Age and Sex Influence the Hippocampal Response and Recovery Following Sepsis

Jolie Barter,Thomas C Foster,Philip A Efron,Dina Nacionales,Mckenzie Hollen,Ashok Kumar,Julie A Stortz,Lyle L Moldawer

doi:10.1007/s12035-019-01681-y

Jolie Barter, Thomas C Foster + Show 6 more

Open Access

https://doi.org/10.1007/s12035-019-01681-y

Copy DOI

Abstract

Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain’s response and recovery following sepsis. Young (~ 4 months) and old (~ 20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age- and sex-matched controls at 1 and 4 days post-CLP. In general, immune- and stress-related genes increased, while neuronal, synaptic, and glial genes decreased 1 day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1, and while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males.

Highlights

Earlier recognition and treatment of sepsis has led to improved short-term survival; survivors of sepsis face complicated clinical trajectories, including an increased risk of cognitive impairment [1,2,3,4,5,6]
Of particular note is that young males, young females, and old females differentially expressed a greater number of genes on day 1 compared to day 4, suggesting recovery over the 4 days
Previous research has described an increased expression of synaptic genes during the progression from normal aging to neurodegenerative disease [79, 80], including genes we observed to increase in older males on day 4 of sepsis (Cacnb1, Cacna1a, Ephb4, Glul, Jph3, Mink1, Nrxn2, Grasp). These results indicate sex and age influence the response of several key biological processes following sepsis, including immune response, neuronal/synaptic function, and regulation of transcription

Summary

Introduction

Earlier recognition and treatment of sepsis has led to improved short-term survival; survivors of sepsis face complicated clinical trajectories, including an increased risk of cognitive impairment [1,2,3,4,5,6]. While the mechanism behind this sexual dimorphism remains uncertain, one explanation is that sex steroids affect the immune response to sepsis [7, 8, 10, 13] Age is another major influential factor in the outcome of sepsis since the incidence of sepsis and the associated complications increase with advancing age [14,15,16,17]. These effects of sepsis may be amplified with advanced age since aging is associated with an increase in microglial activation, oxidative damage, Mol Neurobiol (2019) 56:8557–8572 mitochondrial dysfunction, and altered synaptic plasticity [34,35,36]

Methods

Results

Discussion

Conclusion