Postsynaptic histamine H3 receptors in ventral basal forebrain cholinergic neurons modulate contextual fear memory
Yanrong Zheng, Lishi Fan, Zhuowen Fang, Zong‐Han Liu, Jiahui Chen, Xiangnan Zhang, Yi-Xiang Wang, Yan Zhang, Lei Jiang, Zhong Chen, Weiwei Hu
Abstract
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.