Hungarian and U.S. Researchers' Discovery Brings Science Closer to Treating Memory Disorders

The recall of memories is based on changes in the strength of connections between brain cells, known as synapses. Although this theory has been around for nearly fifty years, scientists have not been able to directly observe such synaptic changes in living rodent models. Only in recent years have advances in microscopic technologies allowed researchers to study the real-time activity of brain cells in living, behaving animals.

“A deeper understanding of the mechanisms underlying memory formation and consolidation is essential for identifying precise genetic and molecular targets for future therapies,” said Attila Losonczy, Principal Investigator at the Zuckerman Institute at Columbia University, emphasizing the societal benefits of the work. The exploration of these mechanisms is key to the mission of the BrainVisionCenter, founded by Botond Roska and Balázs Rózsa, and the therapeutic and diagnostic mission will be partly carried out at the institute.

The hippocampus, a key region involved in memory, is one of the most studied areas of the brain, but research in recent decades has relied primarily on EEG scans and brain slices. While they are valuable, the inability to study brain processes in real time with high spatial and temporal resolution in living animals limits the capabilities of these methods. Observing neural networks in action is essetnial for a more profound knowledge of brain function, which requires technologies capable of rapidly and accurately scanning cells and synapses within large volumes of tissue.

"Current models of learning and memory are based on the idea that the strength of synapses, or connections between cells in the brain, changes during learning and memory consolidation. Although previous insights into the functioning of synaptic plasticity came from experiments with relatively simple animals, such as sea slugs, or from research conducted under artificial conditions, such as from brain cells grown in laboratories, this model of memory has become extremely successful over the past 50 years and has also served as the basis for the rapid development of artificial intelligence. It is not surprising, however, that studies in live animals have not been done until now, as this has been a huge technical challenge for researchers," explained Attila Losonczy.

The team's research, published in Nature, marks a significant breakthrough in overcoming this obstacle. Their goal was to develop a method to measure long-term synaptic plasticity - the changes in synapse strength that can last for hours or days - in the neurons responsible for learning and memory in real-time, using living rodent models. Achieving this required the specialized two-photon laser scanning microscope developed by the group led by Balázs Rózsa at the HUN-REN Institute of Experimental Medicine and utilized at the BrainVisionCenter. Equipped with 3D real-time motion correction, the system compensates for the brain's constant movement, enabling the study of minuscule brain structures such as cells and their extensions.

“In in-vivo measurements, involuntary movements such as heartbeat and breathing, as well as voluntary movements, can cause displacements of tens of micrometers, much larger than the structures being measured. This, in turn, makes measurements with high spatial and temporal resolution impossible because the biological structures of interest (cell bodies, cell processes, dendrites, dendritic spines) constantly evade the laser scan. The femtosecond [one millionth of a thousand billionth of a second, the time it takes light to travel 0.3 micrometers, roughly the size of a bacterium] laser scanning technique that we use compensates for movement in real time and in 3D," explained Balázs Rózsa, Director of BrainVisionCenter, Principal Investigator at HUN-REN KOKI and co-author of the publication, explaining the usefulness of the new method.