This work offers a cell type–resolved atlas of PTSD epigenetic change and reveals new molecular targets for treatment.
#Neuroscience #Epigenetics #PTSD #MDD #BrainResearch #Ketamine

Key findings:
🧬 Distinct & sex-specific methylation signatures across regions
⚙️ Signals in genes tied to GABAergic + stress pathways (ELFN1, CRHR1)
💊 Ketamine treatment alters methylation at ELFN1, MAD1L1, WNT5A

Please RT: rdcu.be/erD4p

Special thanks to all colleagues and coauthors. And support from @yaleschoolofmed.bsky.social @kavliatyale.bsky.social @wutsaiyale.bsky.social

This is the first time that single cell approaches were used to link genetic, chromatin, and transcriptomic dysregulation in PTSD and MDD to exhaustively characterize the molecular landscape of stress disorders.

Finally, we fine mapped credible GWAS loci for PTSD within specific cell types. We identified chromatin looping between the MAD1L1risk loci and the nearby gene ELFN1 within inhibitory neurons. ELFN1 dysregulation is likely at the root of many of the disruptions in SST communication in the cortex.

We mapped chromatin accessibility changes in both the PTSD and MDD brain and identified TF binding changes in disease- specific CREs.

We also found important differences between PTSD and MDD- specifically related to microglia communication. PTSD microglia communication with other cell types was suppressed while MDD increased communication- specifically through the SP1 pathway.

We created a large spatial transcriptomic dataset to validate our findings, but more importantly we were able to capture nuclear and soma transcriptomic differences.

We used an animal model of traumatic stress to mechanistically define decreased inhibitory neuron signaling through GABA signaling to GABRA5, GABBR1, GABRB1 and GABRG1 receptors on excitatory neurons.

The most affected cell types were inhibitory neurons, endothelial cells and microglia. We found that PTSD inhibitory neurons- specifically SST+ had decreased activity and transcription levels.

We examined the transcriptomic and chromatin dynamics of 111 donors with PTSD, MDD or healthy controls at single cell resolution (>2M nuclei). We identified >60 transcriptomic cell subtypes and >1000 DEGs across cell types.

We identified shared and unique brain molecular dysregulations between the two disorders across genomic levels.
This work was funded by @NIDA and the Yale/NIDA Neuroproteomic Center
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