In new study, neuroscientists trigger shelter-seeking response by reactivating memory circuitry

Using a sophisticated brain imaging system, neuroscientists at Johns Hopkins Medicine say they have succeeded in reactivating a specific memory circuit in mice, forcing them to seek shelter when no shelter is actually present.

The researchers say the study, published September 27 in Natural neuroscienceadvances the understanding of how memories are structured in the mammalian brain. The findings may one day point to new ways to slow or prevent the memory loss that accompanies Alzheimer’s and other neurodegenerative diseases.

Specifically, the team found that stimulating neurons in two areas of the mice’s brains – the nucleus accumbens, also known as the “pleasure center” of the brain, responsible for relaying dopamine-dependent behaviors, and the dorsal periaqueductal gray (dPAG), responsible for defensive behavior – reactivated a “spatial memory” and pushed the mice to seek refuge.

“When we artificially reactivate these memory circuits in the brain, it tricks the mouse into doing the same thing it did naturally, even without the fear stimuli that caused it to seek refuge in the first place,” explains the lead author. Hyungbae Kwon, Ph.D., associate professor of neuroscience at Johns Hopkins University School of Medicine.

The scientists say they aimed to determine which areas of the brain are responsible for navigating the environment, a high-level cognitive function in mammals, including humans. Thus, these experiments, which tested whether such cognitive brain functions could be replayed randomly, could have applications for understanding how other mammals behave, perceive and sense their environment.

In the new experiments, the researchers first allowed laboratory mice to explore their environment in a box with shelter in the corner. The team placed a series of visual cues, including triangles, circles and stripes of different colors, to help the mice locate the shelter based on nearby landmarks. The mice acclimated to the area for seven minutes, moving in and out of the shelter.

Next, the researchers added an impending visual or auditory cue to prompt them to seek shelter, also forming a spatial memory relating to their location and visual cues.

To selectively mark shelter memory neurons, the researchers used a light-activated gene expression switching system called Cal-light, which Kwon developed in 2017. Once the scientists identified these neurons in the nucleus accumbens, they activated the expression of genes associated with them, reactivating the shelter-seeking memory in mice while also activating dPAG neurons.

In turn, the mice searched for the area of ​​the box where the shelter once was, when neither the initial threat nor the shelter was present.

To get there, the researchers first selectively activated neurons in the nucleus accumbens, and then separately in the dPAG, to see if activating neurons in a single area of ​​the brain would cause this behavior.

“Surprisingly, we found that mice did not seek shelter when we activated only neurons in the nucleus accumbens,” says Kwon. “While activating neurons in the dPAG caused the mice to respond randomly, but did not guide them specifically to the area where they previously sought refuge.”

“The Cal-light system allowed us to selectively mark a specific brain function, helping us map memory at the cellular level,” says Kwon.

Ultimately, Kwon says this research could provide the basis for reactivating or engineering memory circuits in people with Alzheimer’s disease.

“If we understand the macro structure of memory, we may be able to develop more effective strategies to prevent or slow neurodegenerative diseases using this method,” he says.

Researchers hope to understand the brain-wide structure of memory by selectively marking and reactivating neurons with different functions in different areas of the brain, which leads to other specific behaviors.

“Understanding how all these memory circuits work together will help us better understand how the brain works,” he says.

Other researchers involved in the study are Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi and Seth Blackshaw of Johns Hopkins; Myungmo An of the Florida Max Planck Institute for Neuroscience; and Zirong Gu and Rui M. Costa of the Zuckerman Mind Brain Behavior Institute at Columbia University and the Allen Institute.