The same memory can feel vivid and accessible one moment, and stubbornly out of reach the next, even if the memory itself is intact. A research team led by Professor Hiroshi Nomura of the Institute for Brain Science, Graduate School of Medical Science, Nagoya City University has identified a neural mechanism that may explain this variation.
This study shows that slow spontaneous fluctuations in brain histamine neurons help control moment-by-moment memory access. If the activity of histamine neurons was high just before the memory cue, the mice were more likely to express the learned memory. The same cues were less effective when the activity of histamine neurons was low.
Our findings suggest that the inability to recall is not necessarily due to loss of memory itself. Rather, the brain may find it difficult to access stored memories. ”
Lead author of the study, Hiroshi Nomura
Histamine neurons are located in the tuberomammillary nucleus of the hypothalamus and are best known for controlling wakefulness. It also projects widely to brain areas associated with memory, such as the cortex, hippocampus, and amygdala. However, whether their activity during wakefulness shapes access to stored memories remains unknown.
When the researchers recorded the activity of histamine neurons in awake mice, they found that the activity rose and fell slowly over tens of seconds. These slow fluctuations were accompanied by changes in cortical activity, pupil size, and facial movements, indicating that histamine activity reflects broader brain and body states.
The researchers then trained the mice to associate the sound with a sugar water reward. After learning, the mice licked in response to the sound. This indicates that the sound cue elicited a response associated with the learned reward. Activity in histamine neurons was higher before trials in which the mice showed a strong lick based on memory than before trials in which they did not show a lick. This suggests that histamine activity helps prepare the brain before the cue appears.
To go beyond this correlation, the researchers used a real-time system that monitors the activity of histamine neurons and provides memory cues when they are in high or low activity states. Memory-based lick responses were approximately 40% higher when the cue was presented in the high-histamine condition than in the low-histamine condition.
The researchers further tested causality by manipulating these neurons using optogenetics. Inhibiting histamine neurons immediately before a sound cue reduces memory-based licking, whereas activating histamine neurons increases it. These manipulations did not change general licking behavior, responses to the reward itself, auditory responses, or pupil size, suggesting that this effect cannot be easily explained by widespread changes in arousal, sensory responses, or movement.
The study also identified downstream mechanisms in the basolateral amygdala, a brain region important for learning-reward associations. Calcium imaging showed that when mice strongly expressed a learned memory, a population of amygdala neurons more reliably reproduced the activity patterns associated with the learned cue. When histamine neurons are suppressed before a cue, the amygdala patterns associated with this memory become weaker and less reliable.
Taken together, this finding supports the “primed state” model. That is, spontaneous fluctuations in histamine neuron activity pre-prime memory circuits, making incoming cues more or less likely to trigger appropriate memory-related neural patterns.
“This study provides a new way of thinking about memory recovery,” Nomura said. “Rather than thinking of retrieval as simply retrieving a memorized trace, we show that states inside the brain can control whether that trace is accessible at any given moment.”
Because this study used a reward memory task in mice, further research will be needed to determine whether histamine-dependent brain states shape other forms of memory, such as fear, spatial memory, and social memory, and whether similar fluctuations contribute to fluctuations in everyday memory in humans. The findings may also provide a framework for studying conditions in which cognition fluctuates over time, such as aging and dementia.
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Reference magazines:
Morishita, Y., others. (2026). Infraslow histaminergic dynamics control priming states to gate moment-to-moment access to memory. neuron. DOI: 10.1016/j.neuron.2026.05.019. https://www.cell.com/neuron/fulltext/S0896-6273(26)00411-3
