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

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.

恐惧记忆对于评估和应对威胁性情境至关重要，然而过强的恐惧记忆可能导致令人衰弱的疾病，如创伤后应激障碍（PTSD）。组胺H3受体（H3R）因其较低的周围分布和对组胺及其他神经递质释放的深远影响，成为中枢神经系统（CNS）疾病理想的药物靶点。然而，H3R在恐惧记忆中的角色仍然扑朔迷离，尤其是在特定类型的神经元和亚细胞结构中。本研究评估了ChAT-Cre;Hrh3fl/fl和CaMKIIa-Cre;Hrh3fl/fl小鼠的恐惧记忆，发现H3R在胆碱能神经元中的缺失，而非在谷氨酸能神经元中的缺失，增强了情境恐惧记忆，而不影响条件恐惧记忆。一致地，H3R的基因敲低或腹侧基底前脑（vBF）中胆碱能神经元的化学遗传激活模拟了这种增强的恐惧记忆，而通过在vBF中重新表达H3R或化学遗传抑制胆碱能神经元可以挽救记忆的增强。重要的是，我们观察到组胺能投射与vBF中胆碱能神经元之间的结构和功能联系；具体而言，利用光敏感的视紫红质-H3R融合蛋白对H3R进行时空调节，我们发现vBF中胆碱能神经元的突触后H3R负责增强情境恐惧。相反，背侧海马中胆碱能神经元投射的前突触H3R对调节情境恐惧记忆是可忽略的。总之，我们的研究结果揭示了vBF胆碱能神经元中的突触后组胺H3R在调节情境恐惧记忆中的作用，使其成为PTSD治疗干预的吸引人药物靶点。本研究为H3R相关剂型的开发和在中枢神经系统疾病中的应用奠定了基础。