Abstract
Long-term sepsis survivors sustain cryptic brain injury that leads to cognitive impairment, emotional imbalance, and increased disability burden. Suitable animal models of sepsis, such as cecal ligation and puncture (CLP), have permitted the analysis of abnormal brain circuits that underlie post-septic behavioral phenotypes. For instance, we have previously shown that CLP-exposed mice exhibit impaired spatial memory together with depleted dendritic arbors and decreased spines in the apical dendrites of pyramidal neurons in the CA1 region of the hippocampus. Here we show that contextual fear conditioning, a form of associative memory for fear, is chronically disrupted in CLP mice when compared to SHAM-operated animals. We also find that the excitatory neurons in the basolateral nucleus of the amygdala (BLA) and the granule cells in the dentate gyrus (DG) display significantly fewer dendritic spines in the CLP group relative to the SHAM mice, although the dendritic arbors and gross morphology of the BLA and DG are comparable between the two groups. Moreover, the basal dendrites of CA1 pyramidal neurons are unaffected in the CLP mice. Taken together, our data indicate that the structural damage in the amygdalar-hippocampal network represents the neural substrate for impaired contextual fear memory in long-term sepsis survivors. Further, our data suggest that the brain injury caused by overwhelming sepsis alters the stability of the synaptic connections involved in associative fear. These results likely have implications for the emotional imbalance observed in human sepsis survivors.
Highlights
Sepsis refers to the life-threatening shock and organ dysfunction caused by a dysregulated response to infection, which accounts for ~750,000 patients and ~200,000 deaths per year in the United States alone [1,2]
Mice underwent the context test, in which they were placed in Chamber A for 10 min; freezing levels were compared for the last 5 min, revealing that the cecal ligation and puncture (CLP) group froze significantly less than the sham group during this session (Figure 3C; sham, 38.29 ± 4.19; CLP, 18.76 ± 2.43; P = 8.71 × 10-5; t = 4.03, t test), indicating that CLP mice had a deficit in contextual fear memory
This study demonstrates that mice surviving CLP, a model for clinical sepsis, were impaired in contextual fear memory and exhibited significantly fewer dendritic spines in excitatory neurons of the basolateral nucleus of the amygdala (BLA) and dentate gyrus (DG) when compared with sham animals
Summary
Sepsis refers to the life-threatening shock and organ dysfunction caused by a dysregulated response to infection, which accounts for ~750,000 patients and ~200,000 deaths per year in the United States alone [1,2]. While mortality is high est during the first few months after onset, 50–80% of those patients who survive the acute stage and exit the hospital perish over the two to eight years [3,4,5,6]. Recent preclinical studies using surgical and traumatic models of sepsis have shown that excessive activation of the immune system during a septic episode, with resulting high levels of systemic cytokines, represents a critical causal factor in post-septic brain damage [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. The CLP model has been evaluated at the behavioral level, with studies showing that CLP survivors have transient (~5–15 d) deficits in the open field test, the elevated plus maze and novel object
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