Ferroptosis-Mediated Hippocampal Neuronal Loss Post-mTBI: Chromatin Accessibility Profiling and Single-Nucleus...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal death in the hippocampus after mild traumatic brain injury (mTBI) contributes to cognitive dysfunction.
• The molecular mechanisms driving this neuronal death are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms of neuronal death following mTBI at single-cell resolution.
• To identify potential therapeutic targets for mitigating mTBI-induced cognitive deficits.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) and ATAC sequencing (snATAC-seq) were performed on the hippocampus of mTBI mice.
• Gene set enrichment analysis was used to identify active cell-death pathways.
• Transcription factor binding and gene regulation were analyzed.

Main Results:

• Ferroptosis was identified as the dominant cell-death pathway in hippocampal neurons after mTBI.
• Decreased binding of c-Jun and Rfx3 transcription factors was observed in dentate granule cells.
• The c-Jun-regulated gene Tmsb4x demonstrated neuroprotective effects, counteracted ferroptosis, and improved cognitive function in mice.

Conclusions:

• Ferroptosis is a critical mechanism underlying neuronal death and cognitive dysfunction after mTBI.
• Tmsb4x represents a promising therapeutic target for treating mTBI-related cognitive impairments.