In what its authors call “the largest study of its kind,” a group of university researchers have isolated just how post-traumatic stress disorder (PTSD) alters the human brain at the cellular level. In doing so, the team pulled back the curtain on how trauma rewires molecular machinery in the prefrontal cortex.
“We’re trying to figure out what’s gone wrong in psychiatric disorders so that we can understand the neurobiological mechanisms that are in play in these diseases,” lead-author and assistant professor of psychiatry at the Yale School of Medicine Matthew Girgenti, PhD, explained. “The hope is that we can identify areas where we can potentially treat them – that’s the ultimate goal.”
Methodology
Working with more than 2 million nuclei from 111 post-mortem human brains, scientists from Yale, UC Irvine, and other institutions conducted a single-cell multi-omic analysis of the dorsolateral prefrontal cortex (DLPFC). The sample included PTSD patients, those living with major depressive disorder (MDD), and a control group with no psychiatric diagnosis.
The team combined single-nucleus RNA sequencing (snRNA-seq) and chromatin accessibility mapping (snATAC-seq) to profile gene expression and regulatory elements in fine-grained detail across major brain cell types.
PTSD is Not One-Size-Fits-All
Notably, no single gene or cell type could account for all of the changes. Rather, the researchers found that PTSD appears to disrupt distinct molecular pathways in multiple, specific cell types.
Additionally, the research revealed that somatostatin-expressing interneurons (SST INs) seemed to be selectively vulnerable. In PTSD brains, SST INs showed broad downregulation of gene expression, lower output signaling, and dampened GABAergic transmission to neighboring neurons. The researchers confirmed these changes in both human tissue and a rodent model.
The team also noticed widespread upregulation of the stress-related gene FKBP5. But not in the neurons, as they expected, but mostly in endothelial cells. This shift, they deduced, reflects a compensatory response to low cortisol levels normally found in PTSD patients. It also hints at a more prominent role for the brain’s vasculature in stress physiology than the researchers originally thought.
Molecular Overlap and Divergence
Because PTSD and MDD co-occur so often, the researchers decided to include a psychiatric control group with MDD. While the two conditions shared nearly 60% of differentially expressed genes, they did record several notable differences.
For example, microglial cells in MDD exhibited increased inflammatory signaling through the SPP1 (osteopontin) pathway, a trend reversed in PTSD. Conversely, PTSD showed greater disruption in neuronal connectivity, including reduced communication between SST INs and excitatory neurons.
“PTSD and MDD are generally very similar to each other and have a lot of shared genetic variability,” Girgenti added. “This is a finding that seems to differentiate the two.”
These distinctions help clarify why PTSD and MDD, though often comorbid, manifest differently in both clinical symptoms and treatment responses.
Looking For a Genetic Connections
To understand how inherited risk contributes to these changes, the researchers linked genome-wide association study (GWAS) variants for PTSD to specific regulatory elements in brain cells. They fine-mapped eight credible genetic risk loci, including SNPs associated with ELFN1, MAD1L1, and KCNIP4, all genes that been implicated before in synaptic signaling and neural excitability.
By integrating chromatin accessibility with gene expression, they showed how these variants probably affect transcription in a cell-type-specific manner. In one case, a SNP near MAD1L1 appeared to influence expression of ELFN1 in inhibitory neurons, possibly altering the excitatory-inhibitory balance central to PTSD pathology.
Decoding Circuitry
But the researchers didn’t stop there. The team also took a closer look at how trauma influences communication between cells, leveraging known ligand-receptor pairs and transcriptomic data to rebuild signaling networks.
They found that SST interneurons in PTSD brains delivered dramatically weaker output to both excitatory and non-neuronal targets. Glutamate signaling also appeared to be hampered, while corticotropin-releasing hormone (CRH) transmission shot up, underscoring the hyperactive stress response associated with PTSD.
This novel examination of the traumatized brain lays a new foundation for more precise diagnostics and more-informed targeted therapies. It suggests that the roots of PTSD lie not in a single region or cell type, but in a larger network of disrupted cellular conversations, many of which we can now measure, map, and maybe one day, even modulate.
Further Reading
Impact of PTSD Treatment Type on Engagement
Researchers Identify Link Between Childhood Trauma, PTSD
PTSD vs Other Conditions After Trauma and Life Stress Exposure
