Histamine signaling restores retrieval of forgotten memories

Abstract

Histamine is a biological amine that functions as a neurotransmitter in the brain to regulate arousal, appetite, and cognitive functions. Many pharmacological studies using histamine receptor agonists and antagonists have found that histamine promotes memory consolidation and retrieval. More recently, we have revealed that the activation of the brain histaminergic system by H₃R antagonists/inverse agonists restores retrieval of forgotten long-term memory in mice and humans. The recovery of memory retrieval may involve histamine-induced excitatory effects. Histamine may increase neuronal excitability throughout the neural circuit, including both neurons that are and are not recruited into the memory trace, similar to noise added to the neural circuits for memory retrieval. Stochastic resonance can explain how adding noise to the circuit enhances memory retrieval. Memory is processed not only by consolidation and retrieval, but also by various processes such as maintenance, reconsolidation, extinction, and reinstatement. Further studies that separately analyze the memory processes are needed to elucidate the whole picture of the effects of histamine on learning and memory. Regarding the human histaminergic system, alterations in histamine signaling have been reported in several neuropsychiatric disorders, and these changes have been suggested to be involved in cognitive dysfunction in patients with the neuropsychiatric disorders. Therefore, the drugs that modulate histamine signaling, including H₃R antagonists/inverse agonists, may be effective in the treatment of cognitive dysfunction, including Alzheimer’s disease.