Whole-transcriptome sequencing identifies neuroinflammation, metabolism and blood-brain barrier related processes in the hippocampus of aged mice during perioperative period

Aim: Perioperative neurocognitive disorders (PND) occur frequently after
surgery and anesthesia, especially in aged patients. Previous studies have
shown multiple PND related mechanisms in the hippocampus, however, their
relationships remain unclear. Meanwhile, the perioperative
neuropathological processes are sophisticated and changeable, single
period study could not reveal the accurate mechanisms. Thus, multiperiod
whole-transcriptome study is necessary to elucidate the gene expression
patterns during perioperative period. Methods: Aged C57BL/6 mice were
subjected to exploratory laparotomy under sevoflurane anesthesia.
Whole-transcriptome sequencing (RNA-seq analysis) was performed on the
hippocampi from control condition (Con), 30 minutes (Day0), 2 days (Day2)
and 7 days (Day7) after surgery. Gene Ontology/Kyoto Encyclopedia of Genes
and Genomes analyses, quantitative Real-Time PCR, immunofluorescence and
fear conditioning test were also performed to elucidate the pathological
processes and modulation networks during the period. Results: Through
RNA-seq analysis, 328, 3597 and 4179 differentially expressed genes (DEGs)
were screened out in intraoperative period (Day0 vs Con), early
postoperative period (Day2 vs Day0) and late postoperative period (Day7 vs
Day2). The involved GO biological processes were divided into 9
categories, and positive-regulated processes were more than
negative-regulated ones. Seventy-four transcription factors were
highlighted. The potential synaptic and neuroinflammatory pathways were
constructed for Neurotransmitter, Synapse and Neuronal alteration
categories with 9 DEGs (Htr1a, Rims1, Ezh2, etc.). The metabolic and
mitochondrial pathways were constructed for Metabolism, Oxidative stress
and Biological rhythm categories with 9 DEGs (Gpld1, Sirt1, Cry2, etc.).
The blood-brain barrier and neurotoxicity related pathways were
constructed for Blood-brain barrier, Neurotoxicity and Cognitive function
categories with 10 DEGs (Mmp2, Itpr1, Nrf1, etc.). Conclusion: The results
revealed gene expression patterns and modulation networks in the aged
hippocampus during perioperative period, which provide insights into
overall mechanisms and potential therapeutic targets for prevention and
treatment of perioperative central nervous system diseases, such as PND,
from the genetic level.