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Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

ABSTRACT: Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

SUBMITTER: Chung DY

PROVIDER: S-EPMC8054726 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Chung David Y DY Oka Fumiaki F Jin Gina G Harriott Andrea A Kura Sreekanth S Aykan Sanem A SA Qin Tao T Edmiston William J WJ Lee Hang H Yaseen Mohammad A MA Sakadžić Sava S Boas David A DA Whalen Michael J MJ Ayata Cenk C

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200916 5

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water ...[more]

PMID: 32936728

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Project description: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.

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.

Project description:The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood-brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.

Project description:ObjectiveTo investigate the correlation between the swelling rate of brain volume within the first 48 h after aneurysmal subarachnoid hemorrhage and the subsequent development of delayed cerebral ischemia.MethodsA retrospective analysis was conducted on patients with spontaneous aneurysmal subarachnoid hemorrhage admitted to the Neurosurgery Intensive Care Unit of the First Affiliated Hospital of Chongqing Medical University between January 2020 and January 2023. The clinical data, treatment outcomes, and imaging data were analyzed. Brain volume was evaluated using 3D-Slicer software at two time points post-hemorrhage: within the first 24 h and between 24 and 48 h. The swelling rate of brain volume was defined as the ratio of the absolute difference between two measurements to the smaller of values. Patients were categorized into two groups based on established diagnostic criteria of delayed cerebral ischemia. Univariate and multivariate logistic regression analyses were performed to identify factors influencing delayed cerebral ischemia.ResultsA total of 140 patients were enrolled in this study. 46 patients experienced delayed cerebral ischemia after bleeding. The swelling rate of brain volume was larger in the DCI group (10.66 ± 8.45) compared to the non-DCI group (3.59 ± 2.62), which showed a statistically significant difference. Additionally, advanced age, smoking history, history of hypertension, loss of consciousness, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH were also statistically different between the two groups. Multivariate logistic regression analysis revealed that the swelling rate of brain volume was an independent risk factor for DCI with adjusting the advanced age, smoking history, history of hypertension, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH.ConclusionBrain volume significantly increased in patients with aneurysmal subarachnoid hemorrhage during the early phase (within 48 h post-onset). The larger swelling rate of brain volume is an independent risk factor for the development of delayed cerebral ischemia, and it may hold significant predictive value for the incidence of delayed cerebral ischemia.

Project description:BackgroundAneurysmal subarachnoid hemorrhage (aSAH) leads to a robust systemic inflammatory response. We hypothesized that an early systemic glycolytic shift occurs after aSAH, resulting in a unique metabolic signature and affecting systemic inflammation.MethodsControl patients and patients with aSAH were analyzed. Samples from patients with aSAH were collected within 24 h of aneurysmal rupture. Mass spectrometry-based metabolomics was performed to assess relative abundance of 16 metabolites involved in the tricarboxylic acid cycle, glycolysis, and pentose phosphate pathway. Principal component analysis was used to segregate control patients from patients with aSAH. Dendrograms were developed to depict correlations between metabolites and cytokines. Analytic models predicting functional outcomes were developed, and receiver operating curves were compared.ResultsA total of 122 patients with aSAH and 38 control patients were included. Patients with aSAH had higher levels of glycolytic metabolites (3-phosphoglycerate/2-phosphoglycerate, lactate) but lower levels of oxidative metabolites (succinate, malate, fumarate, and oxalate). Patients with higher clinical severity (Hunt-Hess Scale score ≥ 4) had higher levels of glyceraldehyde 3-phosphate and citrate but lower levels of α-ketoglutarate and glutamine. Principal component analysis readily segregated control patients from patients with aSAH. Correlation analysis revealed distinct clusters in control patients that were not observed in patients with aSAH. Higher levels of fumarate were associated with good functional outcomes at discharge (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.15-2.82) in multivariable models, whereas higher levels of citrate were associated with poor functional outcomes at discharge (OR 0.36, 95% CI 0.16-0.73) and at 3 months (OR 0.35, 95% CI 0.14-0.81). No associations were found with delayed cerebral ischemia. Levels of α-ketoglutarate and glutamine correlated with lower levels of interleukin-8, whereas fumarate was associated with lower levels of tumor necrosis factor alpha.ConclusionsAneurysmal subarachnoid hemorrhage results in a unique pattern of plasma metabolites, indicating a shift toward glycolysis. Higher levels of fumarate and lower levels of citrate were associated with better functional outcomes. These metabolites may represent targets to improve metabolism after aSAH.

Project description:BackgroundCerebral edema (CE) at admission is a surrogate marker of 'early brain injury' (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH.MethodsComputed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0-4 'subarachnoid hemorrhage early brain edema score' (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3-5 days [T3] and 6-8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2).ResultsOf the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002-1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE.ConclusionsWe identified serum cytokines at different time points that were independently associated with persistent CE. Specifically, persistent elevations of Eotaxin is associated with persistent CE after SAH.

Dataset Information

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Publications

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Similar Datasets

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