Intracerebral Hemorrhage-Induced Cognitive Impairment in Rats Is Associated With Brain Atrophy, Hypometabolism, and Network Dysconnectivity

Abstract

The mechanisms underlying intracerebral hemorrhage (ICH)-related cognitive impairment (CI) remain unclear. Long-term structural and functional changes were investigated in the brains of healthy male and female Wistar rats after experimental ICH. Following double injection of autologous blood, rats underwent short-term (onset, 3 and 7 days) and long-term (3 and 6 months) radiological assessment and behavioral tests exploring spontaneous locomotion, anxiety-like behavior and working memory, spatial recognition memory and visual recognition memory. Volumetric and metabolic changes in brain areas were examined by 7Tesla-MRI and [18F] FDG-PET, respectively. Brain connectomic disorders and maladaptive processes were seeked through brain metabolic connectivity analysis and atrophy-related network analysis. From an initial hematoma mean volume of 23.35 ± 9.50 mm3, we found early spontaneous locomotor recovery and significant spontaneous blood resorption (≈ 40% of the initial lesion) from days 0 to 7. After 3 and 6 months, ICH rats exhibited CI in several domains as compared to the sham group (working memory: 58.1 ± 1.2 vs. 70.7 ± 1.2%, p < 0.001; spatial recognition memory: 48.7 ± 1.9 vs. 64 ± 1.8%, p < 0.001 and visual recognition memory: 0.14 ± 0.05 vs. 0.33 ± 0.04, p = 0.013, in female only). Rats that experienced ICH had remote and concomitant cerebral atrophy and hypometabolism of ipsilateral striatum, thalamus, limbic system and cortical areas (temporal and parietal lobes). Interestingly, both structural and metabolic deterioration was found in the limbic system connected to the affected site, but remotely from the initial insult. On the other hand, increased activity and functional connectivity occurred in the contralateral hemisphere. These connectomics results showed that both maladaptative and compensation processes coexist in the rat brain following ICH, even at young age and in a disease-free setting. These radiological findings deepen our understanding of ICH-related CI and may serve as biomarkers in the view of future therapeutic intervention.

Galectin-3 promotes brain injury by modulating the phenotype of microglia via binding TLR-4 after intracerebral hemorrhage

“…The specific number of dead rats in each group and the time of death are presented in Table 2 . The results were consistent with the ICH model death of SD rats approved by the national Ethical Committee in Animal Experimentation (CEEA, Comité d’Ethique en Experimentation Animale), from the French Ministry for Education and Research [ 29 ]. Due to ICH modeling, 24 rats perished.…”

“…ICH results in a complex mechanism of central nervous system injury, including both physical injury and primary injury as a result of hematoma formation. Secondary injury primarily arises from microglial activation, mitochondrial dysfunction, and the release of toxic neurotransmitters and inflammatory mediators [29]. As crucial innate immune cells, microglia serve as the brain's sentinels and are believed to be the first non-neuronal cells to respond to acute brain injury [31][32][33].…”

A Combination of Ex Vivo and In Vivo Strategies for Evaluating How Much New Oral Anticoagulants Exacerbate Experimental Intracerebral Bleeding

“…In a microhemorrhage model in mice, changes in long-term cognitive activities, such as a reduction in visual recognition memory, were observed, 39 but not in spontaneous motor activity, while another work has shown that neuromotor changes can occur 3 days after the hemorrhagic insult. 40 …”