INFRASLOW NEUROMODULATORY DYNAMICS GATE MOMENT-TO-MOMENT MEMORY ACCESSIBILITY

Memory expression fluctuates even in response to identical cues, suggesting that transient internal brain states gate memory accessibility. However, the cellular and circuit mechanisms governing these rapid, state-dependent fluctuations remain unclear. Here, we investigated the role of histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN) in modulating reward-associative memory in mice. We found that TMN histaminergic activity exhibits spontaneous infraslow dynamics (0.05–0.1 Hz) during wakefulness that closely track an integrated brain–body state. Using closed-loop experimental designs, we demonstrated that cue delivery during high spontaneous histaminergic states significantly enhanced memory expression. Causal manipulation via brief optogenetic activation or inhibition of these neurons immediately before the cue bidirectionally modulated memory performance. Furthermore, direct activation of histaminergic terminals in the basolateral amygdala (BLA) was sufficient to enhance memory expression. Conversely, pre-cue histaminergic inhibition impaired the subsequent cue-evoked population response in the BLA. These findings reveal that ongoing histaminergic activity exerts a "state-setting" influence, priming BLA circuits to facilitate robust cue responses. We propose a model where infraslow neuromodulatory dynamics dictate internal brain states, thereby gating moment-to-moment memory accessibility.