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Transcriptome Profiling of Hippocampus After Cerebral Hypoperfusion in Mice
Zengyu Zhang1,2, Zimin Guo1,2, Pengpeng Jin3
1Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China.
Insights
Chronic cerebral hypoperfusion (CCH) causes vascular cognitive impairment (VCI) by damaging gray matter. This study reveals CCH activates interferon-beta signaling and immune responses, primarily affecting microglia and CA1 pyramidal neurons in the hippocampus.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Chronic cerebral hypoperfusion (CCH) is a key factor in vascular cognitive impairment (VCI) pathogenesis.
- Microglial activation and gray matter damage, particularly in the hippocampus, are observed in CCH, but underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of hippocampus damage in CCH.
- To identify specific cell types and pathways involved in CCH-induced VCI.
Main Methods:
- A mouse model of CCH was created using bilateral common carotid artery stenosis (BCAS).
- Cerebral blood flow, hippocampal pathology, and transcriptome profiles were analyzed using RNA-sequencing (RNA-seq) and qRT-PCR.
- Gene Set Enrichment Analysis (GSEA) and integrative analysis with single-cell RNA-seq data were performed.
Main Results:
- BCAS induced decreased cerebral blood flow, hippocampal neuronal loss, and microglial activation.
- GSEA identified activated interferon-beta signaling and inflammatory immune responses.
- Differentially expressed genes were enriched in microglia (up-regulated) and CA1 pyramidal neurons (down-regulated).
Conclusions:
- CCH triggers specific inflammatory pathways, including interferon-beta signaling, in the hippocampus.
- Microglia and CA1 pyramidal neurons are key cell types involved in the pathogenesis of CCH-induced VCI.
- The generated transcriptomic data provides a valuable resource for future research into VCI therapeutic targets.
Abstract:
Chronic cerebral hypoperfusion (CCH) is considered to be one of the major mechanism in the pathogenesis of vascular cognitive impairment (VCI). Increased inflammatory cells, particularly microglia, often parallel hypoperfusion-induced gray matter damage such as hippocampal lesions, but the exact mechanism remains largely unknown. To understand the pathological mechanisms, we analyzed hippocampus-specific transcriptome profiles after cerebral hypoperfusion. The mouse hypoperfusion model was induced by employing the 0.16/0.18 mm bilateral common carotid artery stenosis (BCAS) procedure. Cerebral blood flow (CBF) was assessed after 3-week hypoperfusion. Pathological changes were evaluated via hematoxylin staining and immunofluorescence staining. RNA-sequencing (RNA-seq) was performed using RNA samples of sham- or BCAS-operated mice, followed by quantitative real-time PCR (qRT-PCR) validation. We found that the 0.16/0.18 mm BCAS induced decreased CBF, hippocampal neuronal loss, and microglial activation. Furthermore, GSEA between sham and BCAS mice showed activation of interferon-beta signaling along with inflammatory immune responses. In addition, integrative analysis with published single-cell RNA-seq revealed that up-regulated differentially expressed genes (DEGs) were enriched in a distinct cell type of "microglia," and down-regulated DEGs were enriched in "CA1 pyramidal," not in "interneurons" or "S1 pyramidal." This database of transcriptomic profiles of BCAS-hypoperfusion will be useful for future studies to explore potential targets for vascular cognitive dysfunction.
