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

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Fear memory is critical for evaluating and responding to threatening situations, yet overly strong fear memories can lead to debilitating conditions, such as post-traumatic stress disorder (PTSD). Histamine H3 receptor (H3R) serves as an optimal drug target for CNS disorders thanks to its lower periphery distribution and profound effect on the release of histamine and other neurotransmitters. However, the role of H3R in fear memory remains elusive, especially in certain types of neurons and in certain subcellular compartments. This study evaluated fear memory in ChAT-Cre;Hrh3fl/fland CaMKIIa-Cre;Hrh3fl/fl mice and showed that a deficit of H3R in cholinergic neurons, but not in glutamatergic neurons, reinforces contextual fear memory without affecting cued fear memory. Consistently, genetic knockdown of H3R or chemogenetic activation of cholinergic neurons in the ventral basal forebrain (vBF) mimicked this enhanced fear memory, whereas the memory reinforcement could be rescued by re-expressing H3R or by chemogenetic inhibition of cholinergic neurons in the vBF. Importantly, we observed structural and functional connections between histaminergic projections and cholinergic neurons in the vBF; specifically, using a light-sensitive rhodopsin–H3R fusion protein for spatiotemporal regulation of H3R, we found that postsynaptic H3R in cholinergic neurons in the vBF were responsible for the enhanced contextual fear. In contrast, presynaptic H3R in cholinergic neuron projections in the dorsal hippocampus were dispensable for modulating contextual fear memory. Together, our results reveal that postsynaptic histamine H3R in vBF cholinergic neurons is engaged in modulating contextual fear memory, making it an attractive drug target for therapeutic intervention of PTSD. This study lays the foundation for the development and application of H3R-related agents in CNS disorders.

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