Summary: For the first time, researchers have identified a coordinated “gene expression program” that drives neurotransmission in the living human brain. While previous studies relied on postmortem tissue (which only shows a static “snapshot”), this study integrated real-time intracranial recordings from over 100 neurosurgery patients with molecular profiling.
The findings reveal a specific set of genes that track with active electrical and chemical signaling, providing a new molecular framework for understanding human cognition and psychiatric disorders.
Key Facts
- Beyond Postmortem: This study moves past the limitations of studying “dead” brain tissue by capturing genetic activity while neurons are actively communicating in living patients.
- The Transcriptional Program: Researchers identified a reproducible set of genes whose activity directly correlates with neuronal signaling and synaptic function.
- Neurosurgical Integration: Data was collected during neurosurgical procedures, pairing direct electrical brain measures (electrophysiology) with gene expression data (transcriptomics).
- Disease Implications: Because neurotransmission is disrupted in conditions like depression, schizophrenia, and epilepsy, identifying the “active” genes involved offers a roadmap for precision treatments and neuromodulation.
- Reproducible Architecture: The gene program was found to be consistent across independent groups of patients, proving it is a fundamental aspect of human brain biology.
Source: Mount Sinai Hospital
Researchers have identified a distinct and reproducible gene expression program associated with neurotransmission in the living human brain, offering unprecedented insight into the molecular mechanisms that support human cognition, emotion, and behavior.
The findings were published February 19 in Molecular Psychiatry.
Neurotransmission—the electrical and chemical signaling between neurons—is fundamental to all brain function. Until now, most gene expression studies of the human brain have relied on postmortem tissue, limiting scientists’ ability to understand which genes are actively involved in real-time neuronal communication.
In this study, investigators integrated gene expression profiling from the prefrontal cortex with direct intracranial measures of neurotransmission collected from the brains of more than 100 individuals as they underwent neurosurgical procedures. By combining molecular data with real-time physiological recordings, the team identified a coordinated set of genes whose activity tracks with neuronal signaling—a transcriptional program associated with neurotransmission.
Alexander Charney, MD, PhD, Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, said the findings represent a major shift in the field’s ability to study living brain biology.
“For decades, our understanding of gene expression in the human brain has been limited to postmortem studies,” Dr. Charney said. “This work allows us to examine the molecular architecture of neurotransmission as it is happening in living individuals, bringing us closer to directly linking genes to real-time brain function.”
The study demonstrated that this transcriptional program is reproducible across independent cohorts and aligns with established pathways involved in excitatory neuronal signaling and synaptic function. The findings provide a molecular framework for understanding how gene activity supports active brain communication.
Brian Kopell, MD, Director of the Center for Neuromodulation and Co-Director of The Mount Sinai Hospital’s Movement Disorders Program, emphasized the significance of integrating electrophysiology and molecular science.
“By pairing intracranial recordings with molecular profiling, we’re bridging two worlds that have traditionally been studied separately,” Dr. Kopell said. “This approach gives us a clearer picture of how neural circuits operate at both the electrical and genetic levels, which has profound implications for neuromodulation and precision treatments.”
Because disrupted neurotransmission is central to many psychiatric and neurological disorders—including depression, schizophrenia, epilepsy, and neurodegenerative disease—identifying the genes linked to active signaling could help refine future diagnostic tools and therapeutic strategies.
Ignacio Saez, PhD, Associate Professor of Neuroscience, Neurosurgery, and Neurology at the Icahn School of Medicine at Mount Sinai, noted that the study also advances how researchers interpret complex genomic data.
“The power of this study lies in its integration of large-scale transcriptomic data with direct measures of brain activity,” Dr. Saez said. “Identifying a coordinated transcriptional program associated with neurotransmission provides a new framework for understanding how genetic variation may influence brain function and vulnerability to disease.”
Key Questions Answered:
A: Imagine trying to understand how a car engine works by looking at a photo of a parked car (postmortem) versus looking at the engine while it’s running on the highway (living). Neurotransmission is a dynamic, high-speed electrical process. By studying living brains, scientists can see which genes are actually “turned on” to facilitate the split-second signals that create thoughts and emotions.
A: Not the genes themselves, but their expression—which genes are being “read” by the cell. This study shows that there is a specific, coordinated program of gene activity that syncs up with brain waves. When you are thinking or reacting, your brain is likely engaging this specific molecular “software” to keep the electrical signals moving.
A: Most psychiatric drugs target neurotransmitters (like serotonin or dopamine), but they don’t always work for everyone. By identifying the specific genes that control the “machinery” of these signals, doctors can develop more precise treatments—like targeted neuromodulation or gene therapies—that fix the signal at its molecular source.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neuroscience research news
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Major depressive disorder shares systemic immune signatures and potential therapeutic targets with inflammatory skin diseases” by Helen He, Flurin Cathomas, Lyonna F. Parise, Eden David, Mina Rizk, Kelly Hawkins, Elizabeth Karpman, Scott J. Russo, Emma Guttman & James W. Murrough. Molecular Psychiatry
DOI:10.1038/s41380-025-03383-5
Abstract
Major depressive disorder shares systemic immune signatures and potential therapeutic targets with inflammatory skin diseases
Major depressive disorder (MDD) is a prevalent neuropsychiatric disorder associated with significant morbidity and mortality. Increasing evidence suggests that a subset of MDD patients exhibit a dysregulated immune system.
However, few clinical studies have tested the efficacy of anti-inflammatory drugs in reducing symptoms of depression. In contrast, targeted immunomodulatory drugs have revolutionized the treatment of inflammatory skin disorders, such as atopic dermatitis (AD) and psoriasis.
To assess the viability of a targeted treatment approach in MDD, we first compared the blood proteomic profiles of patients with MDD to those of patients with AD, psoriasis, and healthy controls (HCs).
We demonstrated that the proteomic signatures of MDD patients share Th2 skewing and dysregulation of other immune/neurovascular-related proteins with AD. Next, we performed an in-silico drug repurposing analysis to test whether common biologics used in dermatology could also affect the dysregulated proteomic signature observed in MDD patients.
This computational approach identified dupilumab, which targets the IL-4 receptor α subunit (IL-4Rα) and thus inhibits the Th2 axis, as significantly affecting the MDD signature by reversing the dysregulation of several inflammatory proteins related to Th2 signaling.
Finally, in a mouse model of chronic social defeat stress (CSDS), we showed that pharmacological inhibition of IL-4Rα prevented stress-induced social avoidance behavior.
Our findings underscore the potential role of the Th2 axis in MDD, highlighting the potential of specifically targeting Th2 as a disease-modifying treatment.
Additionally, the back-translational drug repurposing strategy employed in this study may offer a novel approach to identify immunomodulatory drugs in psychiatry.
