and reactivating neurons associated with other behaviors to map broader brain-wide memory architecture.
Other researchers on the paper include Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi and Seth Blackshaw of Johns Hopkins; Myungmo An of the Max Planck Florida Institute for Neuroscience; and Zirong Gu and Rui M. Costa of the Zuckerman Mind Brain Behavior Institute at Columbia University and the Allen Institute.
Funding: This research received support from the Max Planck Florida Institute for Neuroscience, a National Alliance for Research on Schizophrenia and Depression Young Investigator Grant and NIH grants R01MH107460, 5U19NS104649, K99 NS119788, DK108230 and DP1MH119428.
About this memory and neuroscience research news
Author: Alexandria Carolan
Source: Johns Hopkins University
Contact: Alexandria Carolan – Johns Hopkins University
Image: The image is credited to Kanghoon Jung
Original Research: Open access. “Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation” by Kanghoon Jung et al., published in Nature Neuroscience.
Abstract
Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation
Spatial memories allow animals to navigate efficiently to desired locations, but the neuronal and circuit mechanisms that encode goal locations and link them to goal-directed navigation are not fully understood. This study shows that mice rapidly form a spatial memory of a shelter during shelter experiences, and that memory guides escape behavior toward the shelter when animals face a threat.
Dopaminergic neurons in the ventral tegmental area and their projections to the nucleus accumbens encode safety signals related to the shelter. Artificially induced phasic dopamine signals can create a place memory that directs escape navigation. Converging dopaminergic and hippocampal glutamatergic inputs to the nucleus accumbens mediate formation of a goal-related memory within a specific subpopulation of NAc neurons during shelter experiences. Artificial co-activation of this NAc ensemble with dorsal periaqueductal gray neurons is sufficient to trigger memory-guided, rather than random, escape behavior. These findings provide causal evidence for cognitive circuit modules that link memory representations with goal-directed actions.