A research team led by Professor Hiroshi Nomura at the Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, announced on June 11 that slow spontaneous fluctuations in brain histamine neuron activity control moment-to-moment memory accessibility in mice.
The study found that when histamine neuron activity was high just before a memory cue, mice were more likely to express a learned memory. In contrast, low histamine neuron activity made the same cue less effective. Histamine neurons are located in the tuberomammillary nucleus of the hypothalamus and are known for regulating wakefulness. They also project to several memory-related brain regions, including the cortex, hippocampus, and amygdala. The role of their activity during wakefulness in shaping access to stored memories had previously been unclear.
Researchers recorded histamine neuron activity in awake mice and observed slow rises and falls over tens of seconds. These fluctuations coincided with changes in cortical activity, pupil size, and facial movement—indicating that histamine levels reflected broader brain and body states. Mice trained to associate a sound with a sugar-water reward showed higher pre-cue histamine neuron activity before trials where they demonstrated strong learned responses compared to trials without such responses.
To test causality beyond correlation, researchers used a real-time system monitoring histamine neuron activity to deliver cues during either high- or low-activity states. Memory-guided licking responses increased by about 40% when cues were presented during high-histamine states compared to low-histamine states. Further experiments using optogenetics showed that suppressing these neurons immediately before the sound cue reduced memory-guided licking, while activating them increased it. These manipulations did not affect general licking behavior or other non-memory-related behaviors.
The study also identified involvement of the basolateral amygdala—a region important for learned reward associations—where calcium imaging revealed stronger reproduction of learned cue patterns when mice expressed strong memories. Suppressing histamine neurons weakened these patterns.
Professor Nomura said, "This work provides a new way to think about memory retrieval... 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." Researchers note further studies are needed to determine if similar mechanisms apply across different types of memories or contribute to cognitive variability seen in conditions like aging and dementia.
