Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

Abstract

Acknowledgements:We would like to acknowledge the University of Michigan Bioinformatics core for their expertise and data analysis of differentially expressed genes and the University of Michigan DNA sequencing core for their processing of samples. We would like to sincerely thank Dr. Shigeki Iwase and Christina Vallianatos for their advice, support, and assistance with prepping of the RNA samples. We would also very much like to thank them for allowing us to use their laboratory equipment for RNA extraction.We thank Ms. Brynne Raines, Ms. Melanie Gil, and Ms. Caitlin Posillico for their extensive feedback on this manuscript. ABSTRACTMajor illnesses, including major surgery, heart attack, and sepsis, can cause long-lasting cognitive impairments, depression, and progressive memory decline that persist well after recovery from the original illness. Similarly, in animal models, immune challenge results in impairments of learning and memory as well as increased depression-like behaviors. Although neuroimmune signaling is now well established as playing a crucial role in the modulation of neural functions, how transient immune signaling mediates enduring changes in cognition, memory, and emotion remains unknown. We have recently demonstrated that a series of intermittent injections of lipopolysaccharides over a two-week period resulted in sex-specific patterns of memory deficits that persist at least several months after the end of the immune challenge. Here, we examined the persistent changes in hippocampal gene expression three months after this subchronic systemic immune challenge in males and in females. We used RNA-sequencing as a large-scale, unbiased approach to identify both persistent changes in gene expression long after an immune challenge, and changes in transcriptional response to a subsequent immune challenge. Males and females differed in number and patterns of gene expression in the hippocampus. In males, we observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, in the absence of an additional insult. In contrast, females showed few persistent changes under basal conditions, but striking dysregulation of gene expression in response to an additional acute LPS injection. Striking sex differences in the specific genes, pathways, and biological processes affected were observed both after subchronic immune challenge and after a subsequent insult. Thus, subchronic systemic immune activation has enduring and sex-specific consequences for gene expression and response to subsequent stimuli. Such persistent changes in neural functions further suggest that in both males and females, neuroimmune signaling during illness contributes to subsequent vulnerability or resilience to cognitive decline, memory impairments, and affective disorders.