Post-traumatic stress disorder (PTSD) is often associated with depression, substance use disorder, and a higher risk for suicide. Since PTSD was added to the Diagnostic and Statistical Manual of Mental Disorders in 1980, psychotherapeutic interventions have greatly advanced, but their pharmacological counterparts have lagged far behind. Some researchers, including neuroscientist Matthew Girgenti at the Yale School of Medicine, thought that this was partially due to the traditional approach of treating patients with PTSD using drugs that are meant for other conditions, such as major depressive disorder (MDD).
Matthew Girgenti, a neuroscientist at Yale School of Medicine, investigates the molecular mechanisms of neuropsychiatric disorders.
Matthew Girgenti
To test this hypothesis, Girgenti and his team compared the transcriptomic profiles of patients with PTSD and MDD using single nuclei RNA sequencing (snRNA-seq). They discovered cell type-specific differences between the two conditions along with unexpected gene expression changes in non-neuronal cell types.1 Their findings, reported in Nature, provide new insights into why drugs that work well for MDD perform poorly for PTSD treatment.
“This is the largest PTSD profiling study using single cell analysis to date,” said Michael Totty, a neuroscientist at the Lieber Institute for Brain Development who was not involved in the study. “It’s especially important to localize gene expression changes that underlie PTSD pathology to individual cell types, because we now have the technology to actually target these individual cell types.”
Four years ago, Girgenti and his colleagues were the first to compare gene expression in patients with PTSD and MDD using bulk transcriptomics.2 “We were primarily interested in PTSD, but we included an MDD cohort so we could find differences between PTSD and MDD, which are often comorbid,” Girgenti said. They found a significant overlap in the profiles of the two cohorts, as expected, but they identified some differences as well. In 2023, Girgenti’s team dug deeper and compared the transcriptomic profiles of single cells in patients with PTSD and MDD using snRNA-seq in a small study (10–11 participants per cohort).3 Their findings indicated the presence of cell type-specific patterns of gene expression.
Michael Totty is a neuroscientist at the Lieber Institute for Brain Development who uses computational and molecular approaches to study neuropsychiatric conditions. He was not involved in the study.
Michael Totty
To gain further insights into these cell type-specific transcriptomic patterns, in this study, the researchers collected post-mortem tissue samples from the dorsolateral prefrontal cortex, a brain region that's typically associated with psychiatric disorders, of about 36–40 people per cohort. Then, they performed snRNA-seq to profile the transcriptome of each cell within the tissue. Girgenti’s team found 12 genes that were differentially enriched in patients with PTSD and MDD, but in opposite directions, indicating points of divergence between the two conditions.
To better understand the functional consequences of these changes, the researchers analyzed their snRNA-seq data using a computational tool called CellChat, which could infer communication networks between different cells.4 From this analysis, they found higher activation of the microglia, the resident immune cells in the brain, in patients with MDD. This indicated a pro-inflammatory response, a common occurrence in many psychiatric disorders.5 However, the opposite was true for PTSD: The researchers saw reduced cell signaling in the microglia, which signified immunosuppression. “We’re still trying to figure out what this means,” Girgenti said. “But it could be a way to distinguish people with PTSD from those with other psychiatric disorders.”
Totty said, “They used a lot of new technologies to tell a complete, holistic story.”
Girgenti’s team also found that the expression of the PTSD risk gene FKBP5 was upregulated in endothelial cells, but not in neurons.6
“That was very surprising,” Girgenti said. “We had absolutely no idea that [endothelial cells] would have the most changes in gene expression.”
Girgenti and his colleagues thought that the high expression of FKBP5 in endothelial cells, which surround blood vessels, may promote the trafficking of glucocorticoids, which are commonly referred to as stress hormones. They proposed that this mechanism would likely compensate for the low cortisol levels that are often reported in patients with PTSD.7
“We think this may be going on, but we have a lot more work to do to really figure that out,” Girgenti said.
- Hwang A, et al. Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD. Nature. 2025;643:744-754.
- Girgenti MJ, et al. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nat Neurosci. 2021;24(1):24-33.
- Chatzinakos C, et al. Single-nucleus transcriptome profiling of dorsolateral prefrontal cortex: mechanistic roles for neuronal gene expression, including the 17q21.31 locus, in PTSD stress response. Am J Psychiatry. 2023;180(10):739-754.
- Jin S, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12(1):1088.
- Mondelli V, et al. Brain microglia in psychiatric disorders. Lancet Psychiatry. 2017;4(7):563-572.
- Nievergelt CM, et al. Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nat Genet. 2024;56(5):792-808.
- Heim C, et al. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25(1):1-35.
