Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Biol Psychiatry. 2019 Aug 1;86(3):230-239. doi: 10.1016/j.biopsych.2018.11.009. Epub 2019 Jan 8.
A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined.
Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans.
The treatment of H receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance.
These results highlight a novel interaction between the central histamine signaling and memory engrams.
一种能够促进遗忘的长期记忆检索的方法尚未得到很好的建立。中枢神经系统中的组胺与学习和记忆有关，而使用抗组胺药治疗会损害学习和记忆。由于组胺 H 受体反向激动剂会上调组胺的释放，因此这些反向激动剂可能会增强学习和记忆。然而，反向激动剂是否能促进遗忘的长期记忆的检索尚未确定。
在这里，我们采用了多学科的方法，包括小鼠行为、钙成像和化学遗传操作，来研究组胺 H 受体反向激动剂噻哌酰胺和倍他司汀是否以及如何促进小鼠遗忘的长期物体记忆的检索。此外，我们在健康成年参与者中进行了一项随机、双盲、安慰剂对照的交叉试验，以研究倍他司汀治疗是否能促进人类的记忆检索。
H 受体反向激动剂的治疗诱导了遗忘记忆的回忆，即使在训练后 1 周和 1 个月也是如此。这种记忆恢复是通过抑制在边缘皮层中的组胺释放来介导的，组胺释放的抑制激活了组胺 H 受体。组胺使边缘皮层神经元去极化，增强了它们的自发活动，并促进了行为激活神经元集合的再激活。一项人类临床试验表明，H 受体反向激动剂的治疗对于更难记住的项目和表现较差的受试者更为有效。
这些结果强调了中枢组胺信号与记忆印痕之间的一种新的相互作用。
