Immune imbalance in the human hippocampus in PTSD revealed by single-nucleus transcriptomics

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Post-traumatic stress disorder (PTSD) is increasingly viewed as a neuroimmune disorder.
• Disrupted neuron-glia interactions in the hippocampus are implicated in PTSD's cognitive and emotional dysfunction.
• The precise cellular and molecular basis of immune imbalance in the human hippocampus in PTSD is not well understood.

Purpose of the Study:

• To investigate the cellular and molecular underpinnings of immune imbalance in the human hippocampus in PTSD.
• To characterize alterations in neurovascular and glial populations in PTSD using single-nucleus RNA sequencing.
• To elucidate the impact of PTSD on cell-cell communication within the hippocampus.

Main Methods:

• Single-nucleus RNA sequencing was performed on postmortem hippocampal tissues from individuals with PTSD and matched controls.
• Differential gene expression, pathway enrichment, pseudotime trajectory, and cell-cell communication analyses were employed.
• Focus was placed on neurovascular and glial cell types, including astrocytes, microglia, endothelial cells, and mural cells.

Main Results:

• PTSD samples exhibited activated stress-response and inflammatory signaling in astrocytes, microglia, endothelial cells, and mural cells.
• Microglia and astrocytes showed significant transcriptional reprogramming related to immune pathways.
• Reduced communication was observed between glial cells (astrocytes, microglia) and neurons/oligodendrocytes, involving stress- and inflammation-related molecules.

Conclusions:

• PTSD is characterized by widespread immune imbalance at cellular and intercellular levels within the hippocampus.
• Maladaptive glial activation and disrupted neuron-glia communication are central mechanisms in PTSD pathogenesis.
• This study provides a single-cell atlas of the hippocampal neuroimmune landscape in PTSD.