The same memory can feel vivid and accessible one moment, yet stubbornly out of reach the next — even when the memory itself remains intact. A research team led by Professor Hiroshi Nomura at the Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, has identified a neural mechanism that may explain this variability.
The study shows that slow spontaneous fluctuations in brain histamine neurons help control moment-to-moment memory accessibility. When histamine neuron activity was high just before a memory cue, mice were more likely to express a learned memory. When histamine neuron activity was low, the same cue was less effective.
“Our findings suggest that failure to recall is not always due to loss of the memory itself,” said Hiroshi Nomura, senior author of the study. “Instead, the brain may sometimes be in a state in which a stored memory is difficult to access.”
Histamine neurons are located in the tuberomammillary nucleus of the hypothalamus and are best known for regulating wakefulness. They also project widely to memory-related brain regions, including the cortex, hippocampus and amygdala. However, whether their activity during wakefulness shapes access to stored memories has remained unclear.
The team recorded histamine neuron activity in awake mice and found that their activity rose and fell slowly over tens of seconds. These slow fluctuations were accompanied by changes in cortical activity, pupil size, and facial movement, indicating that histamine activity reflected a broader brain and body state.
The researchers then trained mice to associate a sound with a sugar-water reward. After learning, mice licked in response to the sound, indicating that the sound cue elicited a learned reward-related response. Histamine neuron activity was higher before trials in which mice showed strong memory-guided licking than before trials in which they showed no licking, suggesting that histamine activity helps prepare the brain before the cue appears.
To go beyond this correlation, the researchers used a real-time system that monitored histamine neuron activity and delivered a memory cue during either high- or low-activity states. Memory-guided licking responses were about 40% higher when the cue was presented during a high-histamine state than during a low-histamine state.
The researchers further tested causality by manipulating these neurons using optogenetics. Suppressing histamine neurons immediately before the sound cue reduced memory-guided licking, whereas activating them increased it. These manipulations did not alter general licking behavior, responses to the reward itself, auditory responses, or pupil size, suggesting that the effects were not readily explained by broad changes in arousal, sensory responses, or movement.
The study also identified a downstream mechanism in the basolateral amygdala, a brain region important for learned reward associations. Calcium imaging showed that, when mice strongly expressed the learned memory, populations of amygdala neurons more reliably reproduced the activity pattern associated with the learned cue. When histamine neurons were suppressed before the cue, this memory-related amygdala pattern became weaker and less reliable.
Together, the findings support a “priming-state” model: spontaneous fluctuations in histamine neuron activity prepare memory circuits in advance, making it more or less likely that an incoming cue will trigger the appropriate memory-related neural pattern.
“This work provides a new way to think about memory retrieval,” Nomura said. “Rather than viewing recall simply as reading out a stored trace, we show that internal brain state can gate whether that trace becomes accessible at a given moment.”
Because the 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, and social memory, and whether similar fluctuations contribute to everyday memory variability in humans. The findings may also provide a framework for studying conditions in which cognition fluctuates over time, such as aging and dementia.
Neuron
Experimental study
Animals
Infraslow histaminergic dynamics govern priming states to gate moment-to-moment memory accessibility
11-Jun-2026