Age-dependent Transcriptional and Circuit Alterations in the brain Underlie Post-Anesthesia Neurobehavioral Dysfunction

With rising life expectancy, an increasing number of elderly individuals are undergoing surgery, highlighting the need to understand postoperative neurological complications. General anesthesia (GA) has been linked to olfactory dysfunction (OD) and cognitive impairment after surgery, but the underlying mechanisms remain poorly defined. In this study, 20-month-old male C57BL/6 mice underwent laparotomy followed by 2 hours of isoflurane exposure to examine the molecular effects of GA and surgery up to 5 weeks post-intervention using bulk RNA sequencing (RNAseq). Transcriptomic analysis of the olfactory bulb (OB) at 1 day post-GA/operation revealed upregulation of ubiquitin-related proteins and catabolic pathways in aged mice compared to shams. In contrast, RNAseq of the hippocampus (HI) at 5 weeks post-GA/OP showed broader molecular changes, coinciding with delayed cognitive decline. Compared to young adults, aged GA/OP mice exhibited elevated expression of innate immune genes and reduced neurogenesis in the OB, along with increased gliogenesis and impaired RNA splicing in the HI. RNA-Seq gene expression profiling was performed on mice aged 10–12 weeks or approximately 20 months, subjected to either sham treatment or GA (isoflurane) exposure followed by surgery (midline laparotomy). Olfactory bulb and hippocampus tissues were collected at 24 hours or 5 weeks post-GA/operation. Transcriptomic differences between GA/OP and Sham mice were analyzed.