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George Mason University researchers Holger Dannenberg and Giorgio Ascoli, an assistant professor and professor, respectively, of bioengineering and neuroscience, received a grant from the National Institutes of Health for more than $2 million to examine how aging changes the processes that allow us to form and retrieve memories.
Despite decades of advances in neuroscience, Dannenberg said, fundamental questions remain about how the activity of individual cells produces something as complex as a memory. “I think we came a long way, but there's still a lot to discover. I'm not sure if we really have a good understanding of what underlies computations in the brain.”
Combining biological experiments with increasingly sophisticated computational models offers one way to get closer to that understanding, while potentially helping researchers piece together what happens to memory over a lifetime.
“The whole idea is, what happens to the cholinergic system (the network of brain cells that communicate using acetylcholine, a chemical involved in learning and memory) during aging and what are the effects on the hippocampus (a region in the brain critical for forming new episodic memories)?” said Dannenberg. “What are the effects on learning of spatial memories?”
With the gold-standard longitudinal approach of monitoring people from youth through advanced age proving impractical for such research, Dannenberg and Ascoli are combining experiments in mice with a detailed computational model of the brain to fill in gaps and better understand how aging changes memory functioning.
Acetylcholine, which researchers have known for decades has a role in memory, is key to this research. Studies in humans show that blocking the effects of acetylcholine can interfere with the ability to learn new information, while leaving previously formed memories intact.
Dannenberg and Ascoli want to understand what happens to that system as the brain ages. Does the amount of acetylcholine released decline? Does the brain become less able to rapidly shift between higher and lower levels? And how might those changes affect activity in the hippocampus, a brain region critical to memory?
They will use a technique called fiber photometry, employing fluorescent sensors to monitor acetylcholine release in the hippocampus of mice as they perform memory tasks. In addition, they directly measure the activity of individual neurons in the hippocampus using microelectrodes. Researchers can then compare young, middle-aged, and older mice to look for differences in both brain activity and behavior.
The experiments focus on spatial memory, where researchers observe if a mouse remembers relationships between objects and locations it previously explored. But comparing mice of different ages still provides snapshots rather than a continuous picture of aging, which is where Ascoli's computational expertise comes in.
His lab curates Hippocampome.org, a massive knowledge base containing decades of research about the types of neurons found in the hippocampus and how they connect. Using that information, the researchers can create a large-scale computer simulation designed to reproduce hippocampal activity down to the firing, or “spiking,” of individual neurons.
The researchers plan to add acetylcholine to that model as a factor influencing neural activity, something Dannenberg said has not previously been incorporated into this type of large-scale simulation.
They can then feed measurements from the mouse experiments into the computer model and see whether the simulation reproduces what they observed in the animals. Just as importantly, the model can suggest biological mechanisms that might explain those observations. Those predictions can then go back to the laboratory for testing.
“If successful, we would have an experiment-theory loop,” Dannenberg said. “We go from the experiment to the model, and then we go back to the experiment.”
With each trip around that loop, the researchers hope to narrow the possibilities and develop a more detailed picture of how changes in acetylcholine alter activity in the hippocampus and, ultimately, affect the ability to learn and recall information.
The work could also help researchers better understand the boundary between normal aging and diseases that affect memory. The hippocampus and cholinergic system are both affected in Alzheimer's disease, although Dannenberg says that age-related memory changes do not necessarily indicate Alzheimer's or another neurodegenerative condition.