How aging alters brain cells' ability to maintain memory

While it is well established that memory can worsen as people age, it has not been clear what changes occur at the individual brain neuron level to cause this. Now, scientists at Nanyang Technological University, Singapore (NTU Singapore) have demonstrated that communication among memory-coding neurons — nerve cells in the brain responsible for maintaining working memory — is disrupted with aging and that this can begin in middle age.

Previous studies used nerve cells from dead subjects, but the NTU team measured the real-time activity of individual nerve cells in live mice. To make these measurements, the team adopted an optical imaging technique that allowed them to understand the function of each neuron by measuring its neural activity in the context of working memory.

In lab experiments, the scientists investigated how neurons in mice of three different age groups — young, middle age and old age — responded to tasks that required memory. The researchers showed that compared to young mice, middle-aged and old mice required more training sessions to learn new tasks, indicating some decline in memory and learning abilities from middle age. But beyond that, they also found changes in the nerve cells of older mice.

Using advanced optical techniques (calcium imaging and optogenetic manipulation) that allow researchers to observe multiple individual neurons and manipulate their activity, the NTU team discovered that neurons in one part of the brain, the prefrontal cortex, showed robust memory coding ability in young mice. However, this ability to hold memory diminishes in middle-aged and old mice due to weakening connections among the neurons, which causes the mice to take longer to recall and perform tasks.

While scientists know connections between neurons are crucial for storing memory, it has not previously been experimentally demonstrated in the live brain how aging brain cell changes cause weakening connections. The team’s findings, published in the journal Nature Communications, thus suggest that strengthening the weakened connections between the nerve cells, such as through memory training activities, could help delay the deterioration of people’s working memories as they age.

“Our study highlights a significant reduction in communication among neurons responsible for encoding memories in the prefrontal cortex — a key factor in age-related working memory decline, which was a neurological process not widely understood until now,” said Assistant Professor Tsukasa Kamigaki, lead investigator on the study.

“This discovery provides more evidence that proactive intervention can improve neuron communication. Examples of intervention include lifestyle changes such as cognitive training and regular exercise. These activities can potentially mitigate the impact of cognitive aging and enhance people’s overall cognitive health as they age.”

Excitatory neurons in the prefrontal cortex are shown in a fluorescent shade. Image credit: NTU Singapore.

Further experiments also showed that the weakening connections between the nerve cells led to instability of neural circuits in the prefrontal cortex from as early as middle age, resulting in poorer ability to hold memory. The NTU team used optogenetic technology — a method that uses genetically engineered light-sensitive ion channels in neurons, which enables the control of neuronal activity through light stimulation — to briefly turn off neurons in the brain for one to two seconds and found that the working memory circuits in middle-aged mice are particularly sensitive to the short interruptions in neural activity.

“Our four-year study shows that the ongoing function of the prefrontal circuits is critical for memory tasks,” said co-first author Huee Ru Chong. “The fact that the brain circuits showed signs of degradation from middle age highlights the need for clinical strategies to safeguard our mental wellbeing as early as possible.”

Co-first author Dr Yadollah Ranjbar-Slamloo added, “We found that the prefrontal cortex in mice stays active when they remember things, like humans. The finding suggests that mice could be a good model for studying how memory works and its aging process. Our findings therefore indicate that, just as in mice, our brain may start to degrade early on as we age.”

The next steps for this project are to investigate more brain-wide neural changes that occur during middle age to understand how proactive interventions may enhance communication among different brain areas.

Top image credit: iStock.com/Moyo Studio