The brain’s “uncertainty zone” affects its ability to form new memories

Newswise – The neocortex is the largest and most complex part of the brain and has long been considered the ultimate storage site for long-term memories. But how are traces of past events and experiences placed there? Researchers at the Faculty of Medicine of the University of Freiburg, led by Prof. Dr. Johannes Letskus And the Max Planck Institute for Brain Research has discovered that a little-studied region of the brain, the ‘uncertainty zone’ or ‘uncertain zone’, communicates with the neocortex in unconventional ways to rapidly control memory formation. Their work provides the first functional analysis of how long-range inhibition shapes information processing in the neocortex. It is likely that the signals identified in this study are important not only for memory, but also for a number of additional brain functions, such as attention. The results have just been published in the journal nervous.

“Top-down signals” are at the heart of the search

Memory is one of the most important functions of the brain, enabling people to learn from experience and remember the past. Furthermore, the mechanistic understanding of memory has implications that can range from treating memory and anxiety disorders to developing artificial intelligence and efficiently designing hardware and software. To form memories, the brain must make connections between “bottom-up” sensory signals from the environment and internally generated “top-down” signals that convey information about past experiences and current goals. These top-down signals are the focus of current research.

In recent years, researchers have begun to identify a number of top-down projection systems, all of which share a number of common features: they signal through synaptic excitation, the standard method for sending information between cortical regions, and they also display the common system of memory encoding. . A learned related stimulus elicits a stronger response in these systems, suggesting that this positive potentiation is part of the puzzle that is memory tracking.

effect on network function

In contrast to these systems, long-acting inhibitory pathways are fewer and fewer in number, but mounting evidence suggests that they can still have surprisingly powerful effects on network function and behaviour,” says Prof. Freiburg and former research group leader at the Max Planck Institute for the Brain.”We set out to determine whether such inputs might be present in the neocortex and, if so, how they might contribute uniquely to memory.”

Doctor. Anna SchroederD., the study’s first author and a postdoctoral researcher in Litzkus’ lab, decided to focus on the predominantly inhibitory hypothalamic nucleus, the non-inflammasome region, to address this question. While the function of this region of the brain remains as enigmatic as its name suggests, our preliminary findings indicated that the uncorrected region sends inhibitory projections that selectively transmit to neuronal regions of the neocortex known to be important for learning. In her efforts to study the plasticity of this system across all stages of learning, she implemented an innovative approach that allowed her to track the responses of individual synapses in the neocortex before, during, and after a learning paradigm.

Redistribution of activity during learning

“The results were amazing,” Schroeder recalls. “While about half of the synapses developed stronger positive responses during learning, the other half did exactly the opposite. In fact, what we observed was thus a complete redistribution of inhibition within the system due to learning.” This indicates that the zona incerta synapses encode prior experience in a unique bidirectional manner. This was particularly evident when the scientists compared the magnitude of plasticity to the strength of acquired memory. They found a positive correlation, which indicates that the zona incerta projections encode learned relevance from sensory stimuli.

In separate experiments, Schroeder discovered that silencing these projections during the learning phase impairs later memory tracking, suggesting that the bidirectional plasticity that occurs in these projections is required for learning. It also found that these inhibitory projections preferentially form functional connections with other inhibitory neurons in the neocortex, in effect forming a long-term inhibition circuit. “This connection suggests that activation of the affected region should result in net excitation of neocortical circuits,” says Schroeder. “However, combining this with the redistribution of inhibition that we see with learning shows that this pathway likely has richer computational consequences for neocortical processing.”

Changes in stimulus representation

The scientists were particularly intrigued by the zona incerta group of synapses that showed negative strength, as this type of plasticity had not been observed before in previously studied top-down excitatory pathways. They felt that the computational approaches might provide valuable insights into how these unique responses evolve. Further analyzes in collaboration with the laboratory of Prof. Dr. Henning Sprinkler And his team at the Technical University of Berlin revealed that, remarkably, these negative responses are the main drivers of changes in stimulus representation that occur during learning itself.

Furthermore, the incerta area is among the very few regions standardly targeted for deep brain stimulation in human Parkinson’s patients, which opens up an intriguing possibility for future translational action. “Ultimately, we hope this study will inspire other researchers to further explore the role of long-range inhibition in regulating neocortical function, both from the affected region and from additional yet-to-be-identified sources,” Letzkus says.

Facts overview:

  • Original publication: Schroeder, A., Pardi, MB, Keijser, J., Dalmay, T., Groisman, A.I., Schuman, EM, Sprekeler, H.. In: neurons. DOI: https://doi.org/10.1016/j.neuron.2022.12.010
  • The study involved researchers from the University of Freiburg, the Max Planck Institute for Brain Research in Frankfurt am Main, and the Technical University of Berlin. It was funded by the German Research Foundation, the European Commission, the European Molecular Biology Organization and the Alexander von Humboldt Foundation.
  • Study led Johannes LetskusProfessor at the Institute of Physiology, University of Freiburg. His research interests include neural networks of memory and attention, adaptive (masculine) fear memory bases in the neocortex, and the inhibitory system in the neocortex of rodents and humans.

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