Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation

Abstract

Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.

Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation

“…Prior to death, animals would develop high-amplitude convulsions followed by decerebrate posturing. This is consistent with studies which have demonstrated neurologic deficits, including seizure, and neuronal apoptosis in animals suffering from endotoxic shock (Sayyah et al, 2003; Singer et al, 2016; Song et al, 2014). Hypoglycemia is a common cause of seizure, but we found that blood glucose did not differ significantly between groups over time (Figure S2B).…”

Memory deficits in males and females long after subchronic immune challenge

“…ImageJ (NIH, Bethesda, MD) was count microglia, and a fractal analysis plugin in ImageJ was used to determine microglial morphology [FracLac V. 2.5, (Karperien, Ahammer, & Jelinek, 2013)]. Microglial activation state is commonly assessed using number and morphological changes where cells shift from a resting ramified state with extended, branching processes, to an activated ameboid state with a larger cell body and retraction of processes (Kondo, Kohsaka, & Okabe, 2011;Singer et al, 2016;Weberpals et al, 2009). Fractal analysis is a sensitive and quantitative method to assess small changes in microglial shape using measures of pattern complexity and selfsimilarity (fractal dimension) as well as heterogeneity (lacunarity) (Karperien et al, 2013;Young & Morrison, 2018).…”

Effects of Caffeine on Behavioural and Cognitive Deficits in Rats

“…Thus, in its more advanced stages, the septic syndrome disturbs the body immune system, involving the inflammatory mechanisms and the clotting cascade . Furthermore, this inflammatory response can lead to impairment of the central nervous system (CNS), which can trigger severe behavioural and cognitive changes .…”