Deciphering Histamine Pathway Networks in the Human Brain: A Multimodal Approach to Cognition and Psychiatric Disorders

Histamine is a critical neuromodulator influencing cognition, emotion, and behaviour through its interaction with histamine receptors and other neurotransmitter systems. Dysregulation of histaminergic signalling has been implicated in neuropsychiatric and neurodevelopmental disorders, making it a promising target for novel therapeutic interventions. Despite its importance, the histaminergic system remains less characterized in the human brain compared to other neuromodulatory pathways, which has marred significant translational advances in the development of histaminergic therapeutics. This study provides a comprehensive multimodal analysis of the architecture of histaminergic gene expression, integrating transcriptomic, neuroimaging, and functional datasets to map its spatial organization and relevance to cognition and neuropsychiatric disorders. At the single cell level, we identified predominant expression of histamine receptor genes HRH1 and HRH2 in excitatory neuronal populations while histamine receptor gene HRH3 was more restricted within inhibitory neuronal subpopulations. Anatomically, the expression of genes of the histamine pathway was well captured by a single latent component (explaining 41.1% in regional histaminergic gene expression) with higher-than-average expression in limbic and frontal regions, and lower-than-average expression in posterior occipital regions. We confirmed the biological relevance of this transcriptomic signature by demonstrating that it can predict regional variation in H3 receptor binding in the living human brain measured with two different PET tracers in two independent samples of healthy individuals. Macroscale functional decoding of histaminergic gene expression revealed strong associations with brain activity during tasks tapping into cognitive domains including emotion regulation, stress processing, salience detection, impulsivity, addiction, sleep, memory, eating, and pain, highlighting histamine’s widespread neuromodulatory influence. Analyses on brain developmental transcriptomic data demonstrated distinct maturation trajectories, with L-Histidine Decarboxylase (HDC) peaking in early neurodevelopment and HRH3 increasing from childhood to adulthood, mirroring the maturation of prefrontal cognitive networks. Finally, the pattern of regional variation in histaminergic gene expression was significantly correlated with the spatial patterns of structural brain alterations observed in psychiatric disorders, including ADHD, depression, schizophrenia, and anorexia, suggesting a putative role in shaping regional vulnerability to disease pathophysiology. These findings provide new insights into the molecular architecture of the human histaminergic system and its implications for cognition, neurodevelopment, and mental health, offering a foundation for future research into histamine-targeted therapeutic strategies.