How the Brain Tunes Inhibition to Balance Memory Flexibility and Stability

Every time we walk into a familiar room, the brain performs a remarkable balancing act. It must recognise the space as the same place we visited yesterday, even if a chair has been moved, while simultaneously noticing that something has changed. This tension between stability and flexibility lies at the heart of how memory works, and for decades neuroscientists have struggled to understand how the brain manages both demands at once. Now, a team at the Institute for Neurosciences, a joint centre of the Spanish National Research Council (CSIC) and the University Miguel Hernández of Elche (UMH), has identified a mechanism that appears to govern this trade-off, and the answer lies in the activity of inhibitory neurons in a small, enigmatic region of the hippocampus.

The study, published in PLOS Biology, was led by Santiago Canals, head of the Plasticity of Brain Networks laboratory, together with Encarni Marcos, who heads the Neural Mechanisms of Behaviour research line at the same institute. Their findings show that the level of inhibitory tone in the dentate gyrus, a gateway structure within the hippocampus, determines whether the memory system prioritises sensitivity to small differences between experiences or consistency in the face of change. Crucially, the researchers discovered that this is not a fixed setting but a dynamic dial, one whose optimal position depends on how much information the brain is being asked to remember.

Memory, as Canals emphasises, is not a static repository of information but a living and adaptive process. For memory to be useful, the brain cannot simply store a perfect copy of every experience. If every minor variation in the environment generated an entirely new memory trace, we would be unable to recognise our own homes after the slightest rearrangement of furniture. At the same time, the system must remain sensitive enough to distinguish between two experiences when the differences genuinely matter, such as recognising that a familiar route has been blocked or that a normally friendly face is showing signs of anger. The dentate gyrus, the researchers argue, is one of the key places where this compromise is negotiated.

The dentate gyrus occupies a special position in hippocampal circuitry. It receives most of the information flowing into the hippocampus from the surrounding cortex and performs a transformation that neuroscientists call pattern separation, the process by which similar inputs are made more distinct from one another before they are passed deeper into the memory system. Inhibitory interneurons, the cells that suppress the activity of their neighbours, are central to this computation. By experimentally modifying the activity of these inhibitory cells in mice during memory encoding, the window of time in which information is processed to form a new memory, the team was able to shift the balance between sensitivity and consistency in a controlled way.

The behavioural assays the researchers used exploited a natural preference of mice for novelty. When a mouse encounters something it has not seen before, it spends more time exploring it. By presenting animals with objects whose positions had been shifted by varying amounts, the team could infer from exploratory behaviour whether the animals remembered the original arrangement and how finely they could discriminate changes to it. The results were striking. When inhibition was reduced below normal levels, mice became exquisitely sensitive to change: they detected displacements of objects so small that control animals ignored them entirely. Their behaviour, as Marcos describes it, was more consistent with better memory retrieval and more detailed recall. Conversely, when inhibitory activity was increased, the animals became less sensitive to small differences, and their memory representations proved more resistant to change.

At first glance, these results might suggest that lowering inhibition is simply beneficial, producing sharper, more detailed memories. But the team suspected the story was more complicated, and to test that suspicion they turned to computational modelling. The model offers a simplified mathematical representation of how memory representations are formed and retrieved, allowing the researchers to systematically vary the level of inhibition and observe the consequences for two competing performance measures: the ability to distinguish between similar experiences, and the ability to maintain consistent representations across changing conditions. The simulations revealed a fundamental constraint. Lower inhibition improves discrimination, but it also makes the stored representations increasingly vulnerable to interference, the corruption of one memory by another, and this vulnerability grows as the number of items to be remembered increases.

The model generated a specific and testable prediction: there is no single optimal level of inhibition that works in all situations. When memory load is low, reduced inhibitory activity can favour fine discrimination between similar experiences. But as the amount of information to be remembered grows, higher inhibitory activity becomes advantageous because it helps maintain representations that are sufficiently consistent to avoid confusion between memories. In other words, the ideal operating point of the dentate gyrus shifts depending on the cognitive demands of the moment, a prediction that departs from the simpler view of inhibition as a fixed filter.

To test this prediction in living animals, the researchers designed a more demanding task in which mice had to learn associations between objects, locations and different environments, thereby increasing the memory load relative to the simpler object-placement assays. The behavioural results matched the model’s forecasts. Under conditions of higher memory load, the advantages of reduced inhibition diminished and reversed, exactly as the computational framework predicted. This convergence between simulation and experiment is one of the study’s most significant achievements. By combining experimental and computational tools, as Canals explains, the team identified a balance point in memory formation that helps explain when this inherently flexible system updates with new information and when it instead preserves greater consistency.

An important detail of the findings concerns timing. The effects of manipulating inhibition were observed specifically during encoding, the phase in which the initial representation of an experience is constructed. The mechanism identified therefore shapes how memories are built in the first place, rather than how they are later stabilised through consolidation or retrieved from storage. This distinction matters for how neuroscientists think about the dentate gyrus: rather than being a passive relay, it appears to actively set the operating characteristics of new memories at the moment of their creation, determining in advance whether a given representation will lean toward fine-grained discrimination or robust stability.

Taken together, the results suggest that inhibitory circuits in the dentate gyrus place the hippocampus in different functional states. In a high-sensitivity state, the system readily incorporates changes and discriminates between similar experiences, at the cost of greater vulnerability to interference. In a high-consistency state, representations are protected from interference but small differences may go unnoticed. Marcos interprets the findings as evidence for a mechanism that dynamically adjusts the mode of operation by using inhibition, effectively retuning the memory system as task demands change. The researchers are careful to note, however, that the study has not yet identified which signals control this adjustment under natural conditions. Determining which regulatory mechanisms modulate inhibitory activity, and when in the course of natural behaviour the brain shifts between these states, will be the subject of future research. The work was funded by the Spanish State Research Agency, the Ministry of Science, Innovation and Universities, the Severo Ochoa Programme for Centres of Excellence, the European Union’s Next Generation funds, and the Generalitat Valenciana. Beyond its immediate implications for basic neuroscience, the findings may eventually inform our understanding of disorders in which this balance goes awry, from conditions of excessive memory generalisation to those marked by disruptive interference between memories.

Subject of Research: The role of dentate gyrus inhibitory interneurons in balancing memory flexibility and stability

Article Title: Study by the Institute for Neurosciences CSIC-UMH reveals how the brain balances memory flexibility and stability

Article References: Study by the Institute for Neurosciences CSIC-UMH reveals how the brain balances memory flexibility and stability. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: neuroscience, hippocampus, dentate gyrus, memory, inhibitory interneurons, pattern separation, memory encoding, computational model, PLOS Biology, CSIC, memory load, interference