Mapping histamine pathway networks in the human brain across cognition and psychiatric disorders

Abstract Histamine is a key neuromodulator shaping cognition, emotion and behavioral flexibility, yet its organization in the human brain remains incompletely characterized. We conducted a multimodal analysis integrating transcriptomic, neuroimaging, developmental and functional datasets to map the architecture of the histaminergic system. At the single-cell level, histamine receptor H 1 and histamine receptor H 2 were enriched in excitatory neurons, whereas histamine receptor H 3 showed preferential expression in inhibitory populations. Regional expression of core histaminergic genes was captured by a single latent component (41.1% of variance), with higher expression in frontal and limbic regions and lower expression in the occipital cortex. This spatial signature predicted in vivo H 3 receptor binding across independent positron emission tomography datasets. Functional decoding linked histaminergic expression to emotion regulation, salience processing, impulsivity, sleep, memory and reward. Developmentally, histidine decarboxylase expression peaked early, whereas histamine receptor H 3 increased into adulthood. Finally, histaminergic expression correlated with structural alteration patterns in attention deficit hyperactivity disorder, major depressive disorder, schizophrenia and anorexia nervosa, suggesting relevance for regional vulnerability in psychiatric disorders.