What animal models can tell us about long-term cognitive dysfunction following sepsis: A systematic review

Savi, Felipe Figueredo; Oliveira, Alexandre de; Medeiros, Gabriela Ferreira de; Bozza, Fernando A.; Michels, Monique; Sharshar, Tarek; Dal‐Pizzol, Felipe

doi:10.1016/j.neubiorev.2020.12.005

Cited by 51 publications

(37 citation statements)

References 246 publications

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“…Several preclinical studies have already investigated the impact of sepsis on long-term behavioural changes. 30 , 34 , 78–85 Although most of them highlighted sustained anxiety, data differ mainly on aversive or non-aversive memory deficits. These divergences can be explained by a high diversity of variables including the type and the severity of sepsis induction (liposaccharide injection or CLP), post-surgery treatments, animal species, genetic background, age and sex and, most importantly, the fear learning protocol and timing of behavioural evaluation.…”

Section: Discussionmentioning

confidence: 99%

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours

Bourhy

Mazeraud

Costa

et al. 2022

Brain

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Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown. Using a reference mouse model of sepsis, we showed that mice that recovered from sepsis further developed anxiety-related behaviours associated with an exaggerated fear memory. In the brain, sepsis induced an acute pathological activation of a specific neuronal population of the central nucleus of the amygdala, which projects to the ventral bed nucleus of the stria terminalis. Using viral-genetic circuit tracing and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and in the responsiveness of these central amygdala neurons projecting to the ventral bed nucleus of the stria terminalis. The transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the anti-epileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviours. Specific inhibition of brain anxiety and fear circuits during the sepsis acute phase constitutes a preventive approach to preclude the post-infection psychiatric outcomes.

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Section: Discussionmentioning

confidence: 99%

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours

Bourhy

Mazeraud

Costa

et al. 2022

Brain

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“…We tested if the change of c-Fos could affect the performance of C57BL/6 mice in Y-maze. The task is dependent on an intact hippocampus and acquires interaction with the prefrontal cortex [11]. So we verified single alcohol-exposed mice in Y-maze, results indicated that alcohol did not change spontaneous alternations, compared to saline-injected controls (Figs.…”

Section: C-fos Requirements For Alcohol Exposure Impaired Learning An...mentioning

confidence: 68%

Repeated alcohol exposure induced dentate gyrus related spatial memory damage

et al. 2022

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Alcohol is one of the most commonly abused drugs, and it impairs diverse functions of the central nervous system, such as cognition and memorization. The dentate gyrus (DG) region of the hippocampus is crucial for spatial memory coding. However, whether alcohol exposure can affect DG neuron activity and impair spatial memory has not been identified. Here, we discovered hippocampus DG as a key region of alcohol exposure damage. (1) We found repeated alcohol exposure overactivated DG neurons, while this activation was not shown in a single alcohol exposure group. (2) Mice exposed to alcohol repeatedly exhibited obvious spatial memory impairment. In summary, our findings provide convincing evidence that the excessive activation of hippocampus neurons is involved in spatial memory impairment caused by repeated alcohol exposure.

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“…As many studies have shown ( Lewis et al, 2016 ; Savi et al, 2021 ), we initially constructed the SAE model referring to the sepsis model made by peritoneal injection of a moderate dose of LPS in C57BL6J mice. Then, we evaluated the alterations of cytokines, histology, and behaviors prior to the transcriptomics and metabolomics analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Although our study depicted that dysregulated neuroinflammation, metabolism, and synapse pathways were tightly associated with the hippocampus at the early SAE, several key predictions, such as the lipid mediator, and amino acids, need further functional validation. Furthermore, it is still a challenge to directly monitor the cognitive behaviors of SAE rodents at the early stages ( Savi et al, 2021 ) because they move infrequently and are manifested by other alterations in peripheral organ systems or other brain regions at this stage. Additionally, the maturated LPS-sepsis model advanced our studies, but the different sepsis models vary in their mortality and clinic associations ( Lewis et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

Zhang

et al. 2022

Front. Pharmacol.

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Sepsis-associated encephalopathy (SAE) is an intricated complication of sepsis that brings abnormal emotional and memory dysfunction and increases patients’ mortality. Patients’ alterations and abnormal function seen in SAE occur in the hippocampus, the primary brain region responsible for memory and emotional control, but the underlying pathophysiological mechanisms remain unclear. In the current study, we employed an integrative analysis combining the RNA-seq-based transcriptomics and liquid chromatography/mass spectrometry (LC-MS)-based metabolomics to comprehensively obtain the enriched genes and metabolites and their core network pathways in the endotoxin (LPS)-injected SAE mice model. As a result, SAE mice exhibited behavioral changes, and their hippocampus showed upregulated inflammatory cytokines and morphological alterations. The omics analysis identified 81 differentially expressed metabolites (variable importance in projection [VIP] > 1 and p < 0.05) and 1747 differentially expressed genes (Foldchange >2 and p < 0.05) were detected in SAE-grouped hippocampus. Moreover, 31 compounds and 100 potential target genes were employed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Markup Language (KGML) network analysis to explore the core signaling pathways for the progression of SAE. The integrative pathway analysis showed that various dysregulated metabolism pathways, including lipids metabolism, amino acids, glucose and nucleotides, inflammation-related pathways, and deregulated synapses, were tightly associated with hippocampus dysfunction at early SAE. These findings provide a landscape for understanding the pathophysiological mechanisms of the hippocampus in the progression of SAE and pave the way to identify therapeutic targets in future studies.

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What animal models can tell us about long-term cognitive dysfunction following sepsis: A systematic review

Cited by 51 publications

References 246 publications

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours

Repeated alcohol exposure induced dentate gyrus related spatial memory damage

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

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