Postsynaptic histamine H 3 receptors in ventral basal forebrain cholinergic neurons modulate contextual fear memory.

Overly strong fear memories can cause pathological conditions. Histamine H ₃ receptor (H ₃ R) 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 H ₃ R in cholinergic neurons, but not in glutamatergic neurons, enhances freezing level during contextual fear memory retrieval without affecting cued memory. Consistently, genetically knocking down H ₃ R 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 H ₃ R or chemogenetic inhibition of vBF cholinergic neurons. Spatiotemporal regulation of H ₃ R by a light-sensitive rhodopsin-H ₃ R fusion protein suggests that postsynaptic H ₃ Rs in vBF cholinergic neurons, but not presynaptic H ₃ Rs of cholinergic projections in the dorsal hippocampus, are responsible for modulating contextual fear memory. Therefore, precise modulation of H ₃ R in a cell-type- and subcellular-location-specific manner should be explored for pathological fear memory.
Competing Interests: Declaration of interests The authors declare no competing interests.
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