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The ability of organism to detect and respond to novelty is critical to adaptation in a changing environment. Here we studied how brain activity changes as environmental novelty decreases. To this end, we placed mice in an open field (OF) to explore it in four daily sessions and showed a significant decrease in exploration from days 1 to 4. We then analyzed the brain activity by imaging c-Fos expression after mice explored the OF once (high novelty) or four times (low novelty) and found that the decrease in novelty was accompanied by a decrease in cortical (prefrontal, retrosplenial, and somatosensory) and dentate gyrus c-Fos activation. There was no effect of novelty level on c-Fos expression in CA1 and CA3 areas. We further used TRAP technique to compare populations of neurons activated during the first and last OF trials and demonstrated that ~40% of neurons that were activated by the first OF trial in cortical regions and ~20% of such neurons in the hippocampus were reactivated in the fourth OF session. Finally, we used miniscope CA1 calcium imaging to examine the relation between the level of novelty and neuronal selectivity to different environmental features. As novelty decreased, there was no change in the number of place-, speed-, and object-selective neurons. In summary, we demonstrate that c-Fos activation linked to neuronal plasticity diminishes with decreasing novelty, while stable neuronal activity encoding remains essential for behavior manifestation. Support of the Moscow State University School “Brain, Cognitive Systems, Artificial Intelligence” and the INTELLECT Foundation.