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Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury
Published on: November 19, 2012
Ferroptosis-Mediated Hippocampal Neuronal Loss Post-mTBI: Chromatin Accessibility Profiling and Single-Nucleus
Manrui Li1, Qiuyun Yang2, Shengqiu Qu1
1Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
Abstract:
Neuronal death in the hippocampus following mild traumatic brain injury (mTBI) is a hallmark of cognitive dysfunction, yet the underlying molecular mechanisms remain poorly understood. To address this issue, the hippocampus of eCCI-modeled mTBI mice is profiled using single-nucleus RNA-seq and ATAC-seq, producing matched, cell-type-resolved transcriptomic and chromatin-accessibility datasets. Gene sets covering major cell-death pathways are curated and scored for their activity across neuronal subtypes. Ferroptosis emerged as the dominant program. Gene-set enrichment indicated activation of mitochondrial damage-related pathways in neurons, a hallmark of ferroptosis. Transcription-factor analyses, supported by epigenetic data, showed decreased binding of c-Jun and Rfx3 in dentate granule cells. Functional assays show that the c-Jun-regulated gene Tmsb4x protects hippocampal neurons after mTBI. It downregulates Slc2a2, counteracts ferroptosis, and is associated with improved motor and cognitive performance in mice. This study advances understanding of mTBI pathogenesis at single-cell resolution, identifying ferroptosis as a critical determinant of neuronal death and uncovering Tmsb4x as a promising therapeutic target for mitigating cognitive dysfunction.
Insights
Mild traumatic brain injury (mTBI) causes neuronal death via ferroptosis, a process linked to cognitive decline. The gene Tmsb4x shows potential for treating mTBI-induced cognitive dysfunction.
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.
