REGULATION OF THE TRANSITION BETWEEN MEMORY RECALL AND NON- RECALL BY HISTAMINE NEURON ACTIVITY

Abstract Background The spontaneous recollection of forgotten memories remains a puzzling aspect of cognitive function, with uncertain mechanistic underpinnings. Brain histamine is produced in the tuberomammillary nucleus (TMN) and is involved in various functions, including learning and memory. In our previous work, we demonstrated that upregulating histamine release by administrating histamine H3 receptor inverse agonists promotes the recall of forgotten memories. Aims & Objectives The purpose of this study is to examine whether and how histamine neuronal activity regulates the transition between recall and non-recall. Method To probe the dynamics of histaminergic neuronal activity during associative tone-reward learning, we employed fiber photometry. Specifically, a genetically encoded fluorescent calcium sensor GCaMP6s was expressed in histamine neurons within the mouse TMN, and its fluorescence was monitored through implanted optical fibers. We assessed the impact of histamine neuronal activity on associative memory recall by optogenetically inhibiting these neurons. We expressed a light-sensitive chloride ion pump, NpHR, in TMN histamine neurons and utilized green light illumination to modulate their activity. Results After several days of tone-reward conditioning, the mice exhibited predictive licking responses following tone presentations in some trials (recall trials), whereas such responses were absent in other trials (non-recall trials). We compared the histamine neuronal activity between the recall and non-recall and found that the histaminergic neuronal activity preceding the conditioned stimulus (CS) correlated with memory recall performance. To test whether elevated histamine neuron activity preceding the CS fosters associative memory recall, we employed closed-loop CS presentation contingent on histaminergic neuronal activity. The recall performance was enhanced when the CS was presented during elevated histaminergic neuronal activity as opposed to constant activity levels. Furthermore, optogenetic inhibition of histaminergic neurons prior to the CS attenuated associative memory recall. Discussion & Conclusion These results suggest that the activity of histamine neurons preceding the presentation of a memory recall cue is a key regulator in determining the accessibility of stored memories.