Neuronal master switch reshapes brain activity during learning

Memories and learning processes are based on changes in the brain's neuronal connections and, as a result, in signal transmission between neurons. For the first time, DZNE researchers have observed an associated phenomenon in living brains – specifically in mice. This mechanism concerns the cellular pulse generator for neuronal signals (the "axon initial segment") and had previously only been documented in cell cultures and in brain samples. A team led by neuroscientist Jan Gründemann reports on this in the journal "Nature Neuroscience", alongside experts from Switzerland, Italy, and Austria. Their study sheds light on the brain's ability to adapt. Next, the researchers intend to investigate the significance of these findings in Alzheimer's disease.

In the brain, neurons branch out and connect with each other to form a network through which electrical signals are actively exchanged. This network structure is an essential component of the brain's "hardware" and is therefore fundamental to its function, especially with regard to learning processes and memory formation. However, this complex architecture and signal transmission across this network are not fixed; they can change as a result of experiences and events. This flexibility, also known as "neuroplasticity", is the basis for the brain's ability to adapt.

Neuronal pacemaker

Neuronal plasticity largely depends on the ability to adjust the strength of connections and signal transmission between neurons. If we consider these cells as relay stations, their "coupling strength" determines how efficiently signals are transmitted from one cell to another and how well they spread within the neuronal network. Jan Gründemann, a research group leader at DZNE and professor at the University of Bonn, and coworkers were now able to observe how the section that generates the electrical signal changes. Most neurons have such an "axon initial segment", which is characterized by a particularly high density of specific ion channels. "The axon initial segment determines whether a nerve impulse is generated or not," says the neuroscientist. "Thanks to specialized microscopy methods, two members of our team, Chloé Benoit and Dan Ganea, were able to monitor the size of these segments in the living brain during learning – that's a first. Until now, axon initial segments were mostly measured in cell cultures or tissue samples. We have now tracked them in the brain over several days in the context of learning."

Sometimes longer, sometimes shorter

The findings are based on studies in mice: In a behavioral experiment, the animals learned to respond to different situations – thus learning from their experiences and memories and adjusting their behavior accordingly. The researchers observed individual neurons in living animals before and after the training sessions. They were able to repeatedly locate specific nerve cells and their axon initial segments and thus record changes over time. Specifically, they examined an area of the cerebral cortex that is known to be involved in learning processes. "We found that the axon initial segments of the observed neurons changed length; they got longer or shrunk," explains Gründemann. "The length of the axon initial segment determines the excitability of a neuron. Cells with a long initial segment generate stronger pulses than those with a short segment. This mechanism can therefore regulate brain activity. We do not yet know why some segments became longer and others shorter. This is presumably a crucial control lever to optimally adjust neuronal activity."

Master switch

The axon initial segment is part of the "axon" – a fiber-like extension of neurons that transmits electrical impulses to other cells. At the end, the axon ramifies multiple times, allowing a single neuron to contact many other cells. These contact points – called "synapses" – are known to also change during memory formation, thereby influencing the transmission of neuronal signals. "Signals get transmitted from one neuron to another via synapses, but the axon initial segment decides whether a neuron will fire and how strong its output will be. So, in a sense, this is a master switch. Both synapses and axon initial segments influence signal transmission between neurons. Both are sites of neuroplasticity. And our study shows that both can be relevant for memory formation," says Gründemann. "Although we have only studied a specific area of the brain, we assume that, similar to synaptic plasticity, dynamic changes of the axon initial segment are a general principle associated with learning. We are planning to examine this phenomenon in other brain regions, particularly with regard to neurodegenerative diseases."

Studies on Alzheimer's

"In Alzheimer's disease, signal transmission between neurons is impaired. That is why we are interested, for example, in how the protein deposits typical of Alzheimer's affect the function of the initial segments. Such topics can be studied in mice that exhibit disease traits similar to those of Alzheimer's. This could help improve our understanding of the disease process and potentially identify entry points for future therapies," says Gründemann.