Abstract
After subarachnoid hemorrhage (SAH), up to 95% of surviving patients suffer from post-SAH syndrome, which includes cognitive deficits with impaired memory, executive functions, and emotional disturbances. Although these long-term cognitive deficits are thought to result from damage to temporomesial–hippocampal areas, the underlying mechanisms remain unknown. To fill this gap in knowledge, we performed a systematic RNA sequencing screen of the hippocampus in a mouse model of SAH. SAH was induced by perforation of the circle of Willis in mice. Four days later, hippocampal RNA was obtained from SAH and control (sham perforation) mice. Next-generation RNA sequencing was used to determine differentially expressed genes in the whole bilateral hippocampi remote from the SAH bleeding site. Functional analyses and clustering tools were used to define molecular pathways. Differential gene expression analysis detected 642 upregulated and 398 downregulated genes (false discovery rate <0.10) in SAH compared to Control group. Functional analyses using IPA suite, Gene Ontology terms, REACTOME pathways, and MsigDB Hallmark gene set collections revealed suppression of oligodendrocytes/myelin related genes, and overexpression of genes related to complement system along with genes associated with innate and adaptive immunity, and extracellular matrix reorganization. Interferon regulatory factors, TGF-β1, and BMP were identified as major orchestrating elements in the hippocampal tissue response. The MEME-Suite identified binding motifs of Krüppel-like factors, zinc finger transcription factors, and interferon regulatory factors as overrepresented DNA promoter motifs. This study provides the first systematic gene and pathway database of the hippocampal response after SAH. Our findings suggest that damage of the entorhinal cortex by subarachnoid blood may remotely trigger specific hippocampal responses, which include suppression of oligodendrocyte function. Identification of these novel pathways may allow for development of new therapeutic approaches for post-SAH cognitive deficits.
Highlights
Subarachnoid hemorrhage (SAH), blood accumulation in the subarachnoid space [1], in 85% of the cases results from aneurysmal rupture [2, 3]
We aim to explore biological processes and secondary mechanisms at the cusp between degeneration and regeneration happening at 4 days [25, 26] following SAH, closely mimicking delayed cerebral ischemia observed in humans [23] to explore processes at the origin of long-term consequences of SAH
Functional and master regulator’s analysis evidenced for an overexpression of genes related to an innate and adaptive immune response with possible involvement of blood-resident cells as well as parenchymal reorganization in the hippocampus at 4 days. These observations are in line with what has been described in the pathophysiology of stroke as a biphasic mechanism, which has become clear over the years of research [9, 59], with the damaged brain exhibiting an initial detrimental response following the acute injury, and regenerative processes during the recovery phase
Summary
Subarachnoid hemorrhage (SAH), blood accumulation in the subarachnoid space [1], in 85% of the cases results from aneurysmal rupture [2, 3]. Most often localized at the base of the skull [12, 13], blood extravasates into the subarachnoid space damaging basal brain surface, including entorhinal cortices, which issue the main afferents to the hippocampus [14, 15]. Blood toxicity to the brain parenchyma has been wellestablished [19, 20] This would cause global changes in the gene expression resulting in the persistent disturbance of the hippocampal function
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