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Minimal Long-Term Neurobehavioral Impairments after Endovascular Perforation Subarachnoid Hemorrhage in Mice.

ABSTRACT: Cognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.

SUBMITTER: Fanizzi C

PROVIDER: S-EPMC5548778 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:Purpose: Subarachnoid hemorrhage (SAH) is fatal in approximately 40% of cases. However, among survivors up to 95% experience permanent disabilities: post-SAH syndrome, which include impaired memory, executive functions, emotional and cognitive disturbances. Up to 45% of SAH patients are unable to continue with their professional activities. The long-term cognitive deficits result from morphological brain damage, including atrophy of the temporomesial/hippocampal area, which correlates with decreased neurocognitive scores. The mechanisms of the remote brain damage following SAH remain unknown, which hinders the progress in identifying new therapeutic targets. To unveil the leading mechanisms of permanent cognitive abnormalities following SAH and origin of atrophy of the temporomesial/hippocampal area, we analyzed SAH-induced specific hippocampal genomic pathways, which may lead to long term morphological damage. methods: Hippocampal RNA of SAH and Control groups, obtained 4 days after SAH induced by perforation of the circle of Willis in mice, was processed and sequenced. Using the next-generation RNA sequencing we determined differentially expressed genes in the bilateral whole hippocampus remote from SAH and applied different functional analyses and clustering tools to determine the main molecular pathways. Results: Differential gene expression analysis detected 642 upregulated and 398 down-regulated 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 related to 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. Conclusion: Our findings suggest that damage of the entorhinal cortex by the subarachnoid blood remotely triggers specific hippocampal response, which may include suppression of oligodendrocytes functioning due to anterograde degeneration of hippocampal afferents accompanied. Identification of the prominent molecular hippocampal pathways may lead to the development of new therapeutic approaches for the treatment of long-term SAH consequences.

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Minimal Long-Term Neurobehavioral Impairments after Endovascular Perforation Subarachnoid Hemorrhage in Mice.

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