Postsynaptic histamine H₃ receptors in ventral basal forebrain cholinergic neurons modulate contextual fear memory

Overly strong fear memories can cause pathological conditions. Histamine H₃ receptor (H₃R) 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 H₃R in cholinergic neurons, but not in glutamatergic neurons, enhances freezing level during contextual fear memory retrieval without affecting cued memory. Consistently, genetically knocking down H₃R 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 H₃R or chemogenetic inhibition of vBF cholinergic neurons. Spatiotemporal regulation of H₃R by a light-sensitive rhodopsin-H₃R fusion protein suggests that postsynaptic H₃Rs in vBF cholinergic neurons, but not presynaptic H₃Rs of cholinergic projections in the dorsal hippocampus, are responsible for modulating contextual fear memory. Therefore, precise modulation of H₃R in a cell-type- and subcellular-location-specific manner should be explored for pathological fear memory.