A transcriptional program associated with neurotransmission in the living human brain

Journal article

At the foundation of neurotransmission, and by extension at the foundation of brain function, are coordinated programs of gene expression involving many thousands of genes. These programs are poorly defined in humans because most modern studies that characterize human brain gene expression use tissue obtained in the postmortem state when neurotransmission and brain function have ceased. Here, to advance knowledge of the gene expression programs at the foundation of neurotransmission in the human brain, gene expression was characterized in 130 prefrontal cortex (PFC) samples obtained from participants of the Living Brain Project (LBP) during neurosurgical procedures in conjunction with intracranial recordings of neurotransmission traits in deep brain structures. In a group of 15 procedures, participants performed a cognitive task during intracranial recordings of the substantia nigra; in the remaining group of 115 procedures, participants were at rest during intracranial recordings of either the subthalamic nucleus or the globus pallidus. Analyses of the data obtained from the group of 15 procedures, though underpowered to identify individual gene-trait associations, uncovered evidence of transcriptome-wide signatures of PFC gene expression that associated with neurotransmission traits. These signatures were reproduced in analyses of data from the group of 115 procedures and in analyses of data from a third independent human cohort. A set of genes with evidence of association to neurotransmission in multiple cohorts was termed the “transcriptional program associated with neurotransmission” (TPAWN) and analyses of data from studies of model systems and genetic variation in human populations validated the role of TPAWN genes in neurotransmission and brain function. In PFC excitatory neurons of LBP participants, higher expression of TPAWN genes tracked with higher expression of genes that in mouse frontal cortex are markers of excitatory neurons that connect the frontal cortex to deep brain structures. Taken together, the findings of this report help advance knowledge of the transcriptomic foundations of neurotransmission in the living human brain.

Authors: Charney, AW; Liharska, LE; Vornholt, E; Valentine, A; Lund, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Molecular Psychiatry
• Volume: 31
• Issue: 5
• Pages: 2727-2738
• Publication date: 2026-02-19
• Acceptance date: 2025-12-02
• DOI: 10.1038/s41380-025-03420-3
• EISSN: 1476-5578
• ISSN: 1359-4184
• Language: English
• Keywords: Neurotransmission; Human brain; Prefrontal cortex; Gene expression; Dorsolateral prefrontal cortex; Gene; Transmission (telecommunications)