Traumatic brain injury and post-injury sleep fragmentation differentially alter the microglial transcriptome

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Traumatic brain injury (TBI) causes significant long-term disability and psychiatric issues.
• Neuroinflammation, driven by microglia, worsens TBI outcomes and increases vulnerability to secondary immune challenges.
• Previous research indicates sleep fragmentation (SF) worsens TBI-associated neuroinflammation and impairs recovery in mice.

Purpose of the Study:

• To investigate the mechanisms by which microglia contribute to impairment following TBI and SF.
• To analyze the impact of TBI and SF on cellular and gene expression profiles in the brain and peripheral tissues.
• To gain novel insights into microglial dysfunction in the ipsilateral brain after TBI and SF.

Main Methods:

• Flow cytometry was used to analyze cell types in brain and peripheral tissues of mice subjected to TBI or sham injury with SF or control housing.
• Bulk RNA sequencing analyzed gene expression in microglia and ipsilateral brain coronal slices.
• Differential gene expression analysis identified genes uniquely dysregulated by TBI, SF, or their combination.

Main Results:

• Monocyte infiltration to the brain was transient, increasing at 7 days post-injury and resolving by 30 days.
• SF did not exacerbate the immune response in peripheral tissues or the brain.
• Transcriptomic analysis revealed distinct gene expression patterns for TBI, SF, and combined TBI/SF, including dysregulated olfactory genes and enriched cell-cell communication and steroidogenesis pathways in microglia.

Conclusions:

• In-depth transcriptional analysis identified molecular targets underlying TBI-induced microglial activity and the effects of SF.
• Findings shed light on how SF alters microglial responses post-TBI.
• These data may inform therapeutic strategies targeting neuroinflammation to enhance chronic recovery after brain injury.