Postsynaptic histamine H receptors in ventral basal forebrain cholinergic neurons modulate contextual fear memory.

Overly strong fear memories can cause pathological conditions. Histamine H receptor (HR) has been viewed as an optimal drug target for CNS disorders, but its role in fear memory remains elusive. We find that a selective deficit of HR in cholinergic neurons, but not in glutamatergic neurons, enhances freezing level during contextual fear memory retrieval without affecting cued memory. Consistently, genetically knocking down HR or chemogenetically activating cholinergic neurons in the ventral basal forebrain (vBF) mimics this enhanced fear memory, whereas the freezing augmentation is rescued by re-expressing HR or chemogenetic inhibition of vBF cholinergic neurons. Spatiotemporal regulation of HR by a light-sensitive rhodopsin-HR fusion protein suggests that postsynaptic HRs in vBF cholinergic neurons, but not presynaptic HRs of cholinergic projections in the dorsal hippocampus, are responsible for modulating contextual fear memory. Therefore, precise modulation of HR in a cell-type- and subcellular-location-specific manner should be explored for pathological fear memory.