Long-term hippocampal alterations and cognitive impairment in a murine model of surgical sepsis

Abstract

Cognitive impairment in sepsis survivors is a growing clinical challenge as the number of sepsis cases rise and acute mortality rates fall. It is estimated that up to 70% of sepsis patients experience cognitive dysfunction and many report persistent dysfunction post-sepsis. Cognitive impairment is a broad term that refers to sepsis-associated brain dysfunction or encephalopathy (SABD or SAE, respectively). While many contributors, such as inflammation, blood–brain barrier dysfunction, and extended microglial activation are implicated in SABD/SAE development, much is still unknown regarding the underlying mechanistic causes of persistent cognitive defects in sepsis survivors. Here, we employed cecal ligation and puncture (CLP) to model surgical sepsis in mice, after which mice were subjected to multiple memory function assays for up to 2 months post-sepsis. Furthermore, single-cell RNA sequencing and validation studies were performed with murine hippocampi to query alterations in the brain microenvironment. Our study shows that CLP mice exhibited decreased spontaneous alternation at 4 weeks and decreases in both short- and long-term recognition (at 6 weeks and 2 weeks, respectively) accompanied by substantially altered cell type makeup of the hippocampus, including hippocampal neuron and pericyte loss. Finally, transcriptional alterations in the macrophage populations implicate aberrant activation in CLP survivors. In conclusion, post-sepsis mice exhibit reduced memory capacity and altered hippocampal cell composition and transcriptional profiles. This study and associated data set will be valuable for further investigation of the underlying pathophysiology of SABD/SAE and elucidation of potential therapeutic candidates.