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Glimpsing the Elusive Memory Trace

Jesse Jenkins

What is a memory and how is it recorded and stored at the molecular level? New photo-imaging technology is beginning to give researchers some answers. Read more...

In response to stimuli, neural networks fire flurried electrical responses that leave neurological traces like crumb trails. These can be eliminated or strengthened for long-term recall. But understanding how this happens is daunting due to the complexity of the connections and sheer number of neurons in the cortex.

Now, writing in the journal Proceedings of the National Academy of Sciences, researchers describe a new method combining 3D imaging with computational methods to simultaneously track how thousands of neurons respond to external stimuli in the cortex of mice, long-term.

“There are a lot of activities going on in the cortex and it’s really hard to piece out which neurons are responsible for long-term memory,” said the study’s corresponding author, JiSong Guan, Principle Investigator at the Center for Life Sciences at Tsinghua University in China. “For the first time, we’ve directly shown how context environments can specifically activate a very small portion of neurons, and this can be reactivated during recall of memory.”

The team first began by familiarizing mice with three distinct environment-specific trials over a two-month period. To track the neurons activated in cortical circuits during each behavioral trial, they fluorescently tagged early growth response protein (EGR1), which is normally expressed during high-frequency neuronal stimulation and long-term learning processes.

Then the researchers used two-photon imaging technology to visualize neuronal activity in 3D slices of the brain and using a newly developed automatic recognition algorithm, quantitated and reconstructed the activity of thousands of individual neurons in each mouse over time.

The team ultimately found task-specific neuronal activation in cortical layer II, but was surprised to see later activation in multiple cortical regions.

“We were originally expecting some specific region of the cortex to have a strong response to a typical memory because some areas are more important than others,” explained Guan. “But we found that context memories show specific storage in almost each individual cortical area as a sparse response, so that was kind of surprising to us.”

According to Guan, this technology may be used in studies of autism or schizophrenia to observe how neural network responses change in mouse models with physiological disease. For now, the group plans investigate how cortical layer II forms the memory traces.

“We want to better understand how those neural circuits gather together to form a specific response in a very complicated environment,” said Guan. “How those memories change their location and gradually build the remote memory in the cortex is still an important question to ask.”


Xie H, Liu Y, Zhu Y, Ding X, Yang Y, Guan JS. In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2788-93.