Neuroscientists at Johns Hopkins Medicine have utilized an advanced brain-imaging technique to successfully reactivate a memory circuit in mice, prompting them to search for shelter even when none exists.
The team reported in a study published on September 27 in Nature Neuroscience that their findings contribute to the understanding of how memories are organized within the mammalian brain. This research holds potential for developing new approaches to mitigate or prevent memory loss linked to Alzheimer’s and other neurodegenerative disorders.
Specifically, the researchers discovered that by stimulating neurons in two distinct areas of the mouse brains—the nucleus accumbens, which is known as the brain’s “pleasure center” and plays a role in behaviors influenced by dopamine, and the dorsal periaqueductal gray (dPAG), which is involved in defensive actions—they were able to reactivate a “spatial memory” that led the mice to seek out shelter.
Senior author Hyungbae Kwon, Ph.D., an associate professor of neuroscience at Johns Hopkins University School of Medicine, stated, “By artificially reactivating these memory circuits, we prompted the mice to behave similarly to their natural responses, even in the absence of the fear triggers that usually make them look for shelter.”
The scientists aimed to identify which brain regions are crucial for navigating the environment, a complex cognitive ability found in mammals, including humans. This experimentation, which explored whether such cognitive functions can be artificially replayed, could help explain the behaviors and perceptions of other mammals in their environments.
In their experiments, the researchers first allowed laboratory mice to explore a box that had a shelter in one corner. The team introduced various visual markers—shapes like triangles and circles, and different colors—to assist the mice in recognizing the shelter location using nearby landmarks. The mice spent seven minutes familiarizing themselves with the box, entering and exiting the shelter.
Next, the researchers introduced a visual or auditory warning signal to encourage the mice to seek the shelter, thus creating a spatial memory associated with their surrounding context and the visual signals.
To specifically tag neurons related to the shelter memory, the scientists employed a light-activated gene expression method called Cal-light, which Kwon developed in 2017. After identifying the memory-related neurons in the nucleus accumbens, they activated the related gene expressions, reawakening the memory of seeking shelter while also activating neurons in the dPAG.
This led the mice to search for the location of the previously existing shelter, despite the absence of both the original danger and the shelter itself.
To achieve this, the researchers first activated neurons within the nucleus accumbens and then did so separately within the dPAG to determine if stimulating a single area would evoke the shelter-seeking behavior.
Kwon remarked, “We were surprised that the mice did not search for shelter when we activated neurons in the nucleus accumbens alone. On the other hand, stimulating the dPAG resulted in a random response without directing them to the shelter area they previously sought.”
Kwon noted, “The Cal-light system allowed us to pinpoint a specific brain function, aiding in the cellular mapping of memory.”
Looking ahead, Kwon believes that this research could lay the groundwork for reactivating or reconstructing memory circuits in individuals who have Alzheimer’s disease.
“By grasping the overall structure of memory, we may devise more effective strategies to prevent or delay neurodegenerative conditions using this method,” he mentioned.
The researchers aspire to gain a broader understanding of memory across the brain by selectively tagging and reactivating neurons with various functions in different brain regions that lead to specific behaviors.
“Understanding how these memory circuits interact will enhance our comprehension of brain function,” he concluded.
The study included contributions from researchers such as Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi, and Seth Blackshaw from Johns Hopkins; Myungmo An from the Max Planck Florida Institute for Neuroscience; and Zirong Gu and Rui M. Costa from the Zuckerman Mind Brain Behavior Institute at Columbia University and the Allen Institute.
This work received funding from the Max Planck Florida Institute for Neuroscience, a Young Investigator Grant from the National Alliance for Research on Schizophrenia and Depression, as well as multiple National Institutes of Health Grants: R01MH107460, 5U19NS104649, K99 NS119788, DK108230, and DP1MH119428.
